146 PART III MUSCLE PHYSIOLOGY Ca 2 THE ACTIVATION AND INTERNAL CONTROL OF MUSCLE FUNCTION Activation AM*ADP*P i A*M*ADP*P i Control of the contraction of skeletal muscle involves Rest many steps between the arrival of the action potential in a Attachment motor nerve and the final mechanical activity. An impor- tant series of these steps, called excitation-contraction coupling, takes place deep within a muscle fiber. This is the Hydrolysis subject of the remainder of this chapter; the very early Product events (communication between nerve and muscle) and the AM*ADP release and very late events (actual mechanical activity) are discussed Detachment power in Chapter 9. stroke The Interaction Between Calcium and Specialized P i Rigor Proteins Is Central to Muscle Contraction ATP A*M The most important chemical link in the control of muscle ADP protein interactions is provided by calcium ions. The SR controls the internal concentration of these ions, and changes in the internal calcium ion concentration have profound effects on the actions of the contractile proteins The events of the crossbridge cycle in FIGURE 8.10 skeletal muscle. ① At rest, ATP has been of muscle. bound to the myosin head and hydrolyzed, but the energy of the reaction cannot be released until ② the myosin head can interact Calcium and the Troponin-Tropomyosin Complex. The with actin. ③ The release of the hydrolysis products is associated chemical processes of the crossbridge cycle in skeletal mus- with ④ the power stroke. ⑤ The rotated and still-attached cross- cle are in a state of constant readiness, even while the mus- bridge is now in the rigor state. ⑥ Detachment is possible when a cle is relaxed. Undesired contraction is prevented by a spe- new ATP molecule binds to the myosin head and is ⑦ subse- quently hydrolyzed. These cyclic reactions can continue as long cific inhibition of the interaction between actin and 2 as the ATP supply remains and activation (via Ca ) is main- myosin. This inhibition is a function of the troponin- tained. (See text for further details.) A, actin; M, myosin; *, chem- tropomyosin complex of the thin myofilaments. When a ical bond; , a potential interaction. muscle is relaxed, calcium ions are at very low concentra- tion in the region of the myofilaments. The long tropomyosin molecules, lying in the grooves of the en- twined actin filaments, interfere with the myosin binding tion pulls the actin filaments past the myosin filaments, a sites on the actin molecules. When calcium ion concentra- movement called the power stroke (step 4). Following this tions increase, the ions bind to the Tn-C subunit associated movement (which results in a relative filament displace- with each tropomyosin molecule. Through the action of ment of around 10 nm), the actin-myosin binding is still Tn-I and Tn-T, calcium binding causes the tropomyosin strong and the crossbridge cannot detach; at this point in molecule to change its position slightly, uncovering the the cycle, it is termed a rigor crossbridge (A*M, step 5). For myosin binding sites on the actin filaments. The myosin detachment to occur, a new molecule of ATP must bind to (already “charged” with ATP) is allowed to interact with the myosin head (M*ATP, step 6) and undergo partial hy- actin, and the events of the crossbridge cycle take place un- drolysis to M*ADP*P i (step 7). til calcium ions are no longer bound to the Tn-C subunit. Once this new ATP binds, the newly recharged myosin head, momentarily not attached to the actin fila- The Switching Action of Calcium. An effective switching ment (step 1), can begin the cycle of attachment, rota- function requires the transition between the “off” and “on” tion, and detachment again. This can go on as long as the states to be rapid and to respond to relatively small changes muscle is activated, a sufficient supply of ATP is avail- in the controlling element. The calcium switch in skeletal able, and the physiological limit to shortening has not muscle satisfies these requirements well (Fig. 8.11). The been reached. If cellular energy stores are depleted, as curve describing the relationship between the relative force happens after death, the crossbridges cannot detach be- developed and the calcium concentration in the region of cause of the lack of ATP, and the cycle stops in an at- the myofilaments is very steep. At a calcium concentration tached state (at step 5). This produces an overall stiffness of 1 10 8 M, the interaction between actin and myosin of the muscle, which is observed as the rigor mortis that is negligible, while an increase in the calcium concentration sets in shortly after death. to 1 10 5 M produces essentially full force development. The crossbridge cycle obviously must be subject to con- This process is saturable, so that further increases in cal- trol by the body to produce useful and coordinated muscu- cium concentration lead to little increase in force. In skele- lar movements. This control involves several cellular tal muscle, an excess of calcium ions is usually present dur- processes that differ among the various types of muscle. ing activation, and the contractile system is normally fully Here, again, the case of skeletal muscle provides the basic saturated. In cardiac and smooth muscle, however, only description of the control process. partial saturation occurs under normal conditions, and the
CHAPTER 8 Contractile Properties of Muscle Cells 147 Action potential No Ca 2 for troponin Cell membrane T tubule Junctional Ca 2 + complexes translocation Longitudinal SR Terminal Ca reuptake 2 + cisterna Ca release 2 + Ca 2 bound to troponin Myofilaments Excitation-contraction coupling and the FIGURE 8.12 cyclic movement of calcium. (See text for de- The calcium switch for controlling skeletal tails of the process.) FIGURE 8.11 muscle contraction. Calcium ions, via the tro- ponin-tropomyosin complex, control the unblocking of the inter- action between the myosin heads (the crossbridges) and the ac- trical excitation of the surface membrane. An action poten- tive site on the thin filaments. The geometry of each tropomyosin tial sweeps rapidly down the length of the fiber. Its propa- molecule allows it to exert control over seven actin monomers. gation is similar to that in nonmyelinated nerve fibers, in which successive areas of membrane are stimulated by local ionic currents flowing from adjacent areas of excited mem- degree of muscle activation can be adjusted by controlling brane. The lack of specialized conduction adaptations (e.g., the calcium concentration. myelination) makes this propagation slow compared with The switching action of the calcium-troponin- that in the motor nerve, but its speed is still sufficient to en- tropomyosin complex in skeletal and cardiac muscle is ex- sure the practically simultaneous activation of the entire tended by the structure of the thin filaments, which allows fiber. When the action potential encounters the openings one troponin molecule, via its tropomyosin connection, to of T tubules, it propagates down the T tubule membrane. control seven actin monomers. Since the calcium control in This propagation is also regenerative, resulting in numer- striated muscle is exercised through the thin filaments, it is ous action potentials, one in each T tubule, traveling to- termed actin-linked regulation. While the cellular control ward the center of the fiber. In the T tubules, the velocity of smooth muscle contraction is also exercised by changes of the action potentials is rather low, but the total distance in calcium concentration, its effect is exerted on the thick to be traveled is quite short. (myosin) filaments. This is termed myosin-linked regula- At some point along the T tubule, the action potential tion and is described in Chapter 9. reaches the region of a triad. Here the presence of the ac- tion potential is communicated to the terminal cisternae of the SR. While the precise nature of this communication is Excitation-Contraction Coupling Links Electrical and Mechanical Events not yet fully understood, it appears that the T tubule action potential affects specific protein molecules called dihy- When a nerve impulse arrives at the neuromuscular junc- dropyridine receptors (DHPRs). These molecules, which tion and its signal is transmitted to the muscle cell mem- are embedded in the T tubule membrane in clusters of four, brane, a rapid train of events carries the signal to the inte- serve as voltage sensors that respond to the T tubule action rior of the cell, where the contractile machinery is located. potential. They are located in the region of the triad where The large diameter of skeletal muscle cells places interior the T tubule and SR membranes are the closest together, myofilaments out of range of the immediate influence of and each group of four is located in close proximity to a events at the cell surface, but the T tubules, SR, and their specific channel protein called a ryanodine receptor associated structures act as a specialized internal communi- (RyR), which is embedded in the SR membrane. The RyR cation system that allows the signal to penetrate to interior serves as a controllable channel (termed a calcium-release parts of the cell. The end result of electrical stimulation of channel) through which calcium ions can move readily the cell is the liberation of calcium ions into regions of the when it is in the open state. DHPR and RyR form a func- sarcoplasm near the myofilaments, initiating the cross- tional unit called a junctional complex (Fig. 8.12). bridge cycle. When the muscle is at rest, the RyR is closed; when T The process of excitation-contraction coupling, as out- tubule depolarization reaches the DHPR, some sort of link- lined in Figure 8.12, begins in skeletal muscle with the elec- age—most likely a mechanical connection—causes the
148 PART III MUSCLE PHYSIOLOGY RyR to open and release calcium from the SR. In skeletal used, the ATP concentration has fallen by only 10%. This muscle, every other RyR is associated with a DHPR cluster; situation results in a steady source of ATP for contraction the RyRs without this connection open in response to cal- that is maintained despite variations in energy supply and cium ions in a few milliseconds. This leads to rapid release demand. Creatine phosphate is the most important storage of calcium ions from the terminal cisternae into the intra- form of high-energy phosphate; together with some other cellular space surrounding the myofilaments. The calcium smaller sources, this energy reserve is sometimes called the ions can now bind to the Tn-C molecules on the thin fila- creatine phosphate pool. ments. This allows the crossbridge cycle reactions to begin, Two major metabolic pathways supply ATP to energy- and contraction occurs. requiring reactions in the cell and to the mechanisms that Even during calcium release from the terminal cisternae, replenish the creatine phosphate pool. Their relative con- the active transport processes in the membranes of the lon- tributions depend on the muscle type and conditions of gitudinal elements of the SR pump free calcium ions from contraction. A simplified diagram of the energy relation- the myofilament space into the interior of the SR. The ships of muscle is shown in Figure 8.13. The first of the sup- rapid release process stops very soon; there is only one ply pathways is the glycolytic pathway or glycolysis. This burst of calcium ion release for each action potential, and is an anaerobic pathway; glucose is broken down without the continuous calcium pump in the SR membrane reduces the use of oxygen to regenerate two molecules of ATP for calcium in the region of the myofilaments to a low level (1 every molecule of glucose consumed. Glucose for the gly- 10 8 M). Because calcium ions are no longer available to colytic pathway may be derived from circulating blood glu- bind to troponin, the contractile activity ceases and relax- cose or from its storage form in muscle cells, the polymer ation begins. The resequestered calcium ions are moved glycogen. This reaction extracts only a small fraction of the along the longitudinal elements to storage sites in the ter- energy contained in the glucose molecule. minal cisternae, and the system is ready to be activated The end product of anaerobic glycolysis is lactic acid or again. This entire process takes place in a few tens of mil- lactate. Under conditions of sufficient oxygen, this is con- liseconds and may be repeated many times each second. verted to pyruvic acid or pyruvate, which enters another cellular (mitochondrial) pathway called the Krebs cycle. As a result of Krebs cycle reactions, substrates are made avail- ENERGY SOURCES FOR MUSCLE CONTRACTION able for oxidative phosphorylation. The Krebs cycle and oxidative phosphorylation are aerobic processes that re- Because contracting muscles perform work, cellular quire a continuous supply of oxygen. In this pathway, an processes must supply biochemical energy to the contrac- additional 36 molecules of ATP are regenerated from the tile mechanism. Additional energy is required to pump the energy in the original glucose molecule; the final products calcium ions involved in the control of contraction and for are carbon dioxide and water. While the oxidative phos- other cellular functions. In muscle cells, as in other cells, phorylation pathway provides the greatest amount of en- this energy ultimately comes from the universal high-en- ergy, it cannot be used if the oxygen supply is insufficient; ergy compound, ATP. in this case, glycolytic metabolism predominates. Glucose as an Energy Source. Glucose is the preferred Muscle Cells Obtain ATP From Several Sources fuel for skeletal muscle contraction at higher levels of exer- Although ATP is the immediate fuel for the contraction cise. At maximal work levels, almost all the energy used is process, its concentration in the muscle cell is never high derived from glucose produced by glycogen breakdown in enough to sustain a long series of contractions. Most of the muscle tissue and from bloodborne glucose from dietary immediate energy supply is held in an “energy pool” of the sources. Glycogen breakdown increases rapidly during the compound creatine phosphate or phosphocreatine (PCr), first tens of seconds of vigorous exercise. This breakdown, which is in chemical equilibrium with ATP. After a mole- and the subsequent entry of glucose into the glycolytic cule of ATP has been split and yielded its energy, the re- pathway, is catalyzed by the enzyme phosphorylase a. sulting ADP molecule is readily rephosphorylated to ATP This enzyme is transformed from its inactive phosphory- by the high-energy phosphate group from a creatine phos- lase b form by a “cascade” of protein kinase reactions whose phate molecule. The creatine phosphate pool is restored by action is, in turn, stimulated by the increased Ca 2 con- ATP from the various cellular metabolic pathways. These centration and metabolite (especially AMP) levels associ- reactions (of which the last two are the reverse of each ated with muscle contraction. Increased levels of circulat- other) can be summarized as follows: ing epinephrine (associated with exercise), acting through cAMP, also increase glycogen breakdown. Sustained exer- ATP → ADP P i (Energy for contraction) (1) cise can lead to substantial depletion of glycogen stores, which can restrict further muscle activity. ADP PCr → ATP Cr (Rephosphorylation of ATP) (2) Other Important Energy Sources. At lower exercise lev- ATP Cr → ADP PCr (Restoration of PCr) (3) els (i.e., below 50% of maximal capacity) fats may provide Because of the chemical equilibria involved, the concen- 50 to 60% of the energy for muscle contraction. Fat, the tration of PCr can fall to very low levels before the ATP major energy store in the body, is mobilized from adipose concentration shows a significant decline. It has been tissue to provide metabolic fuel in the form of free fatty shown experimentally that when 90% of PCr has been acids. This process is slower than the liberation of glucose
CHAPTER 8 Contractile Properties of Muscle Cells 149 Energy produced Energy used Blood Muscle cell Creatine ADP phosphate 2 PCr ATP restored replenished A Actomyosin ATPase (contraction) 1 Creatine ATP B SR Ca 2 + pump (relaxation) C Other metabolic functions Glycogen 36 (ion pumping, etc.) 2 ATP Glucose ATP 4 Pyruvic acid 3 Glycolysis Krebs cycle and oxidative Lactic Lactic acid phosphorylation acid Oxygen O 2 Carbon dioxide + water CO 2 H 2 O Fatty acids Fatty acids FIGURE 8.13 The major metabolic processes of skeletal actions of the crossbridge cycle. Energy is used by the cell in an A, muscle. These processes center on the supply B, and C order. The scheme shown here is typical for all types of of ATP for the actomyosin ATPase of the crossbridges. Energy muscle, although there are specific quantitative and qualitative sources are numbered in order of their proximity to the actual re- variations. from glycogen and cannot keep pace with the high de- Metabolic Adaptations Allow Contraction to mands of heavy exercise. Moderate activity, with brief rest Continue With an Inadequate Oxygen Supply periods, favors the consumption of fat as muscle fuel. Fatty acids enter the Krebs cycle at the acetyl-CoA-citrate step. Glycolytic (anaerobic) metabolism can provide energy Complete combustion of fat yields less ATP per mole of for sudden, rapid, and forceful contractions of some oxygen consumed than for glucose, but its high energy muscles. In such cases, the ready availability of gly- storage capacity (the equivalent of 138 moles of ATP per colytic ATP compensates for the relatively low yield of mole of a typical fatty acid) makes it an ideal energy store. this pathway, although a later adjustment must be made. The depletion of body fat reserves is almost never a limit- In most muscles, especially under conditions of rest or ing factor in muscle activity. moderate exercise, the supply of oxygen is adequate for In the absence of other fuels, protein can serve as an en- aerobic metabolism (fed by fatty acids and by the end ergy source for contraction. However, protein is used by products of glycolysis) to supply the energy needs of the muscles for fuel mainly during dieting and starvation or contractile system. As the level of exercise increases, during heavy exercise. Under such conditions, proteins are several physiological mechanisms come into play to in- broken down into amino acids that provide energy for con- crease the blood supply (and, thus, the oxygen) to the traction and that can be resynthesized into glucose to meet working muscle. At some point, however, even these other needs. mechanisms fail to supply sufficient oxygen, and the end Many of the metabolic reactions and processes supply- products of glycolysis begin to accumulate. The gly- ing energy for contraction and the recycling of metabolites colytic pathway can continue to operate because the ex- (e.g., lactate, glucose) take place outside the muscle, par- cess pyruvic acid that is produced is converted to lactic ticularly in the liver, and the products are transported to the acid, which serves as a temporary storage medium. The muscle by the bloodstream. In addition to its oxygen- and formation of lactic acid, by preventing a buildup of pyru- carbon dioxide-carrying functions, the enhanced blood vic acid, also allows for the restoration of the enzyme supply to exercising muscle provides for a rapid exchange cofactor NAD , needed for a critical step in the gly- of essential metabolic materials and the removal of heat. colytic pathway, so that the breakdown of glycogen can
150 PART III MUSCLE PHYSIOLOGY continue. Thus, ATP can continue to be produced under Those muscles adapted for mostly aerobic metabolism anaerobic conditions. contain significant amounts of the protein myoglobin. This The accumulation of lactic acid is the largest contributor iron-containing molecule, essentially a monomeric form of (more than 60%) to oxygen deficit, which allows short-term the blood protein hemoglobin (see Chapter 11), gives aer- anaerobic metabolism to take place despite a relative lack of obic muscles their characteristic red color. The total oxy- oxygen. Other depleted muscle oxygen stores have a smaller gen storage capacity of myoglobin is quite low, and it does capacity but can still participate in oxygen deficit. The largest not make a significant direct contribution to the cellular of these is the creatine phosphate pool (approximately 25%). stores; all the myoglobin-bound oxygen could support aer- Tissue fluids (including venous blood) account for another obic exercise for less than 1 second. However, because of 7%, and the protein myoglobin can hold about 2.5%. its high affinity for oxygen even at low concentrations, Eventually the lactic acid must be oxidized in the Krebs myoglobin plays a major role in facilitating the diffusion of cycle and oxidative phosphorylation reactions, and the oxygen through exercising muscle tissue by binding and re- other energy stores (as listed above) must be replenished. leasing oxygen molecules as they move down their con- This “repayment” of the oxygen deficit occurs over several centration gradient. minutes during recovery from heavy exercise, when the Muscles of different types have varying capacities for oxygen consumption and respiration rate remain high and sustaining an oxygen deficit; some skeletal muscles can sus- depleted ATP is restored from the glucose breakdown tain a considerable deficit, while cardiac muscle has an al- products temporarily stored as lactic acid. As the cellular most exclusively aerobic metabolism. Chapters 9 and 10 ATP levels return to normal, the energy stored in the crea- discuss metabolic adaptations that are specific to skeletal, tine phosphate energy pool is also replenished. smooth, and cardiac muscles. REVIEW QUESTIONS DIRECTIONS: Each of the numbered (C) Maintain the separation of thick stretched beyond its optimal length items or incomplete statements in this and thin filaments when the muscle is (but not to the point where damage section is followed by answers or at rest occurs), the reduction in contractile completions of the statement. Select the (D) Promote the binding of calcium force is due to ONE lettered answer or completion that is ions to the regulatory proteins (A) Lengthening of the myofilaments so BEST in each case. 4. Calcium ions are required for the that crossbridges become spaced farther normal activation of all muscle types. apart and can interact less readily 1. Skeletal, smooth, and cardiac muscle Which statement below most closely (B) Decreased overlap between thick all have which of the following in describes the role of calcium ions in and thin filaments, which reduces the common? the control of skeletal muscle number of crossbridges that interact (A) Their cellular structure is based on contraction? (C) The thinning of the muscle, which repeating sarcomeres (A) The binding of calcium ions to reduces its cross-sectional area and, (B) The contractile cells are large regulatory proteins on the thin hence, the force that it can produce relative to the size of the organ they filaments removes the inhibition of (D) A proportional reduction in the comprise. actin-myosin interaction amount of calcium released from the (C) The contractile system is based on (B) The binding of calcium ions to the sarcoplasmic reticulum an enzymatic interaction of actin and thick filament regulatory proteins 7. The major immediate source of myosin. activates the enzymatic activity of the calcium for the initiation of skeletal (D) Initiation of contraction requires myosin molecules muscle contraction is the binding of calcium ions to actin (C) Calcium ions serve as an inhibitor (A) Calcium entry through the filaments of the interaction of thick and thin sarcolemma during the passage of an 2. During the shortening of skeletal filaments action potential muscle, (D) A high concentration of calcium (B) A rapid release of calcium from its (A) The distance between Z lines stays ions in the myofilament space is storage sites in the T tubules the same required to maintain muscle in a (C) A rapid release of calcium from the (B) The width of the I band changes relaxed state. terminal cisternae of the sarcoplasmic (C) The width of the A band changes 5. The normal process of relaxation in reticulum (D) All internal spacings between skeletal muscle depends on (D) A release of calcium that is bound repeating structures change (A) A sudden reduction in the amount to cytoplasmic proteins in the region proportionately of ATP available for the crossbridge of the myofilaments 3. The compound ATP provides the interactions 8. The relaxation of skeletal muscle is energy for muscle contraction during (B) Metabolically supported pumping associated with a reduction in free the crossbridge cycle. A second of calcium out of the cells when the intracellular calcium ion concentration. important function for ATP in the membrane potential repolarizes The effect of this reduction is cycle is to (C) A rapid reuptake of calcium into (A) A reestablishment of the inhibition (A) Provide the energy for relaxation the sarcoplasmic reticulum of the actin-myosin interaction (B) Allow the thick and thin filaments (D) An external force to separate the (B) Deactivation of the enzymatic to detach from each other during the interacting myofilaments activity of the individual actin crossbridge cycle 6. When an isolated skeletal muscle is molecules (continued)
CHAPTER 8 Contractile Properties of Muscle Cells 151 (C) A change in the chemical nature of support contraction at a reduced rate (C) The muscle would continue to the myosin molecules, reducing their 11.In the face of insufficient oxygen to develop force, but its relaxation would enzymatic activity meet its current metabolic be slowed (D) Reduced contractile interaction by requirements, skeletal muscle (D) Activation of the muscle would no the binding of calcium to the active (A) Quickly loses its ability to contract longer be possible sites of the myosin molecules and relaxes until oxygen is again 9. The chemical energy source that most available SUGGESTED READING directly supports muscle contraction is (B) Maintains contraction by using Bagshaw CR. Muscle Contraction. 2nd Ed. (A) Creatine phosphate metabolic pathways that do not require New York: Chapman & Hall, 1993. (B) Glucose oxygen consumption Ford LE. Muscle Physiology and Cardiac (C) ATP (C) Maintains contraction by using a Function. Carmel, IN: Biological Sci- (D) Free fatty acids large internal store of ATP that is kept ences Press-Cooper Group, 2000. 10.In the absence of an adequate supply in reserve Matthews GG. Cellular Physiology of of ATP for skeletal muscle contraction, (D) Contracts more slowly at a given Nerve and Muscle. 2nd Ed. Boston: (A) Myofilament interaction ceases, force, resulting in a saving of energy Blackwell, 1991. and the muscle relaxes 12.If the calcium pumping ability of the Rüegg JC. Calcium in Muscle Contraction: (B) Actin and myosin filaments cannot sarcoplasmic reticulum were impaired Cellular and Molecular Physiology. separate, and the muscle stiffens (but not abolished), 2nd Ed. New York: Springer-Verlag, (C) Creatine phosphate can directly (A) Muscles would relax more quickly 1992. support myofilament interaction, because less calcium would be pumped Squire JM, ed. Molecular Mechanisms in although less efficiently (B) Contraction would be slowed, but Muscle Contraction. Boca Raton: CRC (D) The lower energy form, ADP, can the muscle would relax normally Press, 1990.
Skeletal Muscle CHAPTER 9 and Smooth Muscle 9 Richard A. Meiss, Ph.D. CHAPTER OUTLINE ■ ACTIVATION AND CONTRACTION OF SKELETAL ■ MECHANICAL PROPERTIES OF SKELETAL MUSCLE MUSCLE ■ PROPERTIES OF SMOOTH MUSCLE KEY CONCEPTS 1. The myoneural junction is a specialized synapse between largely by the molecular and cellular ultrastructure of the the motor axon and a skeletal muscle fiber. A motor nerve muscle. and all of the muscle fibers it innervates is called a motor 9. The force-velocity curve describes the inverse relationship unit. between the isotonic force and the shortening velocity in a 2. Neuromuscular transmission involves presynaptic trans- fully activated muscle. mitter release, diffusion of transmitter across the synaptic 10. The power output of an isotonically contracting skeletal cleft, and binding to postsynaptic receptors. muscle is determined by the velocity of shortening, which 3. The immediate postsynaptic electrical response to trans- is determined by the size of the load; it is maximal at ap- mitter molecule binding is a local depolarization called the proximately one-third of the maximal isometric force. endplate potential, which is graded according to the rela- 11. All muscles are arranged so that they may be extended by tive number of channels that have been opened by the the action of antagonistic muscles or by an external force transmitter binding. such as gravity. Muscles do not forcibly reextend them- 4. The endplate potential is localized to the endplate region selves after shortening. and is not propagated. It causes current to flow into the 12. The control of skeletal muscle contraction is exercised muscle fiber at the endplate; the resulting outward current through the thin filaments and is termed actin-linked. across adjacent areas of membrane leads to their depolar- Smooth muscle contraction is controlled primarily via the ization and the generation of propagated nerve-like action thick filaments and is termed myosin-linked. potentials in the muscle cell membrane. 13. The links between cellular excitation and mechanical con- 5. A twitch is a single muscle contraction, produced in re- traction in smooth muscle are varied and complex. In most sponse to a single action potential in the muscle cell mem- of the pathways, the cellular concentration of free calcium brane. A tetanus is a larger muscle contraction that results ions is an important link in the process of activation and from repetitive stimulation (multiple action potentials) of contraction. the cell membrane. Its force represents the temporal sum- 14. The primary step in the regulation of smooth muscle con- mation of many twitch contractions. traction is the phosphorylation of the regulatory light 6. Isometric contraction results when an activated muscle is chains of the myosin molecule, which is then free to inter- prevented from shortening and force is produced without act with actin. Relaxation involves phosphatase-mediated movement. dephosphorylation of the light chains. 7. Isotonic contraction results when an activated muscle 15. The contractions of smooth muscle are considerably shortens against an external force (or load). The external slower than those of skeletal muscle, but are much more load determines the force that the muscle will develop, and economical in their use of cellular energy. A crossbridge the developed force determines the velocity of shortening. mechanism called the “latch state” enables some smooth 8. The length-tension curve describes the effect of the resting muscles to maintain contraction for extremely long periods length of a muscle on the isometric force it can develop. of time. This relationship, which passes through a maximum at the 16. Smooth muscle tissues, especially those in the walls of dis- normal length of the muscle in the body, is determined tensible organs, can operate over a wide range of lengths. 152
CHAPTER 9 Skeletal Muscle and Smooth Muscle 153 hapter 8 dealt with the mechanics and activation of the terminals are located numerous membrane-enclosed vesi- Cinternal cellular processes that produce muscle con- cles containing acetylcholine (ACh). Mitochondria, associ- traction. This chapter treats muscles as organized tissues, ated with the extra metabolic requirements of the terminal, beginning with the events leading to membrane activation are also plentiful. by nerve stimulation and continuing with the outward me- The postsynaptic portion of the junction or endplate chanical expression of internal processes. membrane is that part of the muscle cell membrane lying immediately beneath the axon terminals. Here the mem- brane is formed into postjunctional folds, at the mouths of ACTIVATION AND CONTRACTION which are located many nicotinic ACh receptor molecules. OF SKELETAL MUSCLE These are chemically gated ion channels that increase the cation permeability of the postsynaptic membrane in re- Skeletal muscle is controlled by the central nervous system sponse to the binding of ACh. Between the nerve and mus- (CNS), which provides a pattern of activation that is suited cle is a narrow space called the synaptic cleft. Acetyl- to the task at hand. The resulting contraction is further choline must diffuse across this gap to reach the receptors shaped by mechanical conditions external to the muscle. in the postsynaptic membrane. Also located in the synaptic The connection between nerve and muscle has been stud- cleft (and associated with the postsynaptic membrane) is ied for over a century, and a fairly clear picture of the the enzyme acetylcholinesterase (AChE). process has emerged. While the process functions amaz- ingly well, its complexity means that critical failures can Chemical Events at the Neuromuscular Junction. lead to serious medical problems. When the wave of depolarization associated with a nerve action potential spreads into the terminal of a motor axon, Impulse Transmission From Nerve to Muscle several processes are set in motion. The lowered membrane Occurs at the Neuromuscular Junction potential causes membrane channels to open and external calcium ions enter the axon. The rapid rise in intracellular The contraction of skeletal muscle occurs in response to ac- calcium causes the cytoplasmic vesicles of ACh to migrate tion potentials that travel down somatic motor axons orig- to the inner surface of the axon membrane, where they fuse inating in the CNS. The transfer of the signal from nerve to with the membrane and release their contents. Because all muscle takes place at the neuromuscular junction, also the vesicles are of roughly the same size, they all release called the myoneural junction or motor endplate. This about the same amount—a quantum—of neurotransmitter. special type of synapse has a close association between the The transmitter release is called quantal; although so many membranes of nerve and muscle and a physiology much vesicles are normally activated at once, their individual like that of excitatory neural synapses (see Chapter 3). contributions are not separately identifiable. When the ACh molecules arrive at the postsynaptic The Structure of the Neuromuscular Junction. On membrane after diffusing across the synaptic cleft, they reaching a muscle cell, the axon of a motor neuron typically bind to the ACh receptors. When two ACh molecules are branches into several terminals, which constitute the presy- bound to a receptor, it undergoes a configurational change naptic portion of the neuromuscular junction. The termi- that allows the relatively free passage of sodium and potas- nals lie in grooves or “gullies” in the surface of the muscle sium ions down their respective electrochemical gradients. cell, outside the muscle cell membrane, and a Schwann cell The binding of ACh to the receptor is reversible and rather covers them all (Fig. 9.1). Within the axoplasm of the nerve loose. Soon ACh diffuses away and is hydrolyzed by AChE into choline and acetate, terminating its function as a trans- mitter molecule, and the membrane permeability returns to Axon terminal Schwann cell the resting state. The choline portion is taken up by the presynaptic terminal for resynthesis of ACh, and the ace- Synaptic vesicles tate diffuses away into the extracellular fluid. These events take place over a few milliseconds and may be repeated many times per second without danger of fatigue. Synaptic cleft Schwann cell process Electrical Events at the Neuromuscular Junction. The binding of the ACh molecules to postsynaptic receptors ini- muscle cell tiates the electrical response of the muscle cell membrane, and what was a chemical signal becomes an electrical one. The stages of the development of the electrical signal are Nicotinic acetylcholine shown in Figure 9.2. With the opening of the postsynaptic Postjunctional fold receptors in ionic channels, sodium enters the muscle cell and potassium Acetylcholine molecule postjunctional membrane simultaneously leaves. Both ions share the same membrane Structural features of the neuromuscular channels; in this and several other respects, the endplate FIGURE 9.1 junction. Processes of the Schwann cell that membrane is different from the general cell membrane of overlie the axon terminal wrap around under it and divide the muscles and nerves. The opening of the channels depends junctional area into active zones. only on the presence of neurotransmitter and not on mem-
154 PART III MUSCLE PHYSIOLOGY Postsynaptic Presynaptic 30 Motor axon action potential 0 70 1 Endplate potential 30 15 Reversal potential Membrane voltage (mV) 30 Mixed potential 2 80 Threshold 0 40 Threshold 3 80 Muscle action potential 30 0 Threshold 4 80 0246810 12 Time (msec) FIGURE 9.2 Electrical activity at the neuromuscular sponses because of the close spacing of the electrodes.) Note the junction. The four microelectrodes sample time delays as a result of transmitter diffusion and endplate poten- membrane potentials at critical regions. (These are idealized tial generation. The reversal potential is the membrane potential records drawn to illustrate isolated portions of the response; in an at which net current flow is zero (i.e., inward Na and outward actual recording, there would be considerable overlap of the re- K currents are equal). brane voltage, and the sodium and potassium permeability this endplate current flows out across the muscle membrane changes occur simultaneously (rather than sequentially, as in regions adjacent to the endplate, it depolarizes the mem- they do in nerve or in the general muscle membrane). As a brane and causes voltage-gated sodium channels to open, result of the altered permeabilities, a net inward current, bringing the membrane to threshold. This leads to an ac- known as the endplate current, depolarizes the postsynap- tion potential in the muscle membrane. The muscle action tic membrane. This voltage change is called the endplate potential is propagated along the muscle cell membrane by potential. The voltage at which the net membrane current regenerative local currents similar to those in a nonmyeli- would become zero is called the reversal potential of the nated nerve fiber. endplate (see Fig. 9.2), although time does not permit this The endplate depolarization is graded, and its ampli- condition to become established because the AChE is con- tude varies with the number of receptors with bound ACh. tinuously inactivating transmitter molecules. If some circumstance causes reduced ACh release, the To complete the circuit, the current flowing inward at amount of depolarization at the endplate could be corre- the postsynaptic membrane must be matched by a return spondingly reduced. Under normal circumstances, how- current. This current flows through the local muscle cyto- ever, the endplate potential is much more than sufficient to plasm (myoplasm), out across the adjacent muscle mem- produce a muscle action potential; this reserve, referred to brane and back through the extracellular fluid (Fig. 9.3). As as a safety factor, can help preserve function under abnor-
CHAPTER 9 Skeletal Muscle and Smooth Muscle 155 A receptors. This binding does not result in opening of the C ion channels, however, and the endplate potential is re- Motor axon action potential Muscle action duced in proportion to the number of receptors occupied potential by curare. Muscle paralysis results. Although the muscle can be directly stimulated electrically, nerve stimulation is ineffective. The drug succinylcholine blocks the neuro- 5. External 1. Chemical muscular junction in a slightly different way; this molecule transmitter release return current binds to the receptors and causes the channels to open. Be- cause it is hydrolyzed very slowly by AChE, its action is long lasting and the channels remain open. This prevents resetting of the inactivation gates of muscle membrane sodium channels near the endplate region and blocks sub- 4. Outward membrane sequent action potentials. Drugs that produce extremely current long-lasting endplate potentials are referred to as depolar- 2. Inward izing blockers. membrane current Compounds such as physostigmine (eserine) are potent inhibitors of AChE and produce a depolarizing blockade. In carefully controlled doses, they can temporarily alleviate symptoms of myasthenia gravis, an autoimmune condition that results in a loss of postsynaptic ACh receptors. The principal symptom is muscular weakness caused by end- B 3. Longitudinal myoplasmic current plate potentials of insufficient amplitude. Partial inhibition Endplate potential of the enzymatic degradation of ACh allows ACh to remain effective longer and, thus, to compensate for the loss of re- ceptor molecules. Ionic currents at the neuromuscular junc- FIGURE 9.3 Under normal conditions, ACh receptors are confined tion. A, The inward membrane current is car- to the endplate region of a muscle. If accidental denerva- ried by sodium ions through the channels associated with ACh tion occurs (e.g., by the severing of a motor nerve), the en- receptors. The other currents are nonspecific and are carried by tire muscle becomes sensitive to direct application of ACh appropriately charged ions in the myoplasm and extracellular fluid. B, The endplate potential is localized to the endplate re- within several weeks. This extrasynaptic sensitivity is due gion. C, The muscle action potential is propagated along the sur- to the synthesis of new ACh receptors, a process normally face of the muscle. inhibited by the electrical activity of the motor axon. Arti- ficial electrical stimulation has been shown experimentally to prevent the synthesis of new receptors, by regulating mal conditions. The rate of rise of the endplate potential is transcription of the genes involved. If reinnervation occurs, determined largely by the rate at which ACh binds to the the extrasynaptic receptors gradually disappear. Muscle at- receptors, and indirect clinical measurements of the size rophy also occurs in the absence of functional innervation, and rise time of the endplate potential are of considerable which also can be at least partially reversed with artificial diagnostic importance. The rate of decay is determined by stimulation. a combination of factors, including the rate at which the ACh diffuses away from the receptors, the rate of hydroly- sis, and the electrical resistance and capacitance of the end- MECHANICAL PROPERTIES plate membrane. OF SKELETAL MUSCLE The variety of controlled muscular movements that humans Neuromuscular Transmission Can Be can make is remarkable, ranging from the powerful con- Altered by Toxins, Drugs, and Trauma tractions of a weightlifter’s biceps to the delicate move- ments of the muscles that position our eyes as we follow a The complex series of events making up neuromuscular transmission is subject to interference at several steps. moving object. In spite of this diversity, the fundamental Presynaptic blockade of the neuromuscular junction can mechanical events of the contraction process can be de- occur if calcium does not enter the presynaptic terminal to scribed by a relatively small set of specially defined func- participate in migration and emptying of the synaptic vesi- tions that emphasize particular capabilities of muscle. cles. The drug hemicholinium interferes with choline up- take by the presynaptic terminal and, thus, results in the de- The Timing of Muscle Stimulation Is a pletion of ACh. Botulinum toxin interferes with ACh Critical Determinant of Contractile Function release. This bacterial toxin is used to treat focal dystonias (see Clinical Focus Box 9.1). A skeletal muscle must be activated by the nervous system Postsynaptic blockade can result from a variety of cir- before it can begin contracting. Through the many cumstances. Drugs that partially mimic the action of ACh processes previously described, a single nerve action po- can be effective blockers. Derivatives of curare, originally tential arrives at each motor nerve axon terminal. A single used as arrow poison in South America, bind tightly to ACh muscle action potential then propagates along the length
156 PART III MUSCLE PHYSIOLOGY CLINICAL FOCUS BOX 9.1 Focal Dystonias and Botulinum Toxin tically, has a total molecular weight of 900,000 and is sold Focal dystonias are neuromuscular disorders character- under the trade names Botox and Oculinum. ized by involuntary and repetitive or sustained skeletal The toxin first binds to the cell membrane of presynap- muscle contractions that cause twisting, turning, or tic nerve terminals in skeletal muscles. The initial binding squeezing movements in a body part. Abnormal postures does not appear to produce paralysis until the toxin is ac- and considerable pain, as well as physical impairment, of- tively transported into the cell, a process requiring more ten result. Usually the abnormal contraction is limited to a than an hour. Once inside the cell, the toxin disrupts cal- small and specific region of muscles, hence, the term focal cium-mediated ACh release, producing an irreversible (“by itself”). Dystonia means “faulty contraction.” Spas- transmission block at the neuromuscular junction. The modic torticollis and cervical dystonia (involving neck nerve terminals begin to degenerate, and the denervated and shoulder muscles), blepharospasm (eyelid muscles), muscle fibers atrophy. Eventually, new nerve terminals strabismus and nystagmus (extraocular muscles), spas- sprout from the axons of affected nerves and make new modic dysphonia (vocal muscles), hemifacial spasm synaptic contact with the chemically denervated muscle (facial muscles), and writer’s cramp (finger muscles in fibers. During the period of denervation, which may be the forearm) are common dystonias. Such problems are several months, the patient usually experiences consider- neurological, not psychiatric, in origin, and sufferers can able relief of symptoms. The relief is temporary, however, have severe impairment of daily social and occupational and the treatment must be repeated when reinnervation activities. has occurred. The specific cause is located somewhere in the central Clinically, highly diluted toxin is injected into the indi- nervous system (CNS), but usually its exact nature is un- vidual muscles involved in the dystonia. Often this is done known. A genetic predisposition to the disorder may exist in conjunction with electrical measurements of muscle ac- in some cases. Centrally acting drugs are of limited effec- tivity (electromyography) to pinpoint the muscles in- tiveness, and surgical denervation, which carries a signifi- volved. Patients typically begin to experience relief in a few cant risk of permanent and irreversible paralysis, may pro- days to a week. Depending on the specific disorder, relief vide only temporary relief. However, recent clinical trials may be dramatic and may last for several months or more. using botulinum toxin to produce chemical denervation The abnormal contractions and associated pain are greatly show significant promise in the treatment of these disor- reduced, speech can become clear again, eyes reopen and ders. cease uncontrolled movements and, often, normal activi- Botulinum toxin is produced when the bacterium ties can be resumed. Clostridium botulinum grows anaerobically. It is one of the The principal adverse effect is a temporary weakness of most potent natural toxins; a lethal dose for a human adult the injected muscles. A few patients develop antibodies to is about 2 to 3 g. The active portion of the toxin is a pro- the toxin, which renders its further use ineffective. Studies tein with a molecular weight of about 150,000 that is con- have shown that the toxin’s activity is confined to the in- jugated with a variable number of accessory proteins. jected muscles, with no toxic effects noted elsewhere. Type A toxin, the complex form most often used therapeu- Long-term effects of the treatment, if any, are unknown. of each muscle fiber innervated by that axon terminal. stimulus closely follows the first (even before force has be- This leads to a single brief contraction of the muscle, a gun to decline), the myoplasmic calcium concentration is twitch. Though the contractile machinery may be fully still high (Fig. 9.4C), and the effect of the additional cal- activated (or nearly so) during a twitch, the amount of cium ions is to increase the force and, to some extent, the force produced is relatively low because the activation is duration of the twitch because a larger amount of calcium so brief that the relaxation processes begin before con- is present in the region of the myofilaments. traction is fully established. If stimuli are given repeatedly and rapidly, the result is a sustained contraction called a tetanus. When the contrac- Effects of Repeated Stimulation. The duration of the ac- tions occur so close together that no fluctuations in force tion potential in a skeletal muscle fiber is short (about 5 are observed, a fused tetanus results. The repetition rate at msec) compared to the duration of a twitch (tens or hun- which this occurs is the tetanic fusion frequency, typically dreds of milliseconds, depending on muscle type, tempera- 20 to 60 stimuli per second, with the higher rates found in ture, etc.). This means the absolute refractory period is also muscles that contract and relax rapidly. Figure 9.5 shows brief, and the muscle fiber membrane can be activated these effects in a special situation, in which the interval be- again long before the muscle has relaxed. Figure 9.4 shows tween successive stimuli is steadily reduced and the muscle the result of stimulating a muscle that is already active as a responds at first with a series of twitches that become fused result of a prior stimulus. If the second stimulus is given dur- into a smooth tetanus at the highest stimulus frequency. Be- ing relaxation (Fig. 9.4B), well outside the refractory period cause it involves events that occur close together in time, a caused by the first stimulus, significant additional force is tetanus is a form of temporal summation. developed. This additional force increment is associated with a second release of calcium ions from the SR, which Higher Forces Are Produced During a Tetanus. The adds to the calcium already there and reactivates actin and amount of force produced in a tetanus is typically several myosin interactions (see Chapter 8). When the second times that of a twitch; the disparity is expressed as the
CHAPTER 9 Skeletal Muscle and Smooth Muscle 157 These deformable structures comprise the series elastic component of the muscle, and their extension takes a sig- nificant amount of time. The brief activation time of a twitch is not sufficient to extend the series elastic compo- nent fully, and not all of the potential force of the contrac- tion is realized. Repeated activation in tetanus allows time for the internal “slack” to be more fully taken up, and more force is produced. Muscles with a large amount of series elasticity have a large tetanus-twitch ratio. The presence of series elasticity in human muscles provides some protection against sudden overloads of a muscle and allows for a small amount of mechanical energy storage. In jumping animals, such as kangaroos, a large fraction of muscular energy is stored in the elastic tendons and contributes significantly to the economy of locomotion. Temporal summation of muscle twitches. A, FIGURE 9.4 The first contraction is in response to a single Since a skeletal action potential. B, The next contraction shows the summed re- Partial Activation of a Whole Muscle. muscle consists of many fibers, each supplied by its own sponse to a second stimulus given during relaxation; the two indi- vidual responses are evident. C, The last contraction is the result branch of a motor axon, it is possible (and usual) that only of two stimuli in quick succession. Though measured force was a portion of the muscle will be activated at any one time. still rising when the second stimulus was given, the fact that there The pattern of activation is determined by the CNS and by could be an added response shows that internal activation had be- the distribution of the motor axons among the muscle gun to decline. In all cases, the solid line in the lower graph rep- fibers. A typical motor axon branches as it courses through resents the actual summed tension. the muscle, and each of its terminal branches innervates a single muscle fiber. All the fibers supplied by a single mo- tor axon will contract together when a nerve action poten- tetanus-twitch ratio. The relaxation processes during a tial travels from the central nervous system and divides twitch, particularly the reuptake of calcium, begin to oper- among the branches. ate as soon as the muscle is activated, and full activation is A single motor axon and all of the fibers it innervates are brief (lasting less time than that required for the muscle to called a motor unit. Contractions in only some of the fibers reach its peak force). Multiple stimuli, as in a tetanus, are in a motor unit are impossible, so the motor unit is normally needed for the full force to be expressed. the smallest functional unit of a muscle. In muscles adapted Another factor explaining the higher muscle force pro- for fine and precise control, only a few muscle fibers are as- duced with repetitive stimulation is mechanical. Even if the sociated with a given motor axon; in muscles in which high ends of a muscle are held rigidly, internal dimensional force is more important, a single motor axon controls many changes take place on activation. Some of this internal mo- more muscle fibers. The total force produced by a muscle is tion is associated with the crossbridges, and the tendons at determined by the number of motor units active at any one either end of the muscle make a considerable contribution. time; as more motor units are brought into play, the force increases. This phenomenon, called motor unit summa- tion, is illustrated in Figure 9.6. The force of contraction of the whole muscle is further modified by the degree of acti- vation of each motor unit in the muscle; some may be fully tetanized, while others may be at rest or produce only a se- ries of twitches. During a sustained contraction, the pattern of activity is continually changed by the CNS, and the bur- den of contraction is shared among the motor units. This results in a smooth contraction, with the force precisely controlled to produce the desired movement (or lack of it). Externally Imposed Conditions Also Affect Contraction Mechanical factors external to the muscle also influence the force and speed of contraction. For example, if a muscle is not allowed to shorten when it is stimulated, it will develop more force than it would if its length were allowed to change. If a muscle is in the process of lifting a load, its force of contraction is determined by the size of the load, Fusion of twitches into a smooth tetanus. not by the capabilities of the muscle. The speed with which FIGURE 9.5 The interval between successive stimuli steadily a muscle shortens is likewise determined, at least in part, by decreases until no relaxation occurs between stimuli. external conditions.
158 PART III MUSCLE PHYSIOLOGY A simple apparatus for recording isometric FIGURE 9.7 contractions. The length of the muscle (marked on the graph by the pen attached near its lower end) is adjustable at rest but is held constant during contraction. The force transducer provides a record of the isometric force response to a single stimulus at a fixed length (isometric by definition). (Force, length, and time units are arbitrary.) provided by the load a muscle lifts. This load is called an af- terload, since its magnitude and presence are not apparent Motor unit summation. Two units are shown FIGURE 9.6 to the muscle until after it has begun to shorten. above; their motor nerve action potentials and Recording an isotonic contraction requires modification muscle twitches are shown below. In the first contraction, there is of the apparatus used to study isometric contraction (Fig. a simple summation of two twitches; in the second, a brief tetanus in one motor unit sums with a twitch in the other. 9.8). Here the muscle is allowed to shorten while lifting an afterload, which is provided by the attached weight. This weight is chosen to present somewhat less than the peak Isometric Contraction. If a muscle is prevented from force capability of the muscle. When the muscle is stimu- shortening when activated, the muscle will express its con- lated, it will begin to develop force without shortening, tractile activity by pulling against its attachments and de- since it takes some time to build up enough force to begin veloping force. This type of contraction is termed isomet- to lift the weight. This means that early on, the contraction ric (meaning “same length”). The forces developed during is isometric (phase 1; Fig. 9.8). After sufficient force has an isometric contraction can be studied by attaching a dis- been generated, the muscle will begin to shorten and lift sected muscle to an apparatus similar to that shown in Fig- the load (phase 2). The contraction then becomes isotonic ure 9.7. This arrangement provides for setting the length of because the force exerted by the muscle exactly matches the muscle and tracing a record of force versus time. In a that of the weight, and the mass of the weight does not twitch, isometric force develops relatively rapidly, and sub- vary. Therefore, the upper tracing in Figure 9.8 shows a flat sequent isometric relaxation is somewhat slower. The dura- line representing constant force, while the muscle length tions of both contraction time and relaxation time are re- (lower tracing) is free to change. As relaxation begins lated to the rate at which calcium ions can be delivered to (phase 3), the muscle lengthens at constant force because it and removed from the region of the crossbridges, the actual is still supporting the load; this phase of relaxation is iso- sites of force development. During an isometric contrac- tonic, and the muscle is reextended by the weight. When tion, no actual physical work is done on the external envi- the muscle has been extended sufficiently to return to its ronment because no movement takes place while the force original length, conditions again become isometric (phase is developed. The muscle, however, still consumes energy 4), and the remaining force in the muscle declines as it to fuel the processes that generate and maintain force. would in a purely isometric twitch. In almost all situations encountered in daily life, isotonic contraction is preceded Isotonic Contraction. When conditions are arranged so by isometric force development; such contractions are the muscle can shorten and exert a constant force while do- called mixed contractions (isometric-isotonic-isometric). ing so, the contraction is called isotonic (meaning “same The duration of the early isometric portion of the con- force”). In the simplest conditions, this constant force is traction varies, depending on the afterload. At low after-
CHAPTER 9 Skeletal Muscle and Smooth Muscle 159 Isometric twitch Rise of isometric Force force transducer 3 Isometric relaxation Muscle 2 Force 1 4 1 Force is constant during isotonic phases 0 Stimulator Stimulus Isotonic Isotonic shortening relaxation 5 2 3 6 Length Length 7 during isometric is constant phases Weight 8 Contraction Relaxation 0.0 0.5 1.0 Time FIGURE 9.8 A modified apparatus showing the record- isotonic relaxation the force is constant (isotonic conditions), and ing of a single isotonic switch. The pen at during the final relaxation, conditions are again isometric because the lower end of the muscle marks its length, and the weight at- the muscle no longer lifts the weight. The dotted lines in the force tached to the muscle provides the afterload, while the platform and length traces show the isometric twitch that would have re- beneath the weight prevents the muscle from being overstretched sulted if the force had been too large (greater than 3 units) for the at rest. The first part of the contraction, until sufficient force has muscle to lift. (Force, length, and time units are arbitrary.) (See developed to lift the weight, is isometric. During shortening and text for details.) loads, the muscle requires little time to develop sufficient tion is said to be auxotonic. Drawing back a bowstring is force to begin to shorten, and conditions will be isotonic an example of this type of contraction. If the force of con- for a longer time. Figure 9.9 presents a series of three traction decreases as the muscle shortens, the contraction twitches. At the lowest afterload (weight A only), the iso- is called meiotonic. metric phase is the briefest and the isotonic phase is the In the body, a concentric contraction is one in which longest with the lowest force. With the addition of weight shortening (not necessarily isotonic) takes place. In an B, the afterload is doubled and the isometric phase is eccentric contraction, a muscle is extended (while active) longer, while the isotonic phase is shorter with twice the by an external force. Activities such as descending stairs force. If weight C is added, the combined afterload repre- or landing from a jump utilize this type of contraction. sents more force that the muscle can exert, and the con- Such contractions are potentially dangerous because the traction is isometric for its entire duration. The speed and muscle can experience forces that are larger than it could extent of shortening depend on the afterload in unique develop on its own, and tearing (strain) injuries can re- ways described shortly. sult. A static contraction results in no movement, but this may be due to partial activation (fewer motor units ac- Other Types of Contraction. Other physical situations tive) opposing a load that is not maximal. (This is differ- are sometimes encountered that modify the type of mus- ent from a true isometric contraction, in which shorten- cle contraction. When the force exerted by a shortening ing is physically impossible regardless of the degree of muscle continuously increases as it shortens, the contrac- activation.)
160 PART III MUSCLE PHYSIOLOGY Isometric Completely Force Isometric isometric transducer 3 Isotonic Isotonic Muscle 2 Force ABC 1 AB A 0 Stimulator Stimulus 5 6 Length 7 Afterload 8 weights 01 23 Extra Time weight FIGURE 9.9 A series of afterloaded isotonic contrac- tractions start from the same muscle length. Note the lower force tions. The curves labeled A and A B corre- and greater shortening with the lower weight (A). If weight C (to- spond to the force and shortening records during the lifting of tal weight A B C) is added to the afterload, the muscle those weights. In each case, the adjustable platform prevents the cannot lift it, and the entire contraction remains isometric. (Force, muscle from being stretched by the attached weight, and all con- length, and time units are arbitrary.) Special Mechanical Arrangements Allow a More protected against overextension by attachments to the Precise Analysis of Muscle Function skeleton or by other anatomic structures. If the muscle has not been stimulated, this resisting force is called passive The types of contraction described above provide a basis force or resting force. for a better understanding of muscle function. The isomet- The relationship between force and length is much dif- ric and isotonic mechanical behavior of muscle can be de- ferent in a stimulated muscle. The amount of active force or scribed in terms of two important relationships: active tension a muscle can produce during an isometric • The length-tension curve, treating isometric contraction contraction depends on the length at which the muscle is at different muscle lengths held. At a length roughly corresponding to the natural • The force-velocity curve, concerned with muscle per- length in the body, the resting length, the maximum force formance during isotonic contraction is produced. If the muscle is set to a shorter length and then stimulated, it produces less force. At an extremely short Isometric Contraction and the Length-Tension Curve. length, it produces no force at all. If the muscle is made Because it is made of contractile proteins and connective longer than its optimal length, it produces less force when tissue, an isolated muscle can resist being stretched at rest. stimulated. This behavior is summarized in the length-ten- When it is very short, it is slack and will not resist passive sion curve (Fig. 9.10). extension. As it is made longer and longer, however, its re- In Figure 9.10, the left side of the top graph shows the sisting force increases more and more. Normally a muscle is force produced by a series of twitches made over the range
CHAPTER 9 Skeletal Muscle and Smooth Muscle 161 Passive Total force 5 4 Force 3 2 1 0 0789 Time Length Active 9 Length 8 Optimal length At length 8.5 units FIGURE 9.10 A length-tension curve for skeletal muscle. Contractions are made at several 7 (8.0 units) Total Active resting lengths, and the resting (passive) and peak (total) 6 Active force passive forces for each twitch are transferred to the graph at the 012345 right. Subtraction of the passive curve from the total curve Time yields the active force curve. These curves are further illus- Passive trated in the lower right corner of the figure. (Force, length, and time units are arbitrary.) (See text for details.) of muscle lengths indicated at the left side of the bottom Isotonic Contraction and the Force-Velocity Curve. graph. Information from these traces is plotted at the right. Everyday experience shows that the speed at which a mus- The total peak force from each twitch is related to each cle can shorten depends on the load that must be moved. length (dotted lines). The muscle length is changed only Simply stated, light loads are lifted faster than heavy ones. when the muscle is not stimulated, and it is held constant Detailed analysis of this observation can provide insight (isometric) during contraction. The difference between the into how the force and shortening of muscles are matched total force and the passive force is called the active force to the external tasks they perform, as well as how muscles (see inset; Fig. 9.10). The active force results directly from function internally to liberate mechanical energy from their the active contraction of the muscle. metabolic stores. The analysis is performed by arranging a The length-tension curve shows that when the muscle is muscle so that it can be presented with a series of afterloads either longer or shorter than optimal length, it produces (see Fig. 9.9; Fig. 9.11). When the muscle is maximally less force. Myofilament overlap is a primary factor in deter- stimulated, lighter loads are lifted quickly and heavier loads mining the active length-tension curve (see Chapter 8). more slowly. If the applied load is greater than the maximal However, studies have demonstrated that at very short force capability of the muscle, known as F max , no shorten- lengths, the effectiveness of some steps in the excitation- ing will result and the contraction will be isometric. If no contraction coupling process is reduced—binding of cal- load is applied, the muscle will shorten at its greatest possi- cium to troponin is less and there is some loss of action po- ble speed, a velocity known as V max . tential conduction in the T tubule system. The initial velocity—the speed with which the muscle The functional significance of the length-tension curve begins to shorten—is measured at various loads. Initial ve- varies among the different muscle types. Many skeletal locity is measured because the muscle soon begins to slow muscles are confined by their skeletal attachments to a rel- down; as it gets shorter, it moves down its length-tension atively short region of the curve that is near the optimal curve and is capable of less force and speed of shortening. length. In these cases, the lever action of the skeletal sys- When all the initial velocity measurements are related to tem, not the length-tension relationship, is of primary im- each corresponding afterload lifted, an inverse relationship portance in determining the maximal force the muscle can known as the force-velocity curve is obtained. The curve is exert. Cardiac muscle, however, normally works at lengths steeper at low forces. When the measurements are made on significantly less than optimal for force production, but its a fully activated muscle, the force-velocity curve defines passive length-tension curve is shifted to shorter lengths the upper limits of the muscle’s isotonic capability. In prac- (see Chapter 10). The length-tension relationship is, there- tice, a completely unloaded contraction is very difficult to fore, very important when considering the ability of cardiac arrange, but mathematical extrapolation provides an accu- muscle to adjust to changes in length (related to the volume rate V max value. of blood contained in the heart) to meet the body’s chang- Figure 9.11 shows a force-velocity curve made from such ing needs. The role of the length-tension curve in smooth a series of isotonic contractions. The initial velocity points muscle is less clearly understood because of the great di- (A–D) correspond to the contractions shown at the top. versity among smooth muscles and their physiological Factors that modify muscle performance, such as fatigue or roles. For all muscle types, however, the length-tension incomplete stimulation (e.g., fewer motor units activated), curve has provided important information about the cellu- result in operation below the limits defined by the force-ve- lar and molecular mechanisms of contraction. locity curve.
162 PART III MUSCLE PHYSIOLOGY locity curve (zero force, maximal velocity and maximal V V V force, zero velocity), no work is done because, by defini- Shortening B C D tion, work requires moving a force through a distance. Be- 5 Length 6 velocities tween these two extremes, work and power output pass 7 8 through a maximum at a point where the force is approxi- mately one-third of its maximal value. The peak of the 3 Force 2 1 ABCD curve represents the combination of force and velocity at which the greatest power output is produced; at any after- 0 load force greater or smaller than this, less power can be produced. It also appears in skeletal muscle that the optimal 0 12 3 4 Time power output occurs under nearly the same conditions at V max which muscle efficiency, the amount of power produced 5 for a given metabolic energy input, is greatest. V D In terms of mechanical work, the chemical reactions of muscle are about 20% efficient; the energy from the re- 4 maining 80% of the fuel consumed (ATP) appears as heat. Relative velocity 3 Force-velocity ured efficiency is higher, approaching 40% in some cases. In some forms of locomotion, such as running, the meas- curve This apparent increase is probably due to the storage of mechanical energy (between strides) in elastic elements of 2 V moving body. This energy is then partly returned as work C the muscle and in the potential and kinetic energy of the 1 during the subsequent contraction. It has also been shown V that stretching an active muscle (e.g., during running or de- B F max scending stairs) can greatly reduce the breakdown of ATP, 0 since the crossbridge cycle is disrupted when myofilaments D C B A are forced to slide in the lengthening direction. These force-velocity and efficiency relationships are im- 1 portant when endurance is a significant concern. Athletes Relative power output curve learned to optimize their power output by “pacing” them- who are successful in long-term physical activity have Power selves and adjusting the velocity of contraction of their muscles to extend the duration of exercise. Such adjust- ments obviously involve compromises, as not all of the 0 many muscles involved in a particular task can be used at 0 1 2 3 optimal loading and rate and subjective factors, such as ex- Afterload force perience and training, enter into performance. Force-velocity and power output curves for In rapid, short-term exercise, it is possible to work at an FIGURE 9.11 skeletal muscle. Contractions at four different inefficient force-velocity combination to produce the most afterloads (decreasing left to right) are shown in the top graphs. rapid or forceful movements possible. Such activity must Note the differences in the amounts of shortening. The initial necessarily be of more limited duration than that carried shortening velocity (slope) is measured (V B, V C, V D) and the cor- out under conditions of maximal efficiency. Examples of at- responding force and velocity points plotted on the axes in the tempts at optimal matching of human muscles to varying bottom graph. Also shown is power output, the product of force and velocity. Note that it reaches a maximum at an afterload of loads can be found in the design of human-powered ma- about one-third of the maximal force. (Force, length, and time chinery, pedestrian ramps, and similar devices. units are arbitrary.) Interactions Between Isometric and Isotonic Contractions. The length-tension curve represents the effect of length on Consideration of the force-velocity relationship of mus- the isometric contraction of skeletal muscle. During iso- cle can provide insight into how it functions as a biological tonic shortening, however, muscle length does change motor, its primary physiological role. For instance, V max while the force is constant. The limit of this shortening is represents the maximal rate of crossbridge cycling; it is di- also described by the length-tension curve. For example, a rectly related to the biochemistry of the actin-myosin lightly loaded muscle will shorten farther than one starting ATPase activity in a particular muscle type and can be used from the same length and bearing a heavier load. If the mus- to compare the properties of different muscles. cle begins its shortening from a reduced length, its subse- Because isotonic contraction involves moving a force quent shortening will be reduced. These relationships are (the afterload) through a distance, the muscle does physi- diagrammed in Figure 9.12. In the case of day-to-day skele- cal work. The rate at which it does this work is its power tal muscle activity, these limits are not usually encountered output (see Figure 9.11). The factors represented in the because voluntary adjustments of the contracting muscle are force-velocity curve are thus relevant to questions of mus- usually made to accomplish a specific task. In the case of car- cle work and power. At the two extremes of the force-ve- diac muscle, however, such interrelationships between force
CHAPTER 9 Skeletal Muscle and Smooth Muscle 163 Triceps Biceps Muscle force is 7 kg 1 kg Hand movement Hand force 7 cm Muscle 1 cm shortening 5 cm 35 cm Antagonistic pairs and the lever system of FIGURE 9.13 skeletal muscle. Contraction of the biceps muscle lifts the lower arm (flexion) and elongates the triceps, while contraction of the triceps lowers the arm and hand (exten- sion) and elongates the biceps. The bones of the lower arm are pivoted at the elbow joint (the fulcrum of the lever); the force of the biceps is applied through its tendon close to the fulcrum; the hand is 7 times as far away from the elbow joint. Thus, the hand will move 7 times as far (and fast) as the biceps shortens (lever ra- tio, 7:1), but the biceps will have to exert 7 times as much force as the hand is supporting. skeletal lever system multiplies the distance over which an extremity can be moved (Fig. 9.13). However, this means the muscle must exert a much greater force than the actual weight of the load being lifted (the muscle force is in- The relationship between isotonic and iso- FIGURE 9.12 creased by the same ratio that the length change at the end metric contractions. The top graphs show the of the extremity is increased). In the case of the human contractions from Figure 9.11, with different amounts of shorten- forearm, the biceps brachii, when moving a force applied to ing. The bottom graph shows, for contractions B, C, and D, the the hand, must exert a force at its insertion on the radius initial portion is isometric (the line moves upward at constant length) until the afterload force is reached. The muscle then that is approximately 7 times as great. However, the result- shortens at the afterload force (the line moves to the left) until its ing movement of the hand is approximately 7 times as far length reaches a limit determined (at least approximately) by the and 7 times as rapid as the shortening of the muscle itself. isometric length-tension curve. The dotted lines show that the Muscles may be subject to large forces and this can lead to same final force/length point can be reached by several different muscle injury (see Clinical Focus Box 9.2). approaches. Relaxation data, not shown on the graph, would Acting independently, a muscle can only shorten, and trace out the same pathways in reverse. (Force, length, and time the force to relengthen it must be provided externally. units are arbitrary.) These actions are achieved by the arrangement of muscles into antagonistic pairs of flexors and extensors. For exam- ple, the shortening of the biceps is countered by the action and length are of critical importance in functional adjust- of the triceps; the triceps, in turn, is relengthened by con- ment of the beating heart (see Chapter 10). traction of the biceps. In some cases, gravity provides the restoring force. The Anatomic Arrangement of Muscle Is a Prime Determinant of Function Metabolic and Structural Adaptations Fit Skeletal Muscle for a Variety of Roles Anatomic location places restrictions on muscle function by limiting the amount of shortening or determining the Specific skeletal muscles are adapted for specialized func- kinds of loads encountered. Skeletal muscle is generally at- tions. These adaptations involve primarily the structures tached to bone, and bones are attached to each other. Be- and chemical reactions that supply the contractile system cause of the way the muscles are attached and the skeleton with energy. The enzymatic properties (i.e., the rate of is articulated, the bones and muscles together constitute a ATP hydrolysis) of actomyosin ATPase also vary. The ba- lever system. This arrangement influences the physiology sic structural features of the sarcomeres and the thick/thin of the muscles and the functioning of the body as a whole. filament interactions are, however, essentially the same In most cases, the system works at a mechanical disadvan- among the types of skeletal muscle. tage with respect to the force exerted. The shortening ca- Chapter 8 detailed the biochemical reactions responsi- pability of skeletal muscle by itself is rather limited, and the ble for providing ATP to the contractile system. Recall that
164 PART III MUSCLE PHYSIOLOGY CLINICAL FOCUS BOX 9.2 Strain Injuries to Muscle tract also predispose it to strain injury; laboratory experi- Skeletal muscle is subject to being damaged in several ments have shown that muscles in better physical condition ways. In accidents that result in crushing or laceration, are better able to safely absorb the energy that leads to in- considerable muscle damage can occur. However, dam- jury. Retraining too rapidly or too soon after an injury or re- age directly related to the contractile function of muscle is turning to activity too soon also make reinjury more likely. also possible. Such injuries are incidental to the muscle’s Delayed-onset muscle soreness, as often experienced primary function of exerting force and causing motion. In after unaccustomed exercise, also results from strain in- the areas of sports or physical labor, muscle strain is the jury, but on a smaller scale. Muscle subjected to overload most common type of injury. during eccentric contraction shows reduced contractile The muscles most susceptible to injury are those of the ability and ultrastructural damage to the contractile ele- limbs, especially those that go from joint to joint (e.g., the ments, especially at the Z lines. The pain peaks 1 to 2 days gastrocnemius or the rectus femoris) or that have a com- after exercise; as the healing progresses, the muscle be- plex architecture (e.g., the adductor longus and, again, the comes more able to withstand microinjury. Repeated rectus femoris). Often the injury will be confined to one bouts of exercise are tolerated increasingly well and are muscle of a group used to perform a specific action. Injury associated with the hypertrophy of the muscle; hence, the can occur to a muscle that is overstretched while unstimu- familiar phrase, “No pain, no gain.” lated, but most injuries occur during eccentric contraction, Treatments for muscle strain injury are rather limited. that is, during the forced extension of an activated muscle. They include the application of ice packs and enforced rest Under such circumstances, the force in the muscle may of the injured muscle. Nonsteroidal anti-inflammatory rise to a level considerably higher than could be attained in drugs (NSAIDs) can lessen the pain, but they also appear an isometric contraction; relatively few injuries occur un- to delay healing somewhat. For injuries in which an actual der isometric or isotonic (concentric) contraction condi- separation of the muscle and tendon occurs, surgical re- tions. The site of injury is most often at the myotendinous pair is necessary. Massaging of an injured muscle does not junction, a location that can be determined by physical ex- appear to be as beneficial as light exercise, which may help amination and confirmed by magnetic resonance imaging to increase blood flow and promote healing. Recovery (MRI) or by a computed tomography (CT) scan. There may from strain injury is associated with the gradual regaining also be extensive damage throughout the muscle itself. In of strength, which will eventually reach near-normal levels some cases, there is complete disruption of the muscle if reinjury is avoided. Some muscle tissue is permanently (avulsion), although usually separation is not complete. replaced with scar tissue, which may change the geometry Symptoms of a muscle strain injury include obvious sore- of the muscle. Most recovered muscles will have a some- ness, weakness, delayed swelling, and “bunching up” in what increased susceptibility to injury for an extended pe- extreme cases. riod of time. Several predisposing factors may cause a muscle strain Precautions for avoiding strain injury include adequate injury, including relative weakness of a given muscle, result- physical conditioning and practiced expertise at the task at ing from a lack of training early in a sports season, and fa- hand. Preexercise stretching and warm-up may be of some tigue, which leads to increased injury late in an athletic value in preventing strain injury, although the experimen- event. In general, factors that make a muscle less able to con- tal evidence is equivocal. muscle fibers contain both glycolytic (anaerobic) and ox- supply, where it facilitates oxygen diffusion (and serves as a idative (aerobic) metabolic pathways, which differ in their minor auxiliary oxygen source) in times of heavy demand. ability to produce ATP from metabolic fuels, particularly Red muscle fibers are divided into slow-twitch fibers and glucose and fatty acids. Among muscle fibers, the relative fast-twitch fibers on the basis of their contraction speed importance of each pathway and the presence or absence of (see Table 9.1). The differences in rates of contraction associated supporting organelles and structures vary. These (shortening velocity or force development) arise from dif- variations form the basis for the classification of skeletal ferences in actomyosin ATPase activity (i.e., in the basic muscle fiber types (Table 9.1). A typical skeletal muscle crossbridge cycling rate). Mitochondria are abundant in usually contains a mixture of fiber types, but in most mus- these fibers because they contain the enzymes involved in cles a particular type predominates. The major classifica- aerobic metabolism. tion criteria are derived from mechanical measurements of muscle function and histochemical staining techniques in White Muscle Fibers and Anaerobic Metabolism. White which dyes for specific enzymatic reactions are used to muscle fibers, which contain little myoglobin, are fast- identify individual fibers in a muscle cross section. twitch fibers that rely primarily on glycolytic metabolism. They contain significant amounts of stored glycogen, Red Muscle Fibers and Aerobic Metabolism. The color which can be broken down rapidly to provide a quick differences of skeletal muscles arise from differences in the source of energy. Although they contract rapidly and pow- amount of myoglobin they contain. Similar to the related erfully, their endurance is limited by their ability to sustain red blood cell protein hemoglobin, myoglobin can bind, an oxygen deficit (i.e., to tolerate the buildup of lactic store, and release oxygen. It is abundant in muscle fibers acid). They require a period of recovery (and a supply of that depend heavily on aerobic metabolism for their ATP oxygen) after heavy use. White muscle fibers have fewer
CHAPTER 9 Skeletal Muscle and Smooth Muscle 165 TABLE 9.1 Classification of Skeletal Muscle Fiber Types Fast Twitch Slow Twitch Fast Fast Oxidative- Slow Metabolic Type Glycolytic (White) Glycolytic (Red) Oxidative (Red) Metabolic properties ATPase activity High High Low ATP source(s) Anaerobic glycolysis Anaerobic glycolysis/ Oxidative Oxidative phosphorylation phosphorylation Glycolytic enzyme content High Moderate Low Number of mitochondria Low High High Myoglobin content Low High High Glycogen content High Moderate Low Fatigue resistance Low Moderate High Mechanical properties Contraction speed Fast Fast Slow Force capability High Medium Low 2 SR Ca -ATPase activity High High Moderate Motor axon velocity 100 m/sec 100 m/sec 85 m/sec Structural properties Fiber diameter Large Moderate Small Number of capillaries Few Many Many Functional role in body Rapid and powerful Medium endurance Postural/endurance movements Typical example Latissimus dorsi Mixed-fiber muscle, such Soleus as vastus lateralis mitochondria than red muscle fibers because the reactions idative capacity of a particular muscle fiber type and its fa- of glycolysis take place in the myoplasm. There are indica- tigue resistance, chemical measurements of fatigued skele- tions that enzymes of the glycolytic pathway may be tal muscle specimens have shown that the ATP content, closely associated with the thin filament array. while reduced, is not completely exhausted. In well-moti- vated subjects, CNS factors do not appear to play an im- Red and White Fibers and Muscle Function. The relative portant role in fatigue, and transmission at the neuromus- proportions of red and white muscle fibers fit muscles for cular junction has such a large safety factor that impaired different uses in the body. Muscles containing primarily transmission also does not contribute to fatigue. slow-twitch oxidative red fibers are specialized for functions Studies on isolated muscle have distinguished two dif- requiring slow movements and endurance, such as the main- ferent mechanisms producing fatigue. Stimulation of the tenance of posture. Muscles containing a preponderance of muscle at a rate far above that necessary for a fused tetanus fast-twitch red fibers support faster and more powerful con- quickly produces high-frequency stimulation fatigue; re- tractions. They also typically contain varying numbers of covery from this condition is rapid (a few tens of seconds). fast-twitch white fibers; their resulting ability to use both In this type of fatigue, the principal defect seems to be a aerobic and anaerobic metabolism increases their power and failure in T tubule action potential conduction, which leads speed. Muscles containing primarily fast-twitch white fibers to less Ca 2 release from the SR. Under most in vivo cir- are suited for rapid, short, powerful contractions. cumstances, feedback mechanisms in neural motor path- Fast muscles, both white and red, not only contract rap- ways work to reduce the stimulation to the minimum nec- idly but also relax rapidly. Rapid relaxation requires a high essary for a smooth tetanus, and this type of fatigue is rate of calcium pumping by the SR, which is abundant in probably not often encountered. these muscles. In such muscles, the energy used for calcium Prolonged or repeated tetanic stimulation produces a pumping can be as much as 30% of the total consumed. Fast longer-lasting fatigue with a longer recovery time. This type muscles are supplied by large motor axons with high con- of fatigue—low-frequency stimulation fatigue—is related duction velocities; this correlates with their ability to make to the muscle’s metabolic activities. The buildup of metabo- quick and rapidly repeated contractions. lites produced by crossbridge cycling, especially inorganic phosphate (P i ) and H ions, reduces calcium sensitivity of Muscle Fatigue. During a period of heavy exercise, espe- the myofilaments and the contractile force generated per cially when working above 70% of maximal aerobic capac- crossbridge. The reduced amount of metabolic energy ity, skeletal muscle is subject to fatigue. The speed and available to the calcium transport system in the SR leads to force of contraction are diminished, relaxation time is pro- reduced Ca 2 pumping. As a result, relaxation time in- longed, and a period of rest is required to restore normal creases and there is less Ca 2 available to activate the con- function. While there is a close correlation between the ox- traction with each stimulus, resulting in lowered peak force.
166 PART III MUSCLE PHYSIOLOGY PROPERTIES OF SMOOTH MUSCLE has the effect of restricting flow or stopping it completely. Many sphincters, such as those in the gastrointestinal and The properties of skeletal muscle described thus far apply urogenital tracts, have a special nerve supply and partici- in a general way to smooth muscle. Many of the basic mus- pate in complex reflex behavior. The muscle in sphincters cle properties are highly modified in smooth muscle, how- is characterized by the ability to remain contracted for long ever, because of the very different functional roles it plays periods with little metabolic cost. in the body. The adaptations of smooth muscle structure and function are best understood in the context of the spe- cial requirements of the organs and systems of which Circular and Longitudinal Layers: The Small Intestine. smooth muscle is an integral component. Of particular im- Next, in order of complexity, is the combination of circular portance are the high metabolic economy of smooth mus- and longitudinal layers, as in the muscle of the small intes- cle, which allows it to remain contracted for long periods tine. The outermost muscle layer, which is relatively thin, with little energy consumption, and the small size of its runs along the length of the intestine. The inner muscle cells, which allows precise control of very small structures, layer, thicker and more powerful, has a circular arrange- such as blood vessels. Most smooth muscles are not discrete ment. Coordinated alternating contractions and relaxations organs (like individual skeletal muscles) but are intimate of these two layers propel the contents of the intestine, al- components of larger organs. It is in the context of these though most of the motive power is provided by circular specializations that the physiology of smooth muscle is muscle (see Chapter 26). best understood. Complex Fiber Arrangements. The most complex arrangement of smooth muscle is found in organs such as the urinary bladder and uterus. Numerous layers and orien- Structural Arrangements Equip tations of muscle fibers are present and the effect of their Smooth Muscle for Its Special Roles contraction is an overall reduction of the volume of the or- While there are major differences among the organs and gan. Even with such a complex arrangement of fibers, co- systems in which smooth muscle plays a major part, the ordinated and organized contractions take place. The re- structure of smooth muscle is quite consistent at the tissue lengthening force, in the case of these hollow organs, is level and even more similar at the cellular level. Several provided by the gradual accumulation of contents. In the typical arrangements of smooth muscle occur in a variety urinary bladder, for example, the muscle is gradually of locations. stretched as the emptied organ fills again. The variety of smooth muscle tasks—regulating and In a few instances, smooth muscles are structurally simi- promoting movement of fluids, expelling the contents of lar to skeletal muscles in their arrangement. Some of the organs, moving visceral structures—is accomplished by a structures supporting the uterus, for example, are called lig- few basic types of tissue structures. All of these structures aments; however, they contain large amounts of smooth are subject, like skeletal muscle, to the requirement for an- muscle and are capable of considerable shortening. Pilo- tagonistic actions: If smooth muscle contracts, an external motor muscles, the small cutaneous muscles that erect the force must lengthen it again. The structures described be- hairs, are also discrete structures whose shortening is basi- low provide these restoring forces in a variety of ways. cally unidirectional. Certain areas of mesentery also con- tain regions of linearly oriented smooth muscle fibers. Circular Organization: Blood Vessels. The simplest smooth muscle arrangement is found in the arteries and Small Cell Size Facilitates Precise Control veins of the circulatory system. Smooth muscle cells are oriented in the circumference of a vessel so that shortening The most notable feature of smooth muscle tissue organi- of the fibers results in reducing the vessel’s diameter. This zation, in contrast to that of skeletal muscle, is the small reduction may range from a slight narrowing to a complete size of the cells compared to the tissue they make up. Indi- obstruction of the vessel lumen, depending on the physio- vidual smooth muscle cells (depending somewhat on the logical needs of the body or organ. The orientation of the type of tissue they compose) are 100 to 300 m long and 5 cells in the vessel walls is helical, with a very shallow pitch. to 10 m in diameter. When isolated from the tissue, the In the larger muscular vessels, particularly arteries, there cells are roughly cylindrical along most of their length and may be many layers of cells and the force of contraction taper at the ends. The single nucleus is elongated and cen- may be quite high; in small arterioles, the muscle layer may trally located. Electron microscopy reveals that the cell consist of single cells wrapped around the vessel. The blood margins contain many areas of small membrane invagina- pressure provides the force to relengthen the cells in the tions, called caveoli, which may play a role in increasing vessel walls. This type of muscle organization is extremely the surface area of the cell (Fig. 9.14). Mitochondria are lo- important because the narrowing of a blood vessel has a cated at the ends of the nucleus and near the surface mem- powerful influence on the rate of blood flow through it (see brane. In some smooth muscle cells, the SR is abundant, al- Chapters 12 and 15). This circular arrangement is also though not to the extent found in skeletal muscle. In some prominent in the airways of the lungs, where it regulates cases, it closely approaches the cell membrane, but there is the flow of air. no organized T tubular system as in other types of muscle. A further specialization of the circular muscle arrange- The bulk of the cell interior is occupied by three types ment is a sphincter, a thickening of the muscular portion of of myofilaments: thick, thin, and intermediate. The thin fil- the wall of a hollow or tubular organ, whose contraction aments are similar to those of skeletal muscle but lack the
CHAPTER 9 Skeletal Muscle and Smooth Muscle 167 Dense body Mitochondrion Myofilaments Caveoli Autonomic nerve fiber Gap junction Nucleus Connective tissue fibers FIGURE 9.14 A drawing from electron micrographs of tion and longitudinal section. (Adapted from Krstic RV. General smooth muscle, showing cells in cross sec- Histology of the Mammal. New York, Springer-Verlag, 1984.) troponin protein complex. The length of the individual fil- filaments and to transmit the force of contraction to adja- aments is not known with certainty because of their irregu- cent cells. lar organization. The thick filaments are composed of Smooth muscle lacks the regular sarcomere structure of myosin molecules, as in skeletal muscle, but the details of skeletal muscle. Studies have shown some association the exact arrangement of the individual molecules into fila- among dense bodies down the length of a cell and a ten- ments are not completely understood. The thick filaments dency of thick filaments to show a degree of lateral group- appear to be approximately 2.2 m long, somewhat longer ing. However, it appears that the lack of a strongly periodic than in skeletal muscle (1.6 m). The intermediate fila- arrangement of the contractile apparatus is an adaptation of ments are so named because their diameter of 10 nm is be- smooth muscle associated with its ability to function over a tween that of the thick and thin filaments. Intermediate fil- wide range of lengths and to develop high forces despite a aments appear to have a cytoskeletal, rather than a smaller cellular myosin content. contractile, function. Prominent throughout the cytoplasm are small, dark-staining areas called dense bodies. They are Mechanical Coupling. Because smooth muscle cells are associated with the thin and intermediate filaments and are so small compared to the whole tissue, some mechanical considered analogous to the Z lines of skeletal muscle. and electrical communication among them is necessary. In- Dense bodies associated with the cell margins are often dividual cells are coupled mechanically in several ways. A called membrane-associated dense bodies (or patches) or proposed arrangement of the smooth muscle contractile focal adhesions. They appear to serve as anchors for thin and force transmission system is shown in Figure 9.15. This
168 PART III MUSCLE PHYSIOLOGY Cell-to-cell phenomenon is under hormonal control; in the uterus, for Paired membrane-associated Myofilaments inserting connective example, gap junctions are rare during most of pregnancy, dense bodies in membrane-associated tissue strands and the contractions of the muscle are weak and lack coor- dense body dination. However, just prior to the onset of labor, the number and size of gap junctions increase dramatically and the contractions become strong and well coordinated. Nucleus Shortly after the cessation of labor, these gap junctions dis- appear and tissue function again becomes less coordinated. Electrical coupling among smooth muscle cells is the ba- sis for classifying smooth muscle into two major types: • Multiunit smooth muscle, which has little cell-to-cell communication and depends directly on nerve stimula- Collagen and elastin fibers between cells tion for activation (like skeletal muscle). An example is Network of the iris of the eye. intermediate filaments linking dense bodies and Cytoplasmic • Unitary or single-unit smooth muscle, which has a high membrane-associated dense body degree of coupling among cells, so that large regions of dense bodies tissue act as if they were a single cell. Its cells form a functional syncytium (an arrangement in which many The contractile system and cell-to-cell con- FIGURE 9.15 cells behave as one). This type of smooth muscle makes nections in smooth muscle. Note regions of association between thick and thin filaments that are anchored by up the bulk of the muscle in the visceral organs. the cytoplasmic and membrane-associated dense bodies. A net- work of intermediate filaments provides some spatial organization (see, especially, the left side). Several types of cell-to-cell me- The Regulation and Control of chanical connections are shown, including direct connections and connections to the extracellular connective tissue matrix. Struc- Smooth Muscle Involve Many Factors tures are not necessarily drawn to scale. (See text for details.) Smooth muscle is subject to a much more complex system of controls than skeletal muscle. In addition to contraction picture represents a consensus from many researchers and in response to nerve stimulation, smooth muscle responds areas of investigation. Note that assemblies of myofila- to hormonal and pharmacological stimuli, the presence or ments are anchored within the cell by the dense bodies and lack of metabolites, cold, pressure, and stretch, or touch, at the cell margins by the membrane-associated dense bod- and it may be spontaneously active as well. This multiplic- ies. The contractile apparatus lies oblique to the long axis ity of controlling factors is vital for the integration of of the cell. When single isolated smooth muscle cells con- smooth muscle into overall body function. Skeletal muscle tract, they undergo a “corkscrew” motion that is thought to is primarily controlled by the CNS and by a relatively reflect the off-axis orientation of the contractile filaments. straightforward cellular control mechanism. The control of In intact tissues, the connections to adjacent cells prevent smooth muscle is much more closely related to the many this rotation. factors that regulate the internal environment. It is not sur- Force appears to be transmitted from cell to cell and prising, therefore, that many internal and external path- throughout the tissue in several ways. Many of the mem- ways have as their final effect the control of the interaction brane-associated dense bodies are opposite one another in of smooth muscle contractile proteins. adjacent cells and may provide continuity of force trans- mission between the contractile apparatus in each cell. Innervation of Smooth Muscle. Most smooth muscles There are also areas of cell-to-cell contact, both lateral and have a nerve supply, usually from both divisions of the au- end to end, where myofilament insertions are not apparent tonomic nervous system. There is much diversity in this but where a direct transmission of force could occur. In area; the muscle response to a given neurotransmitter sub- some places, short strands of connective tissue link adjacent stance depends on the type of tissue and its physiological cells; in other places, cells are joined to the collagen and state. Smooth muscle does not contain the highly struc- elastin fibers running throughout the tissue. These fibers, tured neuromuscular junctions found in skeletal muscle. along with reticular connective tissue, comprise the con- Autonomic nerve axons run throughout the tissue; along nective tissue matrix or stroma found in all smooth muscle the length of the axons are many swellings or varicosities, tissues. It serves to connect the cells and to give integrity to which are the sites of release of transmitter substances in re- the whole tissue. In tissues that can resist considerable ex- sponse to nerve action potentials. Released molecules of ex- ternal force, this connective tissue matrix is well developed citatory or inhibitory transmitter diffuse from the nerve to and may be organized into septa, which transmit the force the nearby smooth muscle cells, where they take effect. of many cells. Since the cells are so small and numerous, relatively few are directly reached by the transmitters; those that are not Electrical Coupling. Smooth muscle cells are also cou- reached are stimulated by cell-to-cell communication, as pled electrically. The structure most effective in this cou- described above. Neuromuscular transmission in smooth pling is the gap junction (see Chapter 1). Gap junctions in muscle is a relatively slow process, and in many tissues, smooth muscle appear to be somewhat transient structures nerve stimulation serves mainly to modify (increase or de- that can form and disappear over time. In some tissues, this crease) spontaneous rhythmic mechanical activity.
CHAPTER 9 Skeletal Muscle and Smooth Muscle 169 Activation of Smooth Muscle Contraction. Chemical ical conditions, and types of membrane channels. As a rest- factors that control the function of smooth muscle cells ing membrane potential of 50 mV results in the inactiva- most often have their first influence at the cell membrane. tion of typical fast sodium channels, sodium is usually not Some factors act by opening or closing cell membrane ion the major carrier of inward current during the action po- channels. Others result in production of a second messen- tential. In most cases, it has been shown that the rising (de- ger that diffuses to the interior of the cell, where it causes polarizing) phase of a smooth muscle action potential is further changes (see Chapter 1). The final result of both dominated by calcium, which enters through voltage-gated mechanisms is usually a change in the intracellular concen- membrane channels. Repolarization current is carried by 2 tration of Ca , which, in turn, controls the contractile potassium ions, which leave through several types of chan- process itself. nels, some voltage-controlled and others sensitive to the in- The membrane potential of smooth muscle is subject to ternal calcium concentration. These general ionic proper- many external and internal influences, in contrast to the ties are typical of most smooth muscle types, although case in skeletal and cardiac muscle. In smooth muscle, the specific tissues may have variations within this general linkage between the electrical activity of the cell membrane framework. The most important common feature is the en- and cellular functions, particularly contraction, is much try of calcium ions during the action potential, since this in- more subtle and complex than in the other types of muscle. ward flux is an important source of the calcium that con- The resting potential of most smooth muscles is approxi- trols the contractile process. mately 50 mV. This is less negative than the resting po- In addition to voltage-gated calcium channels, smooth tential of nerve and other muscle types, but here too it is de- muscle also contains receptor-activated calcium channels termined primarily by the transmembrane potassium ion that are opened by the binding of hormones or neurotrans- gradient. The smaller potential is due primarily to a greater mitters. One such ligand-gated channel in arterial smooth resting permeability to sodium ions. In many smooth mus- muscle is controlled by ATP, which acts as a transmitter cles, the resting potential varies periodically with time, pro- substance in some types of smooth muscle tissues. ducing a rhythmic potential change called a slow wave (see Smooth muscle can also be activated via the generation Chapter 26). Action potentials in smooth muscle also have a of second messengers, such as inositol 1,4,5-trisphosphate variety of forms. In many smooth muscles the action poten- (IP 3 ) (see Chapter 1). This form of control involves chemi- tial is a transient depolarization event lasting approximately cal and hormonal activators and does not depend on mem- 50 msec. At times, such action potentials will occur in rapid brane depolarization. The IP 3 causes the release of calcium groups and produce repetitive membrane depolarizations from the SR, which initiates contraction. that last for some time. Relatively rapid twitch-like contrac- tions are usually the result of one or more action potentials. The Role of Calcium in Smooth Muscle Contraction. All Sustained, low-level, partial contraction is often only loosely of the processes described above are ultimately concerned related to the electrical activity of the membrane. with the control of muscle contraction via the pool of in- The ionic basis of smooth muscle action potentials is tracellular calcium. Figure 9.16 summarizes these mecha- complex because of the great variety of tissues, physiolog- nisms in an overall picture of calcium regulation in smooth Calcium entry Calcium exit Direct entry Ligand-gated channel Voltage-gated 2+ channel Ca Ca ATPase Ca 2+ \"Leak\" channel 2 + + Ca /Na exchange Ca 2+ Ca-induced Ca 2+ Ca-release Na + Ca 2 + 2+ Ca Ca 2 + Ca 2 + Sarcoplasmic reticulum DAG Major routes of calcium Myoplasm Ca ATPase FIGURE 9.16 IP 2+ entry and exit from the 3 Ca + cytoplasm of smooth muscle. The ATPase Na PIP reactions are energy-consuming ion pumps. Phospholipase C 2 The processes on the left side increase cyto- + + G Protein Na /K - ATPase plasmic calcium and promote contraction; Receptor those on the right decrease internal calcium K + Agonist and cause relaxation. PIP 2 , phosphatidylinos- itol 4,5-bisphosphate; IP 3 , inositol 1,4,5- Via second messenger trisphosphate; DAG, diacylglycerol.
170 PART III MUSCLE PHYSIOLOGY muscle. These processes may be grouped into those con- nisms are being found in different tissue types. This general cerned with calcium entry, intracellular calcium liberation, scheme is shown in Figure 9.17. and calcium exit from the cell. Calcium enters the cell When smooth muscle is at rest, there is little cyclic in- through several pathways, including voltage-gated and lig- teraction between the myosin and actin filaments because and-gated channels and a relatively small number of unreg- of a special feature of its myosin molecules. As in skeletal ulated “leak” channels that permit the continual passive en- muscle, the S2 portion of each myosin molecule (the paired try of small amounts of extracellular calcium. Within the “head” portion) contains four protein light chains. Two of cell, the major storage site of calcium is the SR; in some these have a molecular weight of 16,000 and are called es- types of smooth muscle, its capacity is quite small and these sential light chains; their presence is necessary for actin- tissues are strongly dependent on extracellular calcium for myosin interaction, but they do not appear to participate in their function. Calcium is released from the SR by at least the regulatory process. The other two light chains have a two mechanisms, including IP 3 -induced release and via cal- molecular weight of 20,000 and are called regulatory light cium-induced calcium release. In this latter mechanism, chains; their role in smooth muscle is critical. These chains calcium that has entered the cell via a membrane channel contain specific locations (amino acid residues) to which causes additional calcium release from the SR, amplifying the terminal phosphate group of an ATP molecule can be its activating effect. attached via the process of phosphorylation; the enzyme Studies in which internal calcium is continuously meas- responsible for promoting this reaction is myosin light- ured while the muscle is stimulated to contract typically re- chain kinase (MLCK). When the regulatory light chains veal a high level of internal calcium early in the contrac- are phosphorylated, the myosin heads can interact in a tion; this activating burst most likely originates from cyclic fashion with actin, and the reactions of the cross- internal SR storage. The level then decreases somewhat, al- bridge cycle (and its mechanical events) take place much as though during the entire contraction it is maintained at a in skeletal muscle. It is important to note that the ATP mol- significantly elevated level. This sustained calcium level is ecule that phosphorylates a myosin light chain is separate the result of a balance between mechanisms allowing cal- and distinct from the one consumed as an energy source by cium entry and those favoring its removal from the cyto- the mechanochemical reactions of the crossbridge cycle. plasm. Calcium leaves the myoplasm in two directions: A For myosin phosphorylation to occur, the MLCK must portion of it is returned to storage in the SR by an active be activated, and this step is also subject to control. Closely 2 transport system (a Ca -ATPase); and the rest is ejected associated with the MLCK is calmodulin (CaM), a smaller from the cell by two principal means. The most important protein that binds calcium ions. When four calcium ions are of these is another ATP-dependent active transport system bound, the CaM protein activates its associated MLCK and located in the cell membrane. The second mechanism, also light-chain phosphorylation can proceed. It is this MLCK- located in the plasma membrane, is sodium-calcium ex- activating step that is sensitive to the cytoplasmic calcium 2 change, a process in which the entry of three sodium ions concentration; at levels below 10 7 M Ca , no calcium is is coupled to the extrusion of one calcium ion. This mech- bound to calmodulin and no contraction can take place. anism derives its energy from the large sodium gradient When cytoplasmic calcium concentration is greater than across the plasma membrane; thus, it depends critically on 10 4 M, the binding sites on calmodulin are fully occupied, the operation of the cell membrane Na /K -ATPase. (The light-chain phosphorylation proceeds at maximal rate, and sodium-calcium exchange mechanism, relatively unimpor- contraction occurs. Between these extreme limits, varia- tant in smooth muscle, is of much greater consequence in tions in the internal calcium concentration can cause corre- cardiac muscle; see Chapter 10.) sponding gradations in the contractile force. Such modula- tion of smooth muscle contraction is essential for its regulatory functions, especially in the vascular system. Biochemical Control of Contraction and Relaxation. The contractile proteins of smooth muscle, like those of Smooth Muscle Relaxation. The biochemical processes skeletal and cardiac muscle, are controlled by changes in controlling relaxation in smooth muscle also differ from the intracellular concentration of calcium ions. Likewise, those in skeletal and cardiac muscle, in which a state of in- the general features of the actin-myosin contraction system hibition returns as calcium ions are withdrawn from being are similar in all muscle types. It is in the control of the con- bound to troponin. In smooth muscle, the phosphorylation tractile proteins themselves that important differences ex- of myosin is reversed by the enzyme myosin light-chain ist. Because the control of contraction in skeletal and car- phosphatase (MLCP). The activity of this phosphatase ap- diac muscle is associated with thin filament proteins, it is pears to be only partially regulated; that is, there is always called actin-linked regulation. The thin filaments of some enzymatic activity, even while the muscle is contract- smooth muscle lack troponin; control of smooth muscle ing. During contraction, however, MLCK-catalyzed phos- contraction relies instead on the thick filaments and is, phorylation proceeds at a significantly higher rate, and therefore, called myosin-linked regulation. In actin-linked phosphorylated myosin predominates. When the cytoplas- regulation, the contractile system is in a constant state of mic calcium concentration falls, MLCK activity is reduced inhibited readiness and calcium ions remove the inhibi- because the calcium dissociates from the calmodulin, and tion. In the myosin-linked regulation of smooth muscle, the myosin dephosphorylation (catalyzed by the phosphatase) role of calcium is to cause activation of a resting state of the predominates. Because dephosphorylated myosin has a low contractile system. The general outlines of this process are affinity for actin, the reactions of the crossbridge cycle can well understood and appear to apply to all types of smooth no longer take place. Relaxation is, thus, brought about by muscle, although a variety of secondary regulatory mecha- mechanisms that lower cytoplasmic calcium concentrations
CHAPTER 9 Skeletal Muscle and Smooth Muscle 171 FIGURE 9.17 Reaction pathways involved in the basic phosphorylated myosin can then participate in a mechanical regulation of smooth muscle contraction crossbridge cycle (lower left) much like that in skeletal muscle, and relaxation. Activation begins (upper right) when cytoplas- although much slower. When calcium levels are reduced (upper mic calcium levels are increased and calcium binds to calmod- left), calcium leaves calmodulin, the kinase is inactivated, and ulin (CaM), activating the myosin light-chain kinase (MLCK). the myosin light-chain phosphatase (MLCP) dephosphorylates The kinase (lower right) catalyzes the phosphorylation of the myosin, making it inactive. The crossbridge cycle stops, and myosin, changing it to an active form (myosin-P or Mp). The the muscle relaxes. or decrease MLCK activity. Because of the importance of Another possible secondary mechanism in some smooth smooth muscle relaxation in physiological processes, this muscle tissues involves the protein caldesmon. This mole- subject will be treated fully later in the chapter. cule, also sensitive to the concentration of cytoplasmic cal- cium, is capable of binding to myosin at one of its ends and Secondary Mechanisms. In addition to myosin phos- to actin and calmodulin at the other. While the process is phorylation to control smooth muscle activation, second- not well understood, it is possible that caldesmon, under ary regulatory mechanisms are present in some types of the control of calcium, could form crosslinks between actin smooth muscle. One of these provides long-term regula- and myosin filaments and, thus, aid in bearing force during tion of contraction in some tissues after the initial calcium- a long-maintained contraction. dependent myosin phosphorylation has activated the con- Other secondary regulatory mechanisms have been pro- tractile system. For example, in vascular smooth muscle, the posed. It is likely that several such mechanisms exist in var- force of contraction may be maintained for long periods. ious tissues, but the calcium-dependent phosphorylation of This extended maintenance of force capability, called the myosin light chains is the primary event in the activation of latch state, appears to be related to a reduction in the cy- smooth muscle contraction. cling rate of crossbridges (possibly related to reduced phos- phorylation) so that each remains attached for a longer por- tion of its total cycle. Even during the latch state, increased Mechanical Activity in Smooth Muscle Is Adapted cytoplasmic calcium appears to be necessary for force to be for Its Specialized Physiological Roles maintained. Not all smooth muscle tissue can enter a latch state, however, and the details of the process are not com- The contraction of smooth muscle is much slower than that pletely understood. of skeletal or cardiac muscle; it can maintain contraction far
172 PART III MUSCLE PHYSIOLOGY longer and relaxes much more slowly. The source of these and this ion pumping requires a significant portion of the differences lies largely in the chemistry of the interaction cell’s energy supply. Internal pumping of calcium ions into between actin and myosin of smooth muscle. Recall that the the SR during relaxation also requires energy, and the crossbridges of muscle form an actin-myosin enzyme system processes that result in phosphorylation of the myosin light (actomyosin ATPase) that releases energy from ATP so that chains consume a further portion of the cellular energy, as it may be converted into a mechanical contraction (i.e., ten- do the other processes of cellular maintenance and repair. sion or shortening). The inherent rate of this ATPase corre- Smooth muscle contains both glycolytic and oxidative lates strongly with the velocity of shortening of the intact metabolic pathways, with the oxidative pathway usually muscle. Most smooth muscles require several seconds (or the most important; under some conditions, a transition even minutes) to develop maximal isometric force. A may temporarily be made from oxidative to glycolytic me- smooth muscle that contracts 100 times more slowly than a tabolism. In terms of the entire body economy, the energy skeletal muscle will have an actomyosin ATPase that is 100 requirements of smooth muscle are small compared with times as slow. The major source of this difference in rates is those of skeletal muscle, but the critical regulatory func- the myosin molecules; the actin found in smooth and skele- tions of smooth muscle require that its energy supply not be tal muscles is rather similar. There is a close association in interrupted. smooth muscle between maximal shortening velocity and degree of myosin light-chain phosphorylation. Modes of Contraction. Smooth muscle contractile activ- A high economy of tension maintenance, typically 300 ity cannot be divided clearly into twitch and tetanus, as in to 500 times greater than that in skeletal muscle, is vital to skeletal muscle. In some cases, smooth muscle makes rapid the physiological function of smooth muscle. Economy, as phasic contractions, followed by complete relaxation. In used here, means the amount of metabolic energy input other cases, smooth muscle can maintain a low level of ac- compared to the tension produced. In smooth muscle, tive tension for long periods without cyclic contraction and there is a direct relationship between isometric tension and relaxation; a long-maintained contraction is called tonus the consumption of ATP. The economy is related to the ba- (rather than tetanus) or a tonic contraction. This is typical sic cycling rate of the crossbridges: Early in a contraction of smooth muscle activated by hormonal, pharmacological, (while tension is being developed and the crossbridges are or metabolic factors, whereas phasic activity is more closely cycling more rapidly), energy consumption is about 4 times associated with stimulation by neural activity. as high as in the later steady-state phase of the contraction. Comparison With Skeletal Muscle. The force-veloc- Compared with skeletal muscle, the crossbridge cycle in ity curve for smooth muscle reflects the differences in smooth muscle is hundreds of times slower, and much more crossbridge functions described previously. Although time is spent with the crossbridges in the attached phase of smooth muscle contains one-third to one-fifth as much the cycle. myosin as skeletal muscle, the longer smooth muscle myo- The cycling crossbridges are not the only energy-utiliz- filaments and the slower crossbridge cycling rate allow it to ing system in smooth muscle. Because the cells are so small produce as much force per unit of cross-sectional area as and numerous, smooth muscle tissue contains a large cell does skeletal muscle. Thus, the maximum values for smooth membrane area. Maintenance of the proper ionic concen- muscle on the force axis would be similar, while the maxi- trations inside the cells requires the activity of the mem- mum (and intermediate) velocity values are very different brane-based ion pumps for sodium/potassium and calcium, (Fig. 9.18). Furthermore, smooth muscle can have a set of FIGURE 9.18 Smooth and skeletal muscle mechanical Skeletal and smooth muscle force-velocity curves. While the characteristics compared. A and B, Typical peak forces may be similar, the maximum shortening velocity of length-tension curves from skeletal and smooth muscle. Note smooth muscle is typically 100 times lower than that of skeletal the greater range of operating lengths for smooth muscle and muscle. (Force and length units are arbitrary.) the leftward shift of the passive (resting) tension curve. C,
CHAPTER 9 Skeletal Muscle and Smooth Muscle 173 force-velocity curves, each corresponding to a different Elastic material Elastic material level of myosin light-chain phosphorylation. Other mechanical properties of smooth muscle are also 5 related to its physiological roles. While its underlying cel- 4 Viscoelastic Viscoelastic lular basis is uncertain, smooth muscle has a length-tension Pressure 3 material material curve somewhat similar to that of skeletal muscle, although 2 there are some significant differences (Fig. 9.18). At lengths 1 at which the maximal isometric force is developed, many 0 smooth muscles bear a substantial passive force. This is 05 10 0 5 mostly a result of the network of connective tissue that sup- Time Time ports the smooth muscle cells and resists overextension; in some cases, it may be partly a result of residual interaction between actin and attached but noncycling myosin cross- 5 Slow stretch Rapid stretch bridges. Compared to skeletal and cardiac muscle, smooth muscle can function over a significantly greater range of Volume lengths. It is not constrained by skeletal attachments, and it makes up several organs that vary greatly in volume during 0 the course of their normal functioning. The shape of the 0 5 10 0 5 length-tension curve can also vary with time and the degree Time Time of distension. For example, when the urinary bladder is Viscoelasticity. The behavior of a viscoelastic highly distended by its contents, the peak of the active FIGURE 9.19 material (e.g., the walls of a hollow, smooth length-tension curve can be displaced to longer muscle muscle-containing organ) are subjected to slow (left) and rapid lengths. This means that as the muscle shortens to expel the (right) elongation. The increase in force (or pressure) is propor- organ’s contents, it can reach lengths at which it can no tional to the rate of extension, and at the end of the stretch, the longer exert active force. After a period of recovery at this force decays exponentially to a steady level. A purely elastic ma- shorter length, the muscle can again exert sufficient force terial (dashed line) maintains its force without stress relaxation. to expel the contents. Stress Relaxation and Viscoelasticity. These re- versible changes in the length-tension relationship are, at is a result of the tonic contractile activity present in most least in part, the result of stress relaxation, which character- smooth muscles under normal physiological conditions. izes viscoelastic materials such as smooth muscle. When a Other processes that are not yet well understood may viscoelastic material is stretched to a new length, it responds also account for some of the length-dependent behavior of initially with a significant increase in force; this is an elastic smooth muscle. In some smooth muscles, mechanical be- response, and it is followed by a decline in force that is ini- havior in the later stages of a contraction depends strongly tially rapid and then continuously slows until a new steady on the length at which the contraction began. This effect, force is reached. If a viscoelastic material is subjected to a called plasticity (not to be confused with nonrecoverable constant force, it will elongate slowly until it reaches a new deformation), appears to arise from molecular rearrange- length. This phenomenon, the complement of stress relax- ments within the contractile protein array and may form the ation, is called creep. In smooth muscle organs, the abundant basis for both long- and short-term mechanical adaptation. connective tissue prevents overextension. The viscoelastic properties of smooth muscle allow it to Modes of Relaxation. Relaxation is a complex process in function well as a reservoir for fluids or other materials; if smooth muscle. The central cause of relaxation is a reduc- an organ is filled slowly, stress relaxation allows the inter- tion in the internal (cytoplasmic) calcium concentration, a nal pressure to adjust gradually, so that it rises much less process that is itself the result of several mechanisms. Elec- than if the final volume had been introduced rapidly. This trical repolarization of the plasma membrane leads to a de- process is illustrated in Figure 9.19 for the case of a hollow crease in the influx of calcium ions, while the plasma mem- smooth muscle organ subjected to both rapid and slow in- brane calcium pump and the sodium-calcium exchange fusions of liquid (since this is a hollow structure, internal mechanism (to a lesser extent) actively promote calcium ef- pressure and volume are directly related to the force and flux. Most important quantitatively is the uptake of calcium length of the muscle fibers in the walls). The dashed lines back into the SR. The net result of lowering the calcium in the top graphs denote the pressure that would result if concentration is a reduction in MLCK activity so that de- the material were simply elastic rather than having the ad- phosphorylation of myosin can predominate over phos- ditional property of viscosity. phorylation. Some of the viscoelasticity of smooth muscle is a prop- erty of the extracellular connective tissue and other materi- Biochemical Mechanisms. Both calcium uptake by als, such as the hyaluronic acid gel, present between the the SR and the MLCK activity may be subject to another cells; some of it is inherent in the smooth muscle cells, control mechanism called -adrenergic relaxation. In some probably because of the presence of noncycling cross- vascular smooth muscles, relaxation occurs in response to bridges in resting tissue. One important feature of smooth the presence of the hormone norepinephrine. Binding of muscle viscoelasticity is the tissue’s ability to return to its this substance to cell membrane receptors causes the acti- original state following extreme extension. This capability vation of adenylyl cyclase and the formation of cAMP (see
174 PART III MUSCLE PHYSIOLOGY Chapter 1). Increased intracellular cAMP concentration is Adaptation to Changing Conditions. Several external in- an effective promoter of relaxation in at least two major fluences, some not well understood, affect the growth and ways. The activity of the enzyme cAMP-dependent pro- functional adaptation of smooth muscle. Some of these tein kinase increases as the concentration of cAMP rises. changes are vital for normal body function, while others This enzyme (and perhaps also cAMP acting directly) en- can be part of a disease process. hances calcium uptake by the SR, resulting in a further low- ering of the cytoplasmic calcium. At the same time, phos- Hormone-Induced Hypertrophy. The uterus and asso- phorylation of MLCK (by the action of cAMP-dependent ciated tissues are under the influence of the female sex hor- protein kinase) reduces its catalytic effectiveness, and mones (see Chapters 38 and 39). During pregnancy, high myosin light-chain phosphorylation is decreased as if intra- levels of progesterone, later followed by high estrogen lev- cellular calcium had been lowered. Since many vascular els, promote significant changes in uterine growth and con- muscles are continuously in a state of partial contraction, - trol. The mass of muscle layers, known as the myometrium, adrenergic relaxation is a physiologically important process increases as much as 70-fold, primarily through an increase in the adjustment of blood flow and pressure. in muscle cell size—hypertrophy—associated with a large Another important relaxation pathway is present in the increase in content of contractile proteins and associated smooth muscle of small arteries (as well as other smooth regulatory proteins. The distension caused by the growing muscle tissues). The lumen of arteries is lined with en- fetus also promotes hypertrophy. Extracellular connective dothelial cells. In addition to their structural role, they tissue also increases. The number of cells increases as well, serve as a controllable source of nitric oxide (NO), which a condition called hyperplasia. was formerly known as endothelium-derived relaxing fac- Throughout most of pregnancy the cells are poorly cou- tor (EDRF) (see Chapter 1). The mechanical shearing effect pled electrically and contractile activity is not well coordi- of the flowing blood causes the endothelial cells to release nated. As pregnancy nears term, the large increase in the NO; it is a small and highly diffusible molecule, and it number of gap junctions permits coordinated contractions quickly binds to membrane receptors on the vascular that culminate in the birth process. Following delivery and smooth muscle cells. This action results in a cascade of ef- the consequent hormonal and mechanical changes, the fects, the first of which is the stimulation of the enzyme processes leading to hypertrophy are reversed and the mus- guanylyl cyclase, which catalyzes the formation of cyclic cle reverts to its nonpregnant state. guanosine 3’,5’-monophosphate (cGMP). By mechanisms Other Forms of Hypertrophy. Chronic obstruction of similar to those in the case of cAMP, this leads to the acti- hollow smooth muscle organs (e.g., the urinary bladder, vation of cGMP-dependent protein kinase (PKG), which small intestine, portal vein) produces a chronically elevated affects several processes leading to relaxation. PKG pro- internal pressure. This acts as a stimulus for smooth muscle motes the reuptake of calcium ions, and it causes the open- hypertrophy, although the cellular mechanisms involved ing of calcium-activated potassium ion channels in the cell are not well understood. In addition to structural changes, membrane, leading to hyperpolarization and subsequent there may be alterations of the metabolic activities, con- relaxation. PKG also blocks the activity of agonist-evoked tractile properties, and response to agonists. Hyperplasia is phospholipase C (PLC), and this action reduces the liber- also present to some degree in these muscle adaptations, ation of stored calcium ions by IP 3 . By mechanisms not well but its relative contribution is difficult to ascertain experi- understood, cGMP reduces the calcium sensitivity of the mentally. Nonmuscular components of the organ wall (e.g., myosin light-chain phosphorylation process, further pro- connective tissue) are also increased. These changes, espe- moting relaxation. Some drugs that relax vascular smooth cially those involving the muscle cells, usually revert to muscle, such as sodium nitroprusside, work by mimicking near normal when the mechanical cause of the hypertrophy the action of NO and causing similar intracellular events. is removed. Vascular smooth muscle, especially of the arteries, is Mechanical Factors. Relaxation is obviously also a me- chanical process. Contractile force decreases as cross- also subject to hypertrophy (and hyperplasia) when it en- bridges detach and myofilaments become free again to counters a sustained pressure overload. This is an important slide past one another. Because most smooth muscle activ- factor in hypertension or high blood pressure. An increase ity involves at least some shortening, relaxation must re- in blood pressure, perhaps a result of chronically elevated quire elongation. As with other types of muscle, an external sympathetic nervous system activity, may be present before force must be applied for lengthening to occur. In the in- smooth muscle hypertrophy occurs. Enlargement of the testine, for example, material being propelled into a re- smooth muscle layer is a response to this stimulus, and cently contracted region provides the extending force. there may be a trophic effect of the sympathetic nervous Smooth muscle relaxation (or its absence) may have impor- system activity as well. The resulting thickening of the vas- tant indirect consequences. Hypertension, for example, can cular wall further reduces the lumen diameter, aggravating be caused by a failure of smooth muscle relaxation. In the the hypertension. Lowering the blood pressure by thera- uterus during labor, adequate relaxation between contrac- peutic means can result in a return of the vessel walls to a tions is essential for the well-being of the fetus. During the near-normal state. Hypertension in the pulmonary vascula- contractions of labor, the muscular walls of the uterus be- ture is also associated with increased smooth muscle come quite rigid and tend to compress the blood vessels growth and with the development of smooth muscle cells that run through them. As a result, blood flow to the fetus in areas of the arterial system that do not normally have is restricted, and failure of the muscle to relax adequately smooth muscle in their walls. between contractions can result in fetal distress. Under some circumstances, smooth muscle cells can
CHAPTER 9 Skeletal Muscle and Smooth Muscle 175 lose most of their contractile function and become syn- tery linings. While the factors involved in initiating and thesizers of collagen and accumulators of low-density sustaining this reversible transition are not well under- lipoproteins. The loss of contractile activity is accompa- stood, they appear to involve growth-promoting sub- nied by a significant loss in the number of myofilaments. stances released from platelets following endothelial in- Such a phenotypic transformation takes place, for ex- jury, while circulating heparin-like substances block the ample, in the formation of atherosclerotic lesions in ar- transformation. REVIEW QUESTIONS DIRECTIONS: Each of the numbered (D) A failure of the muscle to contract (D) Independent of the load, and items or incomplete statements in this at all shortens at a velocity independent of section is followed by answers or 5. The factor most important in the load completions of the statement. Select the producing an isometric contraction is 10.Muscles that are best suited for brief ONE lettered answer or completion that is (A) Keeping the muscle from changing high-intensity exercise would contain BEST in each case. its length which of the following types of fibers? (B) Providing a stimulus adequate to (A) Mostly glycolytic (white) 1. The endplate potential at the activate all motor units (B) Mostly slow-twitch oxidative neuromuscular junction is the result of (C) Determining the resting length of (red) increased postsynaptic membrane the muscle (C) A mix of slow twitch (red) and fast permeability to (D) Stimulating in a tetanic fashion to twitch (red) (A) Sodium first, then potassium produce the maximal force (D) A mix of glycolytic (white) and (B) Sodium and potassium 6. If a muscle is arranged so as to lift an fast twitch (red) simultaneously afterload equal to one-half its maximal 11.Smooth muscles that are in the walls of (C) Sodium only isometric capabilities, the ultimate hollow organs (D) Potassium only force it develops is determined by the (A) Can shorten without developing 2. The endplate potential differs from a (A) Length of the muscle force muscle action potential in several ways. (B) Size of the afterload (B) Can develop force isometrically In which one of the following ways are (C) Strength of the stimulation (C) Have no contractile function, but they similar? (D) Number of motor units activated resist lengthening (A) They are both actively propagated 7. In a series of afterloaded isotonic (D) Shorten as the volume of the down the length of the muscle fiber twitches, as the load is increased, the organ increases (B) They both arise from changes in (A) Force developed by the muscle 12.The relaxation of smooth muscle is the permeability to sodium and increases and the shortening velocity associated with a reduction in free potassium ions decreases intracellular calcium ion concentration. (C) They are both initiated by the flow (B) Force developed by the muscle The effect of the reduction is of electrical (ionic) current increases, while the velocity remains (A) Reestablishment of the inhibition (D) In both cases, the membrane the same of the actin-myosin interaction potential becomes inside-positive (C) Velocity increases to compensate (B) Deactivation of the enzymatic 3. If transmission at the neuromuscular for the increased afterload activity of the individual actin junction were blocked by the (D) Force developed is determined by molecules application of curare, which one of the the velocity of shortening (C) Decreased phosphorylation of events listed below would fail to occur 8. At which point along the isotonic myosin molecules when a motor nerve impulse arrived? force-velocity curve is the power (D) Reduced contractile interaction by (A) Depolarization of the postsynaptic output maximal? blocking the active sites of the myosin membrane (A) At the lowest force and highest molecules (B) Depolarization of the presynaptic velocity (V max ) 13.Which statement below most closely membrane (B) At the highest force and lowest describes the role of calcium ions in (C) Entry of calcium ions into the velocity (F max ) the control of smooth muscle presynaptic terminal (C) At a force that is about one third contraction? (D) Presynaptic release of transmitter of F max (A) Binding of calcium ions to substance (D) At a velocity that is about two regulatory proteins on thin filaments 4. In a certain muscle, it takes 25 msec for thirds of V max removes the inhibition of actin-myosin a single twitch to develop its peak 9. Consider a load being lifted by a interaction force in response to a single stimulus. If human hand. Because of the (B) Binding of calcium ions to this muscle were stimulated with two mechanical effects of the skeletal lever regulatory proteins associated with stimuli spaced 15 msec apart, the result system, the biceps muscle exerts a thick filaments, specifically calmodulin, would be force activates the enzymatic activity of (A) A single twitch identical to the (A) Less than the load, but shortens at myosin molecules one-stimulus twitch a higher velocity (C) Calcium ions serve as a direct (B) A contraction similar to a single (B) Equal to the load, and shortens at a inhibitor of the interaction of thick twitch, but of higher amplitude velocity equal to the load and thin filaments (C) Two distinct contractions of very (C) Greater than the load, but shortens (D) A high concentration of calcium short duration at a lower velocity ions in the myofilament space is (continued)
176 PART III MUSCLE PHYSIOLOGY required to maintain muscle in a (B) Contains the same steps, but some SUGGESTED READING relaxed state of them are slower Bagshaw CR. Muscle Contraction. 2nd Ed. 14.Compared with skeletal muscle, (C) Does not have a step in which New York: Chapman & Hall, 1993. smooth muscle actin and myosin are bound together Barany M, ed. Biochemistry of Smooth (A) Contracts more slowly, but exerts (D) Can proceed without the Muscle Contraction. New York: Acad- considerably more force consumption of ATP emic Press, 1996. (B) Contracts more rapidly, but exerts 16.Receptors in the smooth muscle cell Barr L, Christ GJ, eds. A Functional View considerably less force membrane of Smooth Muscle. Stamford, CT: JAI (C) Maintains long-duration (A) Function only in combination with Press, 2000. contractions economically electrical activation Ford LE. Muscle Physiology and Cardiac (D) Exerts considerable force but can (B) Cannot function if the cell is Function. Carmel, IN: Biological Sci- do little shortening relaxed ences Press-Cooper Group, 2000. 15.Compared with that of skeletal muscle, (C) Play a variety of regulatory roles Kao CY, Carsten ME, eds. Cellular As- the crossbridge cycle of smooth muscle (D) Control chemical activation, pects of Smooth Muscle Function. (A) Is similar, but runs in the reverse but do not affect electrical Cambridge, UK: Cambridge University direction activation Press, 1997.
CHAPTER Cardiac Muscle 10 10 Richard A. Meiss, Ph.D. CHAPTER OUTLINE ■ ANATOMIC SPECIALIZATIONS OF CARDIAC MUSCLE ■ PHYSIOLOGICAL SPECIALIZATIONS OF CARDIAC MUSCLE KEY CONCEPTS 1. Cardiac muscle is a striated muscle, with a sarcomere 6. The contractility of cardiac muscle is changed by inotropic structure much like that of skeletal muscle. It has small interventions that include changes in the heart rate, the cells (as in smooth muscle), firmly connected end-to-end presence of circulating epinephrine, or sympathetic nerve at the intercalated disks. stimulation. 2. The action potential in cardiac muscle is long lasting com- 7. Most changes in cardiac muscle contractility are associated pared to the duration of the contraction, preventing a with changes in the amount of calcium available to activate tetanic contraction. the contractile system. 3. Under normal circumstances, cardiac muscle operates at 8. Calcium enters a cardiac muscle cell during the plateau of lengths somewhat less than the optimal length for peak the action potential. This entry promotes the release of in- force production, facilitating length-dependent regulation ternal calcium stores, which are located mainly in the sar- of the muscle activity. coplasmic reticulum (SR). Primary and secondary 4. A typical cardiac muscle contraction produces less than active transport systems remove calcium from the maximal force, allowing physiologically regulated changes cytoplasm. in contractility to adjust the force of the muscle contraction 9. Cardiac muscle derives its energy primarily from the to the body’s current needs. oxidative metabolism of lactic acid and free fatty 5. As in skeletal muscle, the speed of shortening of cardiac acids. It has very little capacity for anaerobic muscle is inversely related to the force being exerted, as metabolism. expressed in the force-velocity curve. he muscle mass of the heart, the myocardium, shares ANATOMIC SPECIALIZATIONS Tcharacteristics of both smooth muscle and skeletal OF CARDIAC MUSCLE muscle. The tissue is striated in appearance, as in skeletal muscle, and the structural characteristics of the sarco- The heart is composed of several varieties of cardiac mus- meres and myofilaments are much like those of skeletal cle tissue. The atrial myocardium and ventricular my- muscle. The regulation of contraction, involving calcium ocardium, so named for their location, are similar struc- control of an actin-linked troponin-tropomyosin com- turally, although the electrical properties of these two areas plex, is also quite like that of skeletal muscle. However, differ significantly. The conducting tissues (e.g., Purkinje cardiac muscle is composed of many small cells, as is fibers) of the heart have a communicating function similar smooth muscle, and electrical and mechanical cell-to-cell to nerve tissue, but they actually consist of muscle tissue communication is an essential feature of cardiac muscle that is highly adapted for the rapid and efficient conduction structure and function. The mechanical properties of car- of action potentials, and their contractile ability is greatly diac muscle relate more closely to those of skeletal mus- reduced. Finally, there are the highly specialized tissues of cle, although the mechanical performance is considerably the sinoatrial and atrioventricular nodes, muscle tissue more complex and subtle. that is greatly modified into structures concerned with the 177
178 PART III MUSCLE PHYSIOLOGY initiation and conduction of the heartbeat. The discussions tercalated disks (Fig. 10.1). This arrangement aids in the that follow refer primarily to the ventricular myocardium, spread of electrical activity. Cardiac myocytes have a sin- the tissue that makes up the greatest bulk of the muscle of gle, centrally located nucleus, although many cells may the heart. contain two nuclei. The cell membrane and associated fine connective tissue structures form the sarcolemma, as in skeletal muscle. The sarcolemma of cardiac muscle sup- Cardiac Muscle Cells Are Structurally ports the resting and action potentials and is the location of Distinct From Skeletal Muscle Cells ion pumps and ion exchange mechanisms vital to cell func- tion. Just inside the sarcolemma are components of the SR The small size of cardiac muscle cells is one of the critical where significant amounts of calcium ions may be bound aspects in determining the function of heart muscle. The and kept from general access to the cytoplasm. This bound cells are approximately 10 to 15 m in diameter and about calcium can exchange rapidly with the extracellular space 50 m long. Cardiac muscle tissue is a branching network and can be rapidly freed from its binding sites by the pas- of cells, also called cardiac myocytes, joined together at in- sage of an action potential. Capillaries Nuclei Mitochondria Intercalated disks Branched muscle cell Connective tissue FIGURE 10.1 The structure of cardiac muscle tissue. Left: striated structure of the contractile filaments, the many mitochon- A small tissue sample in longitudinal and cross dria, and the three-dimensional structure of the intercalated disks. section. Note the branching nature of the cells and the large (Adapted from Krstic RV. General Histology of the Mammal. number of capillaries. Right: Two cardiac myocytes, showing the New York: Springer-Verlag, 1984.)
CHAPTER 10 Cardiac Muscle 179 As in skeletal muscle, there is a system of transverse (T) necessary for organized function. The small cell size also tubules, but both it and the SR are not as extensive in car- makes each cell more critically dependent on the external diac muscle, together constituting less than 2% of the cell environment, and cardiac function may be greatly altered volume. This correlates with the small cell size and conse- by electrolyte and metabolic imbalances arising elsewhere quent reduction in diffusion distances between the cell sur- in the body. Hormonal messengers, such as norepineph- face membrane and contractile proteins. In cardiac muscle rine, also have quick access to cardiac muscle cells. cells, the T tubules enter the cells at the level of the Z lines. From a mechanical standpoint, the lack of skeletal at- In many cases, the link between a T tubule and the SR is not tachments means cardiac muscle can function over a wide a triad, as in skeletal muscle, but rather a dyad, composed range of lengths. While the length-tension property is not of the T tubule and the terminal cisterna of the SR of only of major importance in the functioning of many skeletal one sarcomere. The small size of the SR also limits its cal- muscles, in cardiac muscle, it is the basis of the remarkable cium storage capacity, and the other source of calcium en- capacity of the heart to adjust to a wide range of physio- try and exit, the sarcolemma, has an important role in the logical conditions and requirements. excitation-contraction coupling process in cardiac muscle. The sarcomeres appear essentially like those of skeletal muscle, with similar A bands and I bands, Z lines, and M PHYSIOLOGICAL SPECIALIZATIONS lines. Myofilaments make up almost half the cell volume and OF CARDIAC MUSCLE are bathed in the cytosol. Numerous mitochondria comprise another 30 to 40% of the cell volume, reflecting the highly Cardiac muscle is a striated muscle, but it functions rather aerobic nature of cardiac muscle function. The rest of the differently from skeletal muscle. The lack of skeletal at- cell volume, about 15%, consists of cytosol, containing nu- tachments provides a wider range of lengths over which it merous enzymes and metabolic products and substrates. can operate. Special features of the excitation-contraction coupling process allow a subtle degree of control at the level of the muscle that is largely independent of the cen- Cardiac Muscle Cells Are Linked in a tral nervous system (CNS). Functional Syncytium Electron microscopy reveals that in the region of the inter- Specialized Electrical and Metabolic Properties calated disk, each cardiac myocyte sends processes deep into its neighboring cell to form an interdigitating junction Control Cardiac Muscle Contraction with a large surface area. Gap junctions in the intercalated A more detailed treatment of the electrical properties of car- disks function like those of smooth muscle, allowing close diac muscle is given in Chapter 13. The discussion here fo- electrical communication between cells. Also plentiful in cuses on the electrical properties most closely related to con- the intercalated disk region are desmosomes, areas where trolling the mechanical function of cardiac ventricular muscle. there is a firm mechanical connection between cells. This mode of attachment, rather than an extensive extracellular The Cardiac Action Potential. As in other types of mus- connective tissue matrix as in smooth muscle, allows the cle and in nerve, the muscle cells of the heart have an ex- transmission of force from cell to cell. The intercalated citable and selectively permeable cell membrane that is re- disk, therefore, allows cardiac muscle to form a functional sponsible for both resting potentials and action potentials. syncytium, with cells acting in concert both mechanically These electrical phenomena are the result of ionic concen- and electrically. tration differences and several ion-selective membrane The stimulus for cardiac muscle contraction arises en- channels, some of which are voltage- and time-dependent. tirely within the heart and is not dependent on its nerve In cardiac muscle, however, the membrane events are more supply (see Chapter 13). The conduction of action poten- diverse and complex than in skeletal muscles and are much tials is solely a function of the muscle tissue. Impulse prop- more closely linked to the actual form of the mechanical agation is aided by the branched nature of the cells, the in- contraction. The closer association of electrical and me- tercalated disks, and specialized conducting tissue, such as chanical events is one key to the inherent properties of car- Purkinje fibers—strands of myocytes, nerve-like in out- diac muscle that suit it to its role in an organ that is largely ward appearance, that are specialized for electrical conduc- self-regulating. tion. Their contractile protein is only about 20% of the cell Figure 10.2 illustrates some features of the cardiac mus- volume, and their large size optimizes their electrical char- cle action potential that pertain directly to myocardial acteristics for rapid action potential conduction. Innerva- function. Note that the duration of the action potential is tion of cardiac muscle comes from both branches of the au- quite long; in fact, it lasts nearly as long as the muscle con- tonomic nervous system, allowing for external regulation of traction. One consequence is that the absolute and relative the heart rate and strength of contraction, as well as pro- refractory periods are likewise extended, and the muscle viding some degree of sensory feedback. cannot be restimulated during any but the latest part of the contraction. During the repolarization phase of the action Cell and Tissue Structure Allow and potential, there is a brief period in which the muscle actu- Require Unique Adaptations ally shows an increased sensitivity to stimulation. This pe- riod of supranormal excitability is due to a lowered potas- As a result of the small size of cardiac muscle cells, the com- sium conductance that persists late in the action potential munication system described above (and in Chapter 13) is (see Chapter 13). If the muscle is accidentally stimulated
180 PART III MUSCLE PHYSIOLOGY RRP ization is from additional SR just inside the cell membrane. ARP SNP As in skeletal muscle, the principal role of the SR is in the rapid release, active uptake, storage, and buffering of cy- tosolic calcium. The action of calcium ions on the tro- Action potential ponin-tropomyosin complex of the thin filaments is similar to that in skeletal muscle, but cardiac muscle differs in its Millivolts 0 cellular handling of the activator, calcium. Along with the calcium ions released from the SR, a sig- Plateau phase nificant amount of calcium enters the cell from outside dur- ing the upstroke and plateau phase of the action potential (see Fig. 10.2). The principal cause of the sustained depo- -80 larization of the plateau phase is the presence of a popula- tion of voltage-gated membrane channels permeable to cal- cium ions. These channels open relatively slowly; while 3 open, there is a net influx of calcium ions, called the slow inward current, moving down an electrochemical gradient. 2 Contraction Although the calcium entering during an action potential Force 1 does not directly affect that specific contraction, it can af- fect the next contraction, and it does increase the cellular calcium content over time because of the repeated nature of 0 the cardiac muscle contraction. In addition, even a small amount of Ca 2 entering through the sarcolemma causes the release of significant 0 0.3 additional Ca 2 from the SR, a phenomenon known as Sec calcium-induced calcium release (similar to that in smooth muscle). This constant influx of calcium requires A cardiac muscle action potential and iso- FIGURE 10.2 that there be a cellular system that can rid the cell of ex- metric twitch. Because of the duration of the action potential, an effective tetanic contraction cannot be pro- cess calcium. Regulation of cellular calcium content has duced, although a partial contraction can be elicited late in the important consequences for cardiac muscle function, be- twitch. ARP, absolute refractory period; RRP, relative refractory cause of the close relationship between calcium and con- period; SNP, period of supranormal excitability. tractile activity. Mechanical Properties of Cardiac Muscle Adapt during this period, the action potentials that are produced have reduced amplitude and duration and give rise to only It to Changing Physiological Requirements small contractions. This period of supranormal excitability The mechanical function of cardiac muscle differs some- can lead to unwanted and untimely propagation of action what from that of skeletal muscle contraction. Cardiac mus- potentials that can seriously interfere with the normal cle, in its natural location, does not exist as separate strips rhythm of the heart. of tissue with skeletal attachments at the ends. Instead, it is The long-lasting refractoriness of the cell membrane ef- present as interwoven bundles of fibers in the heart walls, fectively prevents the development of a tetanic contraction arranged so that shortening results in a reduction of the vol- (see Fig. 10.2); any failure of cardiac muscle to relax fully af- ume of the heart chamber, and its force or tension results in ter every stimulus would make it quite unsuitable to func- an increase in pressure in the chamber. Because of geomet- tion as a pump. When cardiac muscle is stimulated to con- ric complexities of the intact heart and the complex me- tract more frequently (equivalent to an increase in the heart chanical nature of the blood and aorta, shortening contrac- rate), the durations of the action potential and the contrac- tions of the intact heart muscle are more nearly auxotonic tion become less, and consecutive twitches remain separate than truly isotonic (see Chapter 9). contraction-and-relaxation events. The experimental basis for the present understanding of It must be emphasized that contraction in cardiac mus- cardiac muscle mechanics comes largely from studies done cle is not the result of stimulation by motor nerves. Cells in on isolated papillary muscles from the ventricles of exper- some critical areas of the heart generate automatic and imental animals. A papillary muscle is a relatively long, rhythmic action potentials that are conducted throughout slender muscle that can serve as a representative of the the bulk of the tissue. These specialized cells are called whole myocardium. It can be arranged to function under pacemaker cells (see Chapter 13). the same sort of conditions as a skeletal muscle. Analysis of research results is aided by using simple afterloads to pro- Excitation-Contraction Coupling in Cardiac Muscle. duce isotonic contractions. Despite the limitations these The rapid depolarization associated with the upstroke of simplifications impose, many of the unique properties of the action potential is conducted down the T tubule system the intact heart can be understood on the basis of studies of of the ventricular myocardium, where it causes the release isolated muscle. As the various phenomena are explained of intracellular calcium ions from the SR. In cardiac muscle, here, substitute volume changes for length changes and pressure for a large part of the calcium released during rapid depolar- force. You will then be able to relate the function of the
CHAPTER 10 Cardiac Muscle 181 heart as a pump to the properties of the muscle responsible 3. Isotonic lengthening: the load stretches the muscle for its operation (see Chapter 14). back to its starting length. 4. Isometric relaxation: the force dies away. The Length-Tension Curve. Some aspects of the cardiac The isometric contraction and isotonic shortening muscle length-tension curve are associated with its special- phases of a typical cardiac muscle contraction are like those ized construction and physiological role (Fig. 10.3). Over of skeletal muscle. However, in the intact heart at the peak the range of lengths that represent physiological ventricu- of the shortening, the afterload is removed because of the lar volumes, there is an appreciable resting force that in- closing of the aortic and pulmonary valves at the end of the creases with length; at the length at which active force pro- cardiac ejection phase (see Chapter 14). Since the muscle is duction is optimal, this can amount to 10 to 15% of the not allowed to lengthen (the inflow valves are still closed), total force. Because this resting force exists before contrac- it undergoes isometric relaxation at the shorter length. tion occurs, it is known as preload. In the intact heart, the Some time later, the muscle is stretched back to its original preload sets the resting fiber length according to the in- length by an external force (the returning blood), produc- tracardiac blood pressure existing prior to contraction. The ing an isotonic lengthening (isotonic relaxation) phase. Be- passive tension rises steeply beyond the optimal length and cause the muscle has relaxed, only a small force is required prevents overextension of the muscle (or overfilling of the for the reextension. In the intact heart, this force is supplied heart). Note that the resting force curve is associated with by the returning blood. the diastolic (relaxed) phase of the heart cycle, while the The principal difference between these two cycles is sig- active force curve is associated with the systolic (contrac- nificant: in skeletal muscle, the work done on the afterload tion) phase. (by lifting it) is returned to the muscle. In cardiac muscle, The length-tension curve in Figure 10.3 describes iso- the work done on the load is not returned to the muscle but metric behavior; since the working heart never undergoes is imparted to the afterload. The heart muscle is con- completely isometric contractions (see Chapter 14), other strained by its anatomy and functional arrangements to fol- aspects of length-dependent behavior must be responsible low different pathways during contraction and relaxation. for determining the effect length has on cardiac muscle This pattern is seen clearly when the phases of the con- function. One such aspect is the rate at which isometric traction-relaxation cycle are displayed on a length-tension force develops during a twitch. Notice the series of curve. In Figure 10.4, at the beginning of the contraction (A), twitches shown in Figure 9.10; because of the constancy of force increases without any change in length (isometric con- the time required to reach peak force, the rate of rise of ditions); when the afterload is lifted (B), the muscle shortens force also varies with muscle length. Other length-depend- at a constant force (isotonic conditions) to the shortest ent aspects of contraction are encountered when we exam- length possible for that afterload. The afterload is removed ine the complete contraction cycle of cardiac muscle. at the maximal extent of shortening, and the muscle relaxes (C) without any change in length (isometric conditions The Contraction Cycle of Cardiac Muscle. A typical iso- again, but at a reduced length). With sufficient force applied tonic contraction of skeletal muscle (see Fig. 9.8) can be di- to the resting muscle by some external means (D), the mus- vided into four distinct phases: 1. Isometric contraction: the muscle force builds up to reach the afterload. 2. Isotonic shortening: the afterload is lifted. Normal range of operation Total force Muscle force Active force (systolic) Resting force (diastolic) An afterloaded contraction of cardiac mus- Muscle length FIGURE 10.4 cle, plotted in terms of the length-tension The isometric length-tension curve for iso- curve. The limit to force is provided by the afterload; the limit to FIGURE 10.3 lated cardiac muscle. The total force at all shortening by the length-tension curve. A, isometric contraction physiologically significant lengths includes a resting force com- phase; B, isotonic shortening phase; C, isometric relaxation ponent. phase; D, relengthening. (See text for details.)
182 PART III MUSCLE PHYSIOLOGY cle is elongated back to its starting length. Because the mus- and, thus, interacts with the particular afterload chosen. cle is unstimulated and its resting force rises somewhat dur- With smaller afterloads, the muscle will shorten further ing elongation, this phase is not strictly isotonic. than it would with a larger afterload. It is important to real- In physical terms, the area enclosed by this pathway rep- ize that during isotonic shortening, the muscle force is lim- resents work done by the muscle on the external load. If the ited by the magnitude of the afterload and not by the afterload or the starting length (or both) is changed, then a length-tension capability of the muscle. It is the extent of different pathway will be traced (Fig. 10.5, left). The area shortening at a given afterload that is limited by the length- enclosed will differ with changes in the conditions of con- tension property of the muscle; this is a very important con- traction, reflecting differing amounts of external work de- sideration when measuring cardiac performance under con- livered to the load. In a typical skeletal muscle contraction, ditions of changing blood pressure and filling of the heart as shown in Fig. 10.5 (right), steps A and B are reversed dur- (see Chapter 14). This length- and force-dependent behav- ing relaxation. Such a contraction does no net external ior is the key to autoregulation (self-regulation) by cardiac work, and no area is enclosed by the pathway. muscle and is the functional basis of Starling’s law of the heart (see Chapter 14); when the muscle is set to a longer Cardiac Muscle Self-Regulation. Each case in Figure length at rest, the active contraction results in a greater 10.5 (center and left) demonstrates that the active portion shortening that is also more rapid and is preceded by a of the length-tension curve provides the limit to shortening more rapid isometric phase. This allows the heart to adjust Cardiac muscle contraction cycle Long starting length 4 High load 3 B Muscle force 2 C A 1 D 0 Skeletal muscle contraction cycle 2345 Low afterload Muscle length 4 4 4 Short Long 3 3 3 Muscle force 2 B Afterload Muscle force 2 B Muscle force 2 B C 1 C A 1 C A 1 D A D D 0 0 0 2345 2345 2345 Muscle length Muscle length Muscle length FIGURE 10.5 Afterloaded contractions under a variety of the same initial length. Increasing the afterload reduces the conditions. Left: Cardiac muscle contraction amount of shortening possible, as does decreasing the starting cycles. The horizontal box shows the effect of starting at two dif- length; in both cases, the limit to shortening is determined by the ferent initial lengths at the same afterload. The vertical box shows length-tension curve. Right: The contraction cycle of skeletal the effect of two different afterloads on shortening that begins at muscle. Contraction and relaxation pathways are the same.
CHAPTER 10 Cardiac Muscle 183 its pumping to exactly the amount required to keep the cir- particular afterload is chosen (in this case, 0.5 units), the culatory system in balance. initial shortening velocity varies with the starting length, although the curves do tend to converge at the lowest forces. The curves in Figure 10.7B represent contractions Variable Contractility Facilitates made at the same starting length but with the muscle oper- Essential Physiological Adjustments ating at different levels of contractility. Again there is a dif- Under a wide range of conditions, the contractile behavior ference in shortening velocity at a constant afterload, but of skeletal muscle is fixed and repeatable. The peak force and there is no tendency for the curves to converge at the low shortening velocity depend primarily on muscle length and forces. These examples show only one aspect of the effects afterload, and unless the muscle is worked to fatigue, these of changing contractility; those not illustrated include properties will not change from contraction to contraction. changes in the rate of rise of isometric force and changes in For this reason, skeletal muscle is said to possess fixed con- the time required to reach peak force in a twitch. tractility. Contractility or the contractile state of muscle Ultimately, any change in the muscle contraction will may be defined as a certain level of functional capability (as result in a change in the overall performance of the heart, measured by a quantity such as isometric force, shortening but cardiac performance can change drastically even with- velocity, etc.) when measured at a constant muscle length. out changes in contractility because of length-tension ef- (Length must be held constant to preclude the effects of the fects. The need to distinguish such effects from changes in length-tension curve properties already discussed.) The reg- contractility (to guide treatment and therapy) has led to a ulation of skeletal muscle contraction to produce useful ac- search for aspects of muscle performance that are depend- tivity is primarily the task of the CNS, using the mechanisms ent on the state of contractility but independent of muscle of motor unit summation and partially fused tetani (see length. The results of these studies (based on the properties Chapter 9). Cardiac muscle has no motor innervation, but of isolated muscle) are questionable because the compli- has a capacity for adjustment that is not solely accomplished cated structure and function of the intact heart do not per- by changes in afterload and starting length. mit a reliable extrapolation of findings. Instead, several em- The variable contractility of cardiac muscle enables it to pirical measures have been developed from studies of the make adjustments to the varying demands of the circula- intact heart, some of which provide a reasonable and useful tory system. Certain chemical and pharmacological agents, index of contractility (see Chapter 14). as well as physiological circumstances, affect cardiac con- tractility. The collective term for the influence of such The Cellular Basis of Contractility Changes. The basic agents is inotropy. Contractility is altered by inotropic in- determinant of the variable contractility of cardiac muscle is terventions, agents or processes that change the functional the calcium content in the myocardial cell. Under normal state of cardiac muscle. Positive inotropes are inotropic in- conditions, the contractile filaments of cardiac muscle are terventions that increase contractility and include the ac- only partly activated. This is because, unlike with skeletal tion of adrenergic (sympathetic nervous system) stimula- muscle, not enough calcium is released to occupy all of the tion, bloodborne catecholamine hormones, drugs such as troponin molecules, and not all potentially available cross- the digitalis derivatives, and an increase in the rate of stim- bridges can attach and cycle. An increase in the availability ulation (i.e., increased heart rate). Negative inotropes in- of calcium would increase the number of crossbridges acti- clude a decrease in heart rate, disease processes such as my- vated; thus, contractility would be increased. To understand ocarditis or coronary artery disease, and certain drugs. the mechanisms of contractility change, it is necessary to Chronically reduced contractility can lead to the condition consider the factors affecting cellular calcium handling. known as heart failure (see Clinical Focus Box 10.1). The processes linking membrane excitation to contrac- tion via calcium ions are illustrated in Figure 10.8. Since Effects of Inotropic Interventions. Figure 10.6 shows an this involves many possible movements and locations of increase in contractility plotted on a length-tension graph. calcium, the processes are considered in the order in which It has the effect of shifting the active length-tension curve they would be encountered during a single contraction. upward and to the left; relaxation and the passive curve are The initial event is an action potential (1) traveling minimally affected. Careful experiments have shown that along the cell surface. As in skeletal muscle, the action po- one effect of short muscle length on muscle contraction is tential enters a T tubule (2), where it can communicate with actually a reduction in contractility as a result of inefficien- the SR (3) to cause calcium release. This mechanism for re- cies in the excitation-contraction coupling mechanism at lease of calcium in cardiac muscle is much less than in skele- these lengths. Such effects cannot be separated from other tal muscle and is insufficient to cause adequate activation of length-related effects on cardiac muscle functions, and they the contraction. To some extent, activation is aided by a are usually included without mention in the more familiar calcium-induced calcium release mechanism (4) triggered length-dependent changes in muscle performance. by a rise in the cytoplasmic calcium concentration. The ac- An example of the similarities and differences between tion potential (5) on the cell surface (sarcolemma) also changes in resting length and changes in contractility is causes the opening of calcium channels, through which shown in the force-velocity curves in Figure 10.7. The set strong inward calcium current flows. These calcium ions of curves in Figure 10.7A represents the isotonic behavior accumulate just inside the sarcolemma (6), although some of muscle at a constant level of contractility at three differ- probably diffuse rapidly into the cell interior. Calcium in- ent muscle lengths. The maximum force point on each duces the rapid release of calcium from the subsarcolemmal curve shows the isometric length-tension effect. When a SR, and the calcium then diffuses the short distance to the
184 PART III MUSCLE PHYSIOLOGY CLINICAL FOCUS BOX 10.1 Heart Failure and Muscle Mechanics tribute to diastolic failure. Because the muscle cannot be Heart failure is evident when the heart is unable to main- sufficiently lengthened during its rest period (diastole), it tain sufficient output to meet the body’s normal metabolic begins its contraction at too short a length. As the length- needs. It is usually a progressively worsening condition. tension curve would predict, the muscle is unable to The condition is due to either deterioration of the heart shorten sufficiently to pump an adequate volume of blood muscle or worsening of the contributing factors external to with each beat. Because the force-velocity curve is also the heart. The term congestive heart failure refers to fluid length-dependent, the speed at which the muscle can congestion of the lungs that often accompanies heart fail- shorten is also reduced. ure. Treatment of heart failure involves approaches that af- Patients suffering from heart failure may be unable to fect several areas of muscle mechanics. Drugs that in- perform simple everyday tasks without fatigue or short- crease the contractility of cardiac muscle, such as digitalis ness of breath. In later stages, there may be significant dis- and its derivatives, may be used to cause more effective tress even while resting. While many intrinsic and extrinsic contraction and allow the muscle to operate along an im- factors contribute to the condition, this discussion will fo- proved force-velocity curve. Most contractility-increasing cus on those closely related to the mechanical properties drugs work by increasing the amount of intracellular cal- of the heart muscle. cium available to the myofilaments, thereby increasing the Much of poor cardiac function can be understood in number of crossbridges participating in the contractions. terms of the mechanics of the heart muscle as it interacts Care must be taken, however, that the increased contrac- with several external factors that determine the resting tility does not create a metabolic demand that would fur- muscle length (or preload) or the load against which it ther weaken the muscle. Drugs that blunt the response of must contract (the afterload). The most important aspects the heart to the excitatory action of the sympathetic nerv- of the mechanical behavior are described by the length- ous system (which affects both heart rate and muscle con- tension and force-velocity curves, which, together with tractility) can protect against an increased workload. Drugs knowledge of the current state of contractility, can provide that lower blood pressure by their effects on the arterial a complete picture of the muscle function. muscle will reduce the load against which the heart mus- Some heart failure is of the systolic type. If the heart cle must contract, and the muscle can operate on a more has been damaged by a myocardial infarction (heart at- efficient portion of the force-velocity curve. Drugs or di- tack) or ischemia (impaired blood supply to the heart etary regimens that reduce blood volume (via increased re- muscle) or by chronic overload (as with untreated high nal excretion of salt and water) can also lower the load blood pressure), the muscle may become weakened and against which the muscle must contract; the same is true have reduced contractility. In this case, the load pre- of drugs that cause relaxation of the muscle in the walls of sented to the heart by the blood pressure is too high (rel- the venous system. Lowering the blood volume also acts ative to the weakened condition of the muscle), and (as to decrease the over-distension of the heart during dias- the force-velocity curve describes) the rate of shortening tole. While it would seem that an increase in the resting (velocity) of the muscle will be reduced. The length-ten- muscle length would have a beneficial effect on the sion curve indicates that the larger the load, the less the strength of contraction, geometric factors in the intact shortening (see Fig. 10.5). Therefore, less blood will be heart place the overstretched muscle at a mechanical dis- pumped with each beat. Therapy for this type of failure in- advantage that the length-tension curve cannot ade- volves improving the contractility of the muscle and/or re- quately overcome. ducing the load on the heart. Heart failure involves numerous interacting organ sys- Heart failure can also be of the diastolic type (and may tems. The mechanical behavior of the heart muscle, as un- occur along with systolic failure). Here the relaxation is derstood in the context of the length-tension and force-ve- impaired, and the muscle is resistant to the stretch that locity curves, is only a part of the problem. Effective must take place during its filling with blood. Some types of therapy must also consider factors external to the heart hypertrophy or connective tissue fibrosis also may con- muscle itself. myofilaments (7) and activates them. The amount of cal- This mechanism is part of a coupled transport system in which cium in the cytoplasm, the cytosolic calcium pool, deter- three sodium ions, entering the cell down their electrochemi- mines the magnitude of the myofilament activation and, cal gradient, are exchanged for the ejection of one calcium ion. hence, the level of contractility. Proper function of this exchange mechanism requires a steep During relaxation, the cytoplasmic calcium concentration sodium concentration gradient, maintained by the membrane is rapidly lowered through several pathways. The SR mem- Na /K -ATPase (11) located in the sarcolemma. Because the 2 brane contains a vigorous Ca -ATPase (8) that runs continu- Na /Ca 2 exchange mechanism derives its energy from the ously and is further activated, through a protein phosphoryla- sodium gradient, any reduction in the pumping action of the tion mechanism, by high levels of cytoplasmic calcium. At the Na /K -ATPase leads to reduced calcium extrusion. Under level of the sarcolemma, two additional mechanisms work to normal conditions, these mechanisms can maintain a 10,000- rid the cell of the calcium that entered via previous action po- fold Ca 2 concentration difference between the inside and 2 tentials. A membrane Ca -ATPase (9) actively extrudes cal- outside of the cell. Since a cardiac cell contracts repeatedly cium, ejecting one calcium ion for each ATP molecule con- many times per minute with each beat being accompanied by sumed. Additional calcium is removed by a Na /Ca 2 an influx of calcium, the extrusion mechanisms must also work exchange mechanism (10), also located in the cell membrane. continuously to balance the incoming calcium. The mito-
CHAPTER 10 Cardiac Muscle 185 indicators of contractility) increases. This is the basis of the force-frequency relationship, one of the principal means of changing myocardial contractility. Cardiac glycosides are an important class of therapeutic agents used to increase the contractility of failing hearts. The drug digitalis, used for centuries for its effects on the circulation, is typical of these agents. While some details of its action are obscure, the drug has been shown to work by inhibiting the membrane Na /K -ATPase. This allows the cell to gain sodium and reduces the steepness of the sodium gradient. This makes the Na /Ca 2 exchange mechanism less effective, and the cell gains calcium. Since more cal- cium is available to activate the myofilaments, contractility increases. These effects, however, can lead to digitalis tox- icity when the cell gains so much calcium that the capacity of the sarcoplasmic and sarcolemmal binding sites is ex- ceeded. At this point, the mitochondria begin to take up the excess calcium; however, too much mitochondrial cal- Effect of enhanced contractility on the con- FIGURE 10.6 cium interferes with ATP production. The cell, with its traction cycle of cardiac muscle. When con- ATP needs already increased by enhanced contractility, is tractility is increased, the rate of rise of force is increased, the time less able to pump out accumulated calcium, and the final re- to afterload force is decreased, and potential force is increased. The muscle shortens faster and further (A) while isometric relaxation sult is a lowering of metabolic energy stores and a reduction (B) and relengthening (C) are minimally affected (D). in contractility. Some changes in the contractility of car- diac muscle may be permanent and life threatening. Many of these changes are due to disease or factors external to the chondria of cardiac muscle (12) are also capable of accumulat- heart and may be described by the general term cardiomy- ing and releasing calcium, although this system does not ap- opathy (see Clinical Focus Box 10.2). pear to play a role in the normal functioning of the cell. Sources of Energy for Cardiac Muscle Function Calcium and the Function of Inotropic Agents. Inotropic agents usually work through changes in the internal cal- In contrast to skeletal muscle, cardiac muscle does not cium content of the cell. An increase in the heart rate, for have the opportunity to rest from a period of intense ac- instance, allows more separate influxes of calcium per tivity to “pay back” an oxygen debt. As a result, the me- minute, and the amount of releasable calcium in the subsar- tabolism of cardiac muscle is almost entirely aerobic un- colemmal space and SR increases. More crossbridges are der basal conditions and uses free fatty acids and lactate as activated, and the force of isometric contraction (and other its primary substrates. This correlates with the high con- A. Length changes B. Contractility changes Afterload = 0.5 Afterload = 0.5 10 10 Velocity at: Velocity at: Long High Velocity 5 Medium Velocity 5 Normal Short muscle length Low contractility 0 0 0 1 23 0 1 243 Force Force FIGURE 10.7 Effect of length and contractility changes on sible to make a direct measure of a zero-force contraction at each the force-velocity curves of cardiac muscle. length. There is a tendency for the curves to converge at the lower A, Decreased starting length (with constant contractility) produces forces. B, Increased contractility produces increased velocity of lower velocities of shortening at a given afterload. Because of the shortening at a constant muscle length, but there is no tendency for presence of resting force (characteristic of heart muscle), it is impos- the curves to converge at the low forces.
186 PART III MUSCLE PHYSIOLOGY tent of mitochondria in the cells and with the high cellu- lar content of myoglobin. Under conditions of hypoxia (lack of oxygen), the anaerobic component of the metab- olism may approach 10% of the total, but beyond that limit, the supply of metabolic energy is insufficient to sus- tain adequate function. The substrates that provide chemical energy input to the heart during periods of increased activity consist of carbo- hydrates (mostly in the form of lactic acid produced as a re- sult of skeletal muscle exercise; see Chapters 8 and 9), fats (largely as free fatty acids), and, to a small degree, ketone body acids and amino acids. The relative amounts of the various metabolites vary according to the nutritional status of the body. Because of the highly aerobic nature of cardiac muscle metabolism, there is a strong correlation between the amount of work performed and the amount of oxygen consumed. Under most conditions, the contraction of car- diac muscle in the intact heart is approximately 20% effi- cient, with the remainder of the energy going to other cel- lular processes or wasted as heat. Regardless of the dietary or metabolic source of energy, ATP (as in all other muscle types) provides the immediate energy for contraction. As in The paths of calcium in and out of the car- skeletal muscle, cardiac muscle contains a “rechargeable” FIGURE 10.8 diac muscle cell and its role in the regula- creatine phosphate buffering system that supplies the tion of contraction. (See text for details.) short-term ATP demands of the contractile system. CLINICAL FOCUS BOX 10.2 Cardiomyopathies: Abnormalities of Heart Muscle does the actual damage to the muscle. This damage may Heart disease takes many forms. While some of these are occur at the subcellular level by interfering with energy related to problems with the valves or the electrical con- metabolism while producing little apparent structural dis- duction system (see Chapters 13 and 14), many are due to ruption. Such conditions, which can usually only be diag- malfunctions of the cardiac muscle itself. These condi- nosed by direct muscle biopsy, are difficult to treat effec- tions, called cardiomyopathy, result in impaired heart tively, although spontaneous recovery can occur. function that may range from being essentially asympto- Excessive and chronic consumption of alcohol can also matic to malfunctions causing sudden death. cause cardiomyopathy that is often reversible if total absti- There are several types of cardiomyopathy, and they nence is maintained. In tropical regions, infection with a have several causes. In hypertrophic cardiomyopathy, trypanosome (Chagas’ disease) can produce chronic car- an enlargement of the cardiac muscle fibers occurs be- diomyopathy. The tick-borne spirochete infection called cause of a chronic overload, such as that caused by hyper- Lyme disease can cause heart muscle damage and lead tension or a defective heart valve. Such muscle may fail to heart block, a conduction disturbance (see Chapter 13). because its high metabolic demands cannot be met, or fa- Another important kind of cardiomyopathy arises from tal electrical arrhythmias may develop (see Chapter 13). ischemia, an inadequate oxygen (blood) supply to working Congestive or dilated cardiomyopathy refers to car- cardiac muscle. An acute ischemic episode may be fol- diac muscle so weakened that it cannot pump strongly lowed by a stunned myocardium, with reduced me- enough to empty the heart properly with each beat. In re- chanical performance. Chronic ischemia can produce a hi- strictive cardiomyopathy, the muscle becomes so stiff- bernating myocardium, also with reduced mechanical ened and inextensible that the heart cannot fill properly be- performance. Ischemic tissue has impaired calcium han- tween beats. Chronic poisoning with heavy metals, such as dling, which can lead to destructively high levels of inter- cobalt or lead, can produce toxic cardiomyopathy. The nal calcium. These conditions can be improved by reestab- skeletal muscle degeneration associated with muscular lishing an adequate oxygen supply (e.g., following clot dystrophy is often accompanied by cardiomyopathy (see dissolution or coronary bypass surgery), but even this Chapter 8). treatment is risky because rapidly restoring the blood flow The cardiomyopathy arising from viral myocarditis is to ischemic tissue can lead to the production of oxygen difficult to diagnose and may show no symptoms until radicals that cause significant cellular damage. The use of death occurs. The action of some enteroviruses (e.g., cox- calcium blockers and free radical scavengers, such as vita- sackievirus B) may cause an autoimmune response that min E, following ischemic episodes may limit this damage.
CHAPTER 10 Cardiac Muscle 187 REVIEW QUESTIONS DIRECTIONS: Each of the numbered (D) The electrical activity is conducted (A) The resting muscle length from which items or incomplete statements in this too slowly for tetanus to occur contraction begins section is followed by answers or 5. The contraction cycle for cardiac (B) The size of the preload, which sets completions of the statement. Select the muscle differs in significant ways from the initial length ONE lettered answer or completion that is that of skeletal muscle. Which (C) The size of the afterload during BEST in each case. situation below is more typical of isotonic shortening cardiac muscle? (D) The rate (velocity) at which the 1. Which of the following sets of attrib- (A) The cycle involves only isometric muscle shortens utes best characterizes cardiac muscle? contraction and relaxation 9. The factor common to most changes in (A) Large cells, electrically isolated, (B) Isometric relaxation occurs at a cardiac muscle contractility is the neurally stimulated shorter length than isometric (A) Amplitude of the action potential (B) Small cells, electrically coupled, contraction (B) Availability of cellular ATP chemically stimulated (C) The muscle relaxes along the same (C) Cytoplasmic calcium (C) Small cells, electrically coupled, combination of lengths and forces that concentration spontaneously active it took during contraction (D) Rate of neural stimulation (D) Small cells, electrically isolated, (D) The complete cycle in cardiac 10.At a given muscle length, the velocity spontaneously active muscle is isotonic of contraction depends on 2. Cardiac muscle functions as both an 6. What is the physiological role of the (A) Only the afterload electrical and a mechanical syncytium. passive length-tension curve in cardiac (B) Only the contractility of the The structural basis of this ability muscle? muscle is the (A) It ensures that force stays constant (C) Both the contractility and the (A) T tubule system as the muscle is stretched afterload (B) Intercalated disks (B) It allows the muscle to be extended (D) Only the preload because the (C) Striated nature of the contractile without limit when it is at rest contractility is constant system (C) It lets the resting muscle length (D) Extensive SR to be set in proportion to the 3. The regulation of contraction in preload SUGGESTED READING cardiac muscle is (D) It prevents a contraction from American Heart Association. Website: (A) Most like that of smooth muscle having an isometric phase at shorter http://www.americanheart.org. (i.e., myosin-linked) lengths Braunwald EG, Ross JR, Sonnenblick EH. (B) Most like that of skeletal muscle 7. Why does cardiac muscle shorten less Mechanisms of Contraction of the (i.e., actin-linked) at higher afterloads? Normal and Failing Heart. Boston: Lit- (C) Independent of filament-related (A) Higher loads cause a reduction in tle, Brown, 1976. proteins contractility and this limits the Heller LJ, Mohrman DE. Cardiovascular (D) Dependent on autonomic neural shortening Physiology. New York: McGraw-Hill, stimulation (B) Higher loads cause rapid fatigue, 1981. 4. What prevents cardiac muscle from which limits the shortening Ford LE. Muscle Physiology and Cardiac undergoing a tetanic contraction? (C) Moving a heavy load causes Function. Carmel, IN: Biological Sci- (A) The rate of neural stimulation is premature relaxation ences Press-Cooper Group, 2000. limited by the CNS (D) It encounters the limit set by the Katz AM. Physiology of the Heart. 2nd (B) The muscle fatigues so quickly that length-tension curve with less Ed. New York: Raven, 1992. it must relax fully between contractions shortening Noble D. The Initiation of the Heart- (C) The refractory period of the action 8. What factor provides the most beat. Oxford: Oxford University potential lasts into the relaxation phase important limit to force production in Press, 1979. of the contraction cardiac muscle? WebMD. Website: http://www.webmd.org. CASE STUDIES FOR PART III • • • CASE STUDY FOR CHAPTER 8 four limbs, but the woman does not complain of muscu- lar soreness. She is somewhat underweight, slightly Polymyositis in an Older Patient short of breath, and speaks in a low voice. Laboratory A 67-year-old woman consulted her physician because of tests show a moderately elevated creatine kinase level. recent and progressive muscle weakness. She reported There is no family history of muscle problems, and she is difficulty in rising out of a chair and had intermittent diffi- not currently taking any medication. culty in swallowing. Physical examination reveals the Because of the symptoms present, no muscle biopsy presence of a light purple rash around her eyes and on or electromyographic study is carried out. A tentative di- her knuckles and elbows. Muscle weakness is noted in all agnosis of polymyositis/dermatomyositis was made. The (continued)
188 PART III MUSCLE PHYSIOLOGY woman is placed on high-dose prednisone, and arrange- steroidal drug to manage the pain and inflammation and ments are made for periodic tests for circulating muscle is told to lessen the pain by applying ice packs to the af- enzymes. Because of her age, she is referred to a cancer fected region. He is advised to avoid stair climbing as specialist to screen for a possible underlying malig- much as possible during this time, but to begin walking nancy, and physical therapy is strongly recommended. as soon as he could do it without undue pain. On a fol- In follow-up visits, the woman shows gradual im- low-up visit 2 weeks later, he is experiencing little im- provement in muscle strength, and her rash is much less pairment in walking, although the strength of the leg is apparent. No malignancy is detected. She maintains a still less than normal and stair climbing is still somewhat regimen of physical therapy and is able to have the pred- of a problem. He is advised to return to regular activity, nisone dosage progressively reduced over the course of but to avoid any undue overloading of the affected leg the next year. for the foreseeable future. Questions Questions 1. What was a likely cause for the patient’s underweight condi- 1. What kind of contraction was the injured muscle undergo- tion? ing at the time of the injury? Why does this kind of activity 2. Could the shortness of breath also have been a result of pose a special risk for injury? polymyositis? 2. What factors contributed to the occurrence and severity of 3. Does the pattern of recovery suggest that the diagnosis was this injury? correct? 3. Why was the pain localized to the lower portion of the 4. What was the underlying cause of her disease? thigh? Answers to Case Study Questions for Chapter 8 4. What sort of activity would be most likely to reinjure the 1. Patients with polymyositis involving the pharyngeal and muscle? esophageal muscles have difficulty swallowing. This leads 5. What precautions should be taken to avoid reinjury? to reduced nutritional intake, to the point where it may be 6. Why was the patient given a limited supply of the pain med- life threatening. ication? 2. Although several things could contribute to shortness of Answers to Case Study Questions for Chapter 9 breath, weakness of the respiratory muscles can lead to hy- 1. The muscle was undergoing an eccentric contraction; that poventilation; this, too, can be life threatening. is, the muscle was activated in order to break the fall upon 3. The response to therapy was what one would expect for a landing, and the body weight extended it while it was ac- person suffering from polymyositis. Conditions such as tive. Such a stretch can produce a force considerably in ex- muscular dystrophy would not have responded as well to cess of the maximal isometric capability of a muscle. the prednisone therapy. 2. The first factor was the sudden eccentric contraction (see 4. Because a malignancy was ruled out, this case must be con- above). Second, because the patient was not accustomed to sidered, like most cases of polymyositis, to be of idiopathic the activity in question, the muscle was not conditioned to origin. absorb the suddenly applied stretch. Third, the height from References which the patient jumped could potentially generate a force Dalakas MC, ed. Polymyositis and Dermatomyositis. London: considerably greater than the capability of the muscle. Butterworth, 1988. 3. The pain was localized in the general area of the myotendi- Maddison PJ, et al., eds. Oxford Textbook of Rheumatology. nous junction, the area where damage is most likely to oc- Vol 2. New York: Oxford University Press, 1993. cur. 4. Given the same conditions, a similar jump to the one caus- CASE STUDY FOR CHAPTER 9 ing the injury would be quite likely to result in reinjury. In general, any activity that would lead to an eccentric contrac- A Muscle-Pull Injury tion of the muscle would put it at risk. This would explain A 35-year-old man visited his family physician early on a the caution against stair climbing during the early stages of Monday morning. He walked into the waiting room with recovery. a pronounced limp, favoring his right leg, and was in ob- 5. There should be a gradual return to full activity, with ade- vious discomfort. When he arose from the waiting-room quate time for healing and repair, without any sudden in- chair, it was with some difficulty and with considerable crease in the use of the muscle. The initial precipitating be- assistance from his arms and his left leg. He related that, havior should be avoided. during the weekend, he had been putting up a swing in a 6. The use of the anti-inflammatory medication should be lim- backyard tree for his children. At one point during the ited because its continued use has been shown to delay the work, he jumped to the ground from a ladder leaning healing process, and it could also mask warning signs of against the tree, a distance of about 4 feet. As he landed, reinjury. he felt a sharp pain in the front of his right thigh, and he References fell to his knees upon landing. He was immediately in Best TM. Soft-tissue injury and muscle tears. Clin Sports Med considerable discomfort, and the pain did not lessen 1997;16:419–434. over the course of the weekend. Garrett WE. Muscle strain injuries. Am J Sports Med Physical examination reveals a somewhat swollen as- 1996;24:S2–S8. pect to the lower part of the anterior surface of his right thigh. The area is tender to the touch, but the pain does CASE STUDY FOR CHAPTER 10 not involve the knee joint. Using the left leg for compari- son, he is considerably impaired in his ability to extend Heart Failure the lower portion of his right leg and doing so causes A 50-year-old man consulted his family physician with great discomfort. the principal complaint of shortness of breath and fa- After the physical examination, he is told that he has tigue upon rather mild exertion and a recent weight gain. most likely experienced a strain (or “pull”) of the rectus He appears to be rather pale, moderately overweight, femoris muscle. He is given a few days’ supply of a non- and somewhat short of breath from walking from his car (continued)
CHAPTER 10 Cardiac Muscle 189 to the office. A careful history yields several pieces of in- 7. Did the beneficial effects of his therapy relate more to formation: He has been a light smoker for most of his changes in contractility or to changes in the mechanical sit- adult life, although he has tried to quit; he attributes his uation of the heart muscle? morning cough, which resolves after being up for a 8. What is the benefit of a drug that tends to relax both arterial while, to the smoking habit. He reports that sometimes and venous smooth muscle? he awakens suddenly during the night with a feeling of Answers to Case Study Questions for Chapter 10 suffocation; sitting upright for a while makes this feeling 1. Because of the continuous overload of the heart muscle, it go away. He has been treated for chronic hypertension, had hypertrophied. At this stage of the patient’s disease, but is no longer taking his prescribed medication. Minor however, even the added muscle strength was not sufficient chest pain that he associates with heavy exertion quickly to handle the demands of the body during exercise. ceases on resting. 2. With a lowered systolic pressure, the afterload during short- Physical examination notes some swelling of his an- kles and feet, and palpation reveals a somewhat en- ening would be reduced. An examination of the length-ten- larged and tender liver. Distinct basilar rales (abnormal sion curve shows that more shortening would be possible, sounds that indicate pulmonary congestion) are heard and the force-velocity curve would predict that the contrac- during auscultation of the chest. A chest X-ray shows tion would also be more rapid. moderate enlargement of the heart, and the same find- 3. The use of drugs such as digitalis could have relieved the ing (cardiomegaly) was apparent in an ultrasound exam- patient’s symptoms sooner, but the risks of such drugs ination. (heart rhythm disturbances, systemic and cardiac toxicity, The patient is placed on a mild diuretic, along with a etc.) make it advisable, if at all possible, to let the inherent drug designed to relax the smooth muscle in the walls of properties of the muscle, when properly aided, to correct both arteries and veins. He is advised to limit salt intake the problem. to less than 4 grams per day; other dietary restrictions 4. The diuretic therapy reduced the blood volume, which include a reduction in the amount of saturated fat and meant that the heart muscle was less distended at rest. A red meat. He is advised that moderate exercise, such as lowered arterial volume would have also lowered the after- walking, would be beneficial if it is tolerated well. He is load on the muscle. Thus, both aspects of the problem were referred to a support program to help him quit smoking. addressed. During the next few weeks, significant improvement 5. Because the cough went away soon after arising, it was in exercise tolerance is noted, and both systolic and dias- more likely a result of fluid accumulation in the lungs. The tolic blood pressures are reduced. His weight has de- creased somewhat. The abnormal lung sounds are ab- increased heart rate and contractility of the muscle associ- sent, and he has been able to quit smoking. ated with waking activity would have at least partly over- come this problem as the day progressed. Questions 6. The feeling of fatigue is related to the lack of blood circula- 1. The X-ray and ultrasound data show an increase in the tion in the skeletal muscle. This was most directly related to amount of heart muscle. If this was the case, why did the the weakened state of the heart muscle during contraction, patient suffer from the problems reported above? which would reduce the amount of blood that could be 2. What effect would lowering the systolic blood pressure pumped with each beat. have on the ability of the heart muscle to shorten. Why? 7. Because the patient was not given drugs that directly ad- 3. This patient was not treated with contractility-enhancing dressed the contractility of the muscle, the beneficial drugs. Would such medication have been helpful in this changes must have come about principally through the re- case? duction of the preload and afterload on the muscle. 4. Did the result of the diuretic therapy relate most directly to 8. Such drugs can address problems of both excessive after- the properties of the muscle at rest or during contraction? 5. Was the patient’s morning cough most likely a result of load and preload at the same time. smoking? Reference 6. Did the complaint of fatigue during exercise relate more Poole-Wilson PA, Colucci WS, Massie BM, Chatterjee K, Coats strongly to problems of the muscle at rest or during con- AJS. Heart Failure: Scientific Principles and Clinical Practice. traction? New York: Churchill Livingstone, 1997.
Blood and Cardiovascular PART IV Physiology CHAPTER Components, Immunity, 11 and Hemostasis 11 Denis English, Ph.D. CHAPTER OUTLINE ■ THE COMPONENTS OF BLOOD ■ HEMOSTASIS ■ THE IMMUNE SYSTEM KEY CONCEPTS 1. Blood functions as a dynamic tissue. 7. In protecting the body against irritants and pathogens, the 2. Blood consists of erythrocytes, leukocytes, and platelets process of inflammation often results in the destruction of suspended within a solute-rich plasma. healthy tissue. 3. Erythrocytes carry oxygen to the tissues. 8. Adaptive immunity is specific and acquired. 4. Leukocytes protect the body against pathogens. 9. During clotting, platelets release biologically active cofac- 5. Platelets and plasma proteins control hemostasis, a tors, which promote wound healing, process that stops blood loss after injury and promotes 10. inflammation, angiogenesis (blood vessel formation), and wound healing. host defense. 6. Blood cells are derived from bone marrow precursors. lood is a highly differentiated, complex living tissue the blood. These cells, also known as leukocytes, exert their Bthat pulsates through the arteries to every part of the effects in conjunction with antibodies and protein cofactors body, interacts with individual cells via an extensive capil- in blood. In this chapter, we will see how certain leukocytes lary network, and returns to the heart through the venous act without prior sensitization to neutralize offending system. Many of the functions of blood are undertaken in pathogens, while others require a prior infectious insult to the capillaries, where the blood flow slows dramatically, al- deal with invaders. lowing the efficient diffusion and transport of oxygen, glu- In addition to infectious assault, the body is continually cose, and other molecules across the monolayer of en- threatened by the devastating consequences of vascular dothelial cells that form the thin capillary walls. In addition leak or hemorrhage as a result of even the most innocuous to transport, blood and the cells within it mediate other es- tissue injury. A highly organized clotting system, consist- sential aspects of immunity and hemostasis. ing of blood platelets that work in conjunction with blood The human body is continually invaded by pathogenic plasma clotting factors, prevents excessive fluid loss by rap- microorganisms that enter through skin cuts, mucous mem- idly forming a hemostatic plug. In addition to physically branes, and other sites of infection and tissue disruption. To constraining fluids within ruptured vessels, platelets release oppose pathogenic microbes, the body has developed a potent biological cofactors during the development of this highly sophisticated immune system. Cells of the immune hemostatic plug, which promote wound healing, prevent system, the white blood cells, are derived from bone mar- further infection, and promote the development and vascu- row precursors and are delivered to their sites of action by larization of new tissue. 191
192 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY THE COMPONENTS OF BLOOD Blood is an opaque, red liquid consisting of several types of cells suspended in a complex, amber fluid known as plasma. When blood is allowed to clot or coagulate, the suspending medium is referred to as serum. Blood Has a Higher Density and Viscosity than Water Blood is normally confined to the circulation, including the heart and the pulmonary and systemic blood vessels. Blood accounts for 6 to 8% of the body weight of a healthy adult. The blood volume is normally 5.0 to 6.0 L in men and 4.5 to 5.5 L in women. The density (or specific gravity) of blood is approxi- mately 1.050 g/mL. Density depends on the number of Determination of the erythrocyte sedimen- blood cells present and the composition of the plasma. The FIGURE 11.1 tation rate (ESR). Fresh, anticoagulated blood density of individual blood cells varies according to cell is allowed to settle at room temperature in a graduated cylinder. type and ranges from 1.115 g/mL for erythrocytes to 1.070 After a fixed time interval (1 hour), the distance (in millimeters) g/mL for certain leukocytes. that the erythrocytes sediment is measured. While blood is only slightly heavier than water, it is cer- tainly much thicker. The viscosity of blood, a measure of resistance to flow, is 3.5 to 5.5 times that of water. Blood’s Determination of hematocrit values is a simple and im- viscosity increases as the total number of cells present in- portant screening diagnostic procedure in the evaluation of creases and when the concentration of large molecules hematological disease. Hematocrit values of the blood of (macromolecules) in plasma increases. At pathologically healthy adults are 47 5% for men and 42 5% for high viscosity, blood flows poorly to the extremities and in- women. Decreased hematocrit values often reflect blood ternal organs. loss as a result of bleeding or deficiencies in blood cell pro- duction. Low hematocrit values indicate the presence of anemia, a reduction in the number of circulating erythro- The Erythrocyte Sedimentation Rate cytes. Increased hematocrit levels may likewise indicate a and Hematocrit Are Important serious imbalance in the production and destruction of red Diagnostic Measurements cells. Increased production (or decreased rate of destruc- tion) of erythrocytes results in polycythemia, as reflected Erythrocytes are the red cells of blood. Since erythrocytes have only a slightly higher density than the suspending by increased hematocrit values. Dehydration, which de- plasma, they normally settle out of whole blood very creases the water content and, thus, the volume of plasma, slowly. To determine the erythrocyte sedimentation rate also results in an increase in hematocrit. (ESR), anticoagulated blood is placed in a long, thin, grad- uated cylinder (Fig. 11.1). As the red cells sink, they leave Blood Functions as a Dynamic Tissue behind the less dense leukocytes and platelets in the sus- pending plasma. Erythrocytes in the blood of healthy men While the cellular and plasma components of blood may sediment at a rate of 2 to 8 mm/hr; those in the blood of act alone, they often work in concert to perform their func- healthy women sediment slightly faster (2 to 10 mm/hr). tions. Working together, blood cells and plasma proteins The ESR can be an important diagnostic index, as values play several important roles, including are often significantly elevated during infection, in patients • Transport of substances from one area of the body to with arthritis, and in patients with inflammatory diseases. In another some diseases, such as sickle-cell anemia, polycythemia (ab- • Immunity, the body’s defense against disease normal increase in red cell numbers), and hyperglycemia • Hemostasis, the arrest of bleeding (elevated blood sugar levels), the ESR is slower than normal. • Homeostasis, the maintenance of a stable internal envi- The reasons for alterations in the ESR in disease states are ronment not always clear, but the cells tend to sediment faster when the concentration of plasma proteins increases. Transport. Blood carries several important substances Blood cells can be quickly separated from the suspend- from one area of the body to another, including oxygen, ing fluid by simple centrifugation. When anticoagulated carbon dioxide, antibodies, acids and bases, ions, vitamins, blood is placed in a tube that is rotated about a central cofactors, hormones, nutrients, lipids, gases, pigments, point, centrifugal forces pull the blood cells from the sus- minerals, and water. Transport is one of the primary and pending plasma. The hematocrit is the portion of the total most important functions of blood, and blood is the pri- blood volume that is made up of red cells. This value is de- mary means of long-distance transport in the body. Sub- termined by the centrifugation of small capillary tubes of stances can be transported free in plasma, bound to plasma anticoagulated blood to pack the cells. proteins, or within blood cells.
CHAPTER 11 Blood Components, Immunity, and Hemostasis 193 Oxygen and carbon dioxide are two of the more impor- tant molecules transported by blood. Oxygen is taken up TABLE 11.1 Some Components of Plasma by the red cells as they pass through capillaries in the lung. In tissue capillaries, red cells release oxygen, which is then Normal used by respiring tissue cells. These cells produce carbon Concentration dioxide and other wastes. Class Substance Range The blood also transports heat. By doing so, it maintains Cations Sodium (Na ) 136–145 mEq/L the proper temperature in different organs and tissues, and Potassium (K ) 3.5–5.0 mEq/L in the body as a whole. Calcium (Ca ) 4.2–5.2 mEq/L 2 2 Magnesium (Mg ) 1.5–2.0 mEq/L 3 Immunity. Blood leukocytes are involved in the body’s Iron (Fe ) 50–170 g/dL 2 battle against infection by microorganisms. While the skin Copper (Cu ) 70–155 g/dL and mucous membranes physically restrict the entry of in- Hydrogen (H ) 35–45 nmol/L fectious agents, microbes constantly penetrate these barri- Anions Chloride (Cl ) 95–105 mEq/L 22–26 mEq/L ers and continuously threaten internal infection. Blood Bicarbonate (HCO 3 ) 0.67–1.8 mEq/L Lactate leukocytes, working in conjunction with plasma proteins, Sulfate (SO 4 ) 0.9–1.1 mEq/L 2 continuously patrol for microbial pathogens in the tissues Phosphate 3.0–4.5 mg/dL and in the blood. In most cases, penetrating microbes are (HPO 4 /H 2 PO 4 ) 2 efficiently eliminated by the sophisticated and elaborate Proteins Total 6–8 g/dL antimicrobial systems of the blood. Albumin 3.5–5.5 g/dL Globulin 2.3–3.5 g/dL Hemostasis. Bleeding is controlled by the process of he- Fats Cholesterol 150–200 mg/dL mostasis. Complex and efficient hemostatic mechanisms Phospholipids 150–220 mg/dL have evolved to stop hemorrhage after injury, and their fail- Carbohydrates Triglycerides 35–160 mg/dL 70–110 mg/dL Glucose ure can quickly lead to fatal blood loss (exsanguination). Vitamins, 200–800 pg/mL Both physical and cellular mechanisms participate in he- cofactors, and Vitamin B 12 0.15–0.6 g/mL Vitamin A mostasis. These mechanisms, like those of the immune sys- enzymes Vitamin C 0.4–1.5 mg/dL tem, are complex, interrelated, and essential for survival. 2,3-Diphosphoglycerate 3–4 mmol/L (DPG) Homeostasis. Homeostasis is a steady state that provides Transaminase (SGOT) 9–40 U/mL an optimal internal environment for cell function (see Alkaline phosphatase 20–70 U/L Chapter 1). By maintaining pH, ion concentrations, osmo- Acid phosphatase 0.5–2 U/L 0.6–1.2 mg/dL lality, temperature, nutrient supply, and vascular integrity, Other substances Creatinine 0.18–0.49 mmol/L Uric Acid the blood system plays a crucial role in preserving home- Blood urea nitrogen 7–18 mg/dL ostasis. Homeostasis is the result of normal functioning of Iodine 3.5–8.0 g/dL the blood’s transport, immune, and hemostatic systems. CO 2 23–30 mmol/L Bilirubin (total) 0.1–1.0 mg/dL Aldosterone 3–10 ng/dL Plasma Contains Many Important Solutes Cortisol 5–18 g/dL Ketones 0.2–2.0 mg/dL Plasma is composed mostly of water (93%) with various dissolved solutes, including proteins, lipids (fats), carbohy- drates, amino acids, vitamins, minerals, hormones, wastes, cofactors, gases, and electrolytes (Table 11.1). The solutes gest and destroy invading microorganisms. Eosinophils and basophils are polymorphonuclear cells that are present in plasma play crucial roles in homeostasis, such as main- in low numbers in blood (1 to 6% of total leukocytes) and taining normal plasma pH and osmolality. participate in allergic hypersensitivity reactions. Mononu- clear cells, including monocytes and lymphocytes, com- prise 20 to 50% of the total leukocytes. These cells gener- There Are Three Types of Blood Cells ate antibodies and mount cellular immune reactions against Blood cells include erythrocytes (red blood cells), invading agents. leukocytes (white blood cells), and platelets (thrombo- The number and relative proportion of the leukocyte cytes). Each microliter (a millionth of a liter) of blood subtypes can vary widely in different disease states. For ex- contains 4 to 6 million erythrocytes, 4,500 to 10,000 ample, the absolute neutrophil count often increases during leukocytes, and 150,000 to 400,000 platelets. There are infection, presumably in response to the infection. several subtypes of leukocytes, defined by morphological Eosinophil counts increase when allergic individuals are ex- differences (Fig. 11.2), each with vastly different func- posed to allergens. Lymphocyte counts decrease in AIDS tional characteristics and capabilities. Table 11.2 lists the and during some other viral infections. For this reason, in normal circulating levels of different blood cell types. addition to a blood cell count, a differential analysis of Of the total leukocytes, 40 to 75% are neutrophilic, leukocyte subtypes, performed by microscopic examina- polymorphonuclear (multinucleated) cells, otherwise tion of stained slides, can provide important clues to the di- known as neutrophils. These phagocytic cells actively in- agnosis of disease.
194 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY (ATP). The plasma membrane possesses ion pumps that maintain a high level of intracellular potassium and a low level of intracellular calcium and sodium. Hemoglobin, the red, oxygen-transporting protein of Neutrophil Eosinophil Basophil erythrocytes, consists of a globin (or protein) portion and four heme groups, the iron-carrying portion. The molecu- Granulocytes lar weight of hemoglobin is about 64,500. This complex protein possesses four polypeptide chains: two -globin molecules of 141 amino acids each and two molecules of another type of globin chain (, , , or ), each contain- ing 146 amino acid residues (Fig. 11.3). LGL (large granular lymphocyte)/ Four types of hemoglobin molecules can be found in hu- Null cell/NK cell Mature Helper/inducer Suppressor man erythrocytes: embryonic, fetal, and two different types (natural killer cell) B cell T cell T cell found in adults (HbA, HbA 2 ). Each hemoglobin molecule is designated by its polypeptide composition. For example, Lymphocytes the most prevalent adult hemoglobin, HbA, consists of two chains and two chains. Its formula is given as 2 2 . HbA 2 , which makes up about 1.5 to 3% of total hemoglo- bin in an adult, has the subunit formula 2 2 . Fetal hemo- globin ( 2 2 ) is the major hemoglobin component during intrauterine life. Its levels in circulating blood cells decrease Monocyte Macrophage rapidly during infancy and reach a concentration of 0.5% in Types of leukocytes in blood and tissues. adults. Embryonic hemoglobin is found earlier in develop- FIGURE 11.2 All of the cells shown here are found in the cir- ment. It consists of two chains and two chains ( 2 2 ). culation except the macrophage, which differentiates from acti- The production of chains ceases at about the third month vated monocytes in tissue. of fetal development. The production of each type of globin chain is con- trolled by an individual structural gene with five different Erythrocytes Carry Oxygen to Tissues loci. Mutations, which can occur anywhere in these five loci, have resulted in the production of over 550 types of Erythrocytes are the most numerous cells in blood. These abnormal hemoglobin molecules, most of which have no biconcave disks lack a nucleus and have a diameter of about known clinical significance. Mutations can arise from a sin- 7 m and a maximum thickness of 2.5 m. The shape of gle substitution within the nucleic acid of the gene coding the erythrocyte optimizes its surface area, increasing the ef- for the globin chain, a deletion of the codons, or gene re- ficiency of gas exchange. arrangement as a result of unequal crossing over between The erythrocyte maintains its shape by virtue of its com- homologous chromosomes. Sickle-cell anemia, for exam- plex membrane skeleton, which consists of an insoluble ple, results from the presence of sickle-cell hemoglobin mesh of fibrous proteins attached to the inside of the (HbS), which differs from normal adult hemoglobin A be- plasma membrane. This structural arrangement allows the erythrocyte great flexibility as the cell twists and turns through small, curved vessels. In addition to structural pro- teins of the membrane, several functional proteins are found in the cytoplasm of erythrocytes. These include he- moglobin (the major oxygen-carrying protein), antioxidant enzymes, and glycolytic systems to provide cellular energy TABLE 11.2 Circulating Blood Cell Levels Blood Cell Type Approximate Normal Range Erythrocytes (cells/L) Men 4.3–5.9 10 6 Women 3.5–5.5 10 6 Leukocytes (cells/L) 4,500–11,000 Neutrophils 4,000–7,000 Lymphocytes 2,500–5,000 Monocytes 100–1,000 FIGURE 11.3 Structure of hemoglobin A. Each molecule of Eosinophils 0–500 hemoglobin possesses four polypeptide chains, Basophils 0–100 each containing iron bound to its heme group (Modified from Platelets (cells/L) 150,000–400,000 Dickerson RE, Geis I. The Structure and Action of Proteins. New York: Harper & Row, 1969;3.)
CHAPTER 11 Blood Components, Immunity, and Hemostasis 195 cause of the substitution of a single amino acid in each of The MCV value reflects the average volume of each red the two chains. cell. It is calculated as follows: Oxyhemoglobin (HbO 2 ), the oxygen-saturated form of hemoglobin, transports oxygen from the lungs to tissues, MCV Hematocrit/Number of red cells (3) 12 where the oxygen is released. When oxygen is released, Example: 0.450/(5 10 cells/L) 0.090 10 12 L/ HbO 2 becomes reduced hemoglobin (Hb). While oxygen- cell 90 fL (1 fL 10 15 L) saturated hemoglobin is bright red, reduced hemoglobin is Each gram of hemoglobin can combine with and trans- bluish-red, accounting for the difference in the color of port 1.34 mL of oxygen. Thus, the oxygen carrying capac- blood in arteries and veins. ity of 1 dL of normal blood containing 15 g of hemoglobin Certain chemicals readily block the oxygen-transport- is 15 1.34 20.1 mL of oxygen. ing function of hemoglobin. For example, carbon monox- ide (CO) rapidly replaces oxygen in HbO 2 , resulting in the formation of the stable compound carboxyhemoglobin Red Cell Morphology. In addition to revealing alter- (HbCO). The formation of HbCO accounts for the as- ations in absolute values, stained blood films may provide phyxiating properties of CO. Nitrates and certain other valuable information based on the morphological appear- chemicals oxidize the iron in Hb from the ferrous to the ance of blood cells. Erythrocytes are formed from precursor ferric state, resulting in the formation of methemoglobin blast cells in the bone marrow (Fig. 11.4). This process, (metHb). MetHb contains oxygen bound tightly to ferric termed erythropoiesis, is regulated by erythropoietin, a iron; as such, it is useless in respiration. Cyanosis, the dark- hormone produced in the kidneys. blue coloration of skin associated with anoxia, becomes ev- Changes in red cell appearance occur in a variety of ident when the concentration of reduced hemoglobin ex- pathological conditions (Fig. 11.5). Excessive variation in ceeds 5 g/dL. Cyanosis may be rapidly reversed by oxygen the size of cells is referred to as anisocytosis. Larger-than- if the condition is caused only by a diminished oxygen sup- ply. However, cyanosis caused by the intestinal absorption of nitrates or other toxins, a condition known as enteroge- nous cyanosis, is due to the accumulation of stabilized methemoglobin and is not rapidly reversible by the admin- istration of oxygen alone. Normal Red Cell Values. In evaluating patients for hema- tological diseases, it is important to determine the hemoglo- Erythropoietin bin concentration in the blood, the total number of circulat- ing erythrocytes (the red cell count), and the hematocrit. From these values several other important blood values can be calculated, including mean cell hemoglobin concentration (MCHC), mean cell hemoglobin (MCH), mean cell volume (MCV), and blood oxygen carrying capacity. The MCHC provides an index of the average hemoglo- bin content in the mass of circulating red cells. It is calcu- lated as follows: MCHC Hb (g/L)/hematocrit (1) Example: 150 g/L 0.45 333 g/L Low MCHC values indicate deficient hemoglobin syn- thesis. High MCHC values do not occur in erythrocyte dis- orders, because normally the hemoglobin concentration is close to the saturation point in red cells. Note that the MCHC value is easily obtained by a simple calculation from measurements that can be made without sophisticated instrumentation. The MCH value is an estimate of the average hemoglo- bin content of each red cell. It is derived as follows: MCH Blood hemoglobin (g/L)/ Red cell count (cells/L) (2) FIGURE 11.4 Erythropoiesis. Erythrocyte production in 12 Example: 150 g/L (5 10 cells/L) 30 10 12 g/ healthy adults occurs in marrow sinusoids. Dri- cell 30 pg/cell ven by the hormone erythropoietin, the uncommitted stem cell differentiates along the erythrocyte lineage, forming normoblasts Since the red cell count is usually related to the hemat- (also referred to as erythroblasts or burst-forming cells), reticulo- ocrit, the MCH is usually low when the MCHC is low. Ex- cytes and, finally, mature erythrocytes, which enter the blood- ceptions to this rule yield important diagnostic clues. stream by the process of diapedesis.
196 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY Pathological changes in erythrocyte morphology. FIGURE 11.5 normal erythrocytes are termed macrocytes; smaller-than- many blood and marrow disorders, and their presence can normal erythrocytes are referred to as microcytes. Poikilo- be of diagnostic significance. One type of nucleated red cytosis is the presence of irregularly shaped erythrocytes. cell, the normoblast (see Fig. 11.4), is seen in several types Burr cells are spiked erythrocytes generated by alterations of anemias, especially when the marrow is actively re- in the plasma environment. Schistocytes are fragments of sponding to demand for new erythrocytes. In seriously ill red cells damaged during blood flow through abnormal patients, the appearance of normoblasts in peripheral blood blood vessels or cardiac prostheses. is a grave prognostic sign preceding death, often by several The hemoglobin content of erythrocytes is also re- hours. Another nucleated erythrocyte, the megaloblast, is flected in the staining pattern of cells on dried films. Nor- seen in peripheral blood in pernicious anemia and folic acid mal cells appear red-orange throughout, with a very slight deficiency. central pallor as a result of the cell shape. Hypochromic cells appear pale with only a ring of deeply colored hemo- Erythrocyte Destruction. Red cells circulate for about globin on the periphery. Other pathological variations in 120 days after they are released from the marrow. Some of red cell appearance include spherocytes—small, densely the senescent (old) red cells break up (hemolyze) in the staining red cells with loss of biconcavity as a result of con- bloodstream, but the majority are engulfed by genital or acquired cell membrane abnormalities; and tar- macrophages in the monocyte-macrophage system. The get cells—which have a densely staining central area with hemoglobin released on destruction of red cells is metabol- a pale surrounding area. Target cells are thin but bulge in ically catabolized and eventually reused in the synthesis of the middle, unlike normal erythrocytes. This alteration is a new hemoglobin. Hemoglobin released by red cells that consequence of hemoglobinopathies, mutations in the lyse in the circulation either binds to haptoglobin, a pro- structure of hemoglobin. Target cells are observed in liver tein in plasma, or is broken down to globin and heme. disease and after splenectomy. Heme binds a second plasma carrier protein, hemopexin, Nucleated red cells are normally not seen in peripheral which, like haptoglobin, is cleared from the circulation by blood because their nuclei are lost before they move from macrophages in the liver. In the macrophage, released he- the bone marrow into the blood. However, they appear in moglobin is first broken into globin and heme. The globin
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