Muscles A Medical Dictionary Bibliography and Annotated Research Guide to Internet References

Studies 43 • Project Title: MOLECULAR AND BIOCHEMICAL STUDY OF COLLAGEN IN PROLAPSE Principal Investigator & Institution: Visco, Anthony G.; Assistant Professor; Obstetrics and Gynecology; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: (Adapted from Applicant's Description): Pelvic floor dysfunction including urinary incontinence and pelvic organ prolapse is a major health issue for women resulting in an 11 percent lifetime risk of requiring surgery. The cost of urinary incontinence alone in 1995 alone was estimated at $26 billion in the United States. Several studies have identified pregnancy related risk factors for pelvic floor dysfunction including vaginal parity, increased infant birth weight, forceps and vacuum assisted vaginal delivery, episiotomy and prolonged second stage of labor. However, vaginal delivery fails to fully explain the genesis and progression of pelvic floor dysfunction since severe pelvic organ prolapse has been observed in nulliparous women and most women who deliver vaginally do not develop prolapse. Pelvic organ prolapse and urinary incontinence result from failure of the support mechanism derived from pelvic fascia and muscles. Many researchers have hypothesized that a parturition- related denervation injury to the female pelvic floor leads to weakness of the levator ani muscles which in turn results in marked stress placed on the uterosacral cardinal ligaments and endopelvic fascia, ultimately leading to secondary failure of the fascia and development of prolapse. Other studies suggest a primary failure of the fascia. Associations have been reported between prolapse, joint hypermobility and abdominal striac suggesting a generalized connective tissue defect affecting pelvic organ support, joints and skin. One explanation is a defect in collagen biosynthesis. Such a generalized connective tissue disorder might affect collagen's biomechanical strength and be explained at the genetic level. The long-term objective, therefore, is to gain insight into the mechanisms of pelvic floor dysfunction through the study of collagen at the molecular and biochemical levels. Collagen cross-linking is critical for the stability and mechanical strength of the collagen molecule and for the cohesiveness of the collagen fibrils. Hydroxylation of lysine is critical for the cross-linking process and the level of hydroxylation varies among tissues, Lysyl oxidase and lysyl hydroxylase are two enzymes involved in the early steps of the cross-linking process. We hypothesize that alterations in the intermolecular cross-linking may result in weakened connective tissue which may lead to pelvic floor dysfunction. Few studies have examined the biochemical nature of connective tissue or genetic differences in women with pelvic floor dysfunction. The specific aims are to compare: 1. total collagen content, 2. the six characterized collagen cross-links, 3. the ratio of Type I/III collagen, 4. the level of lysine hydroxylation, 5. collagen solubility, and 6. the genes coding for lysyl oxidase and the three isoforms of lysyl hydroxylase (LH1, LH2, LH3), in patients with advanced-stage pelvic organ prolapse and age and parity matched controls. This study would be the first large-scale comprehensive description of collagen cross-linking, lysine hydroxylation, and of genes coding for enzymes involved in the cross-linking process, in patients with pelvic organ prolapse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: MOLECULAR BASIS FOR MUSCLE PROTEIN LOSS IN CACHEXIA Principal Investigator & Institution: Lecker, Stewart H.; Assistant Professor of Medicine; Cell Biology; Harvard University (Medical School) Medical School Campus Boston, Ma 02115

44 Muscles Timing: Fiscal Year 2002; Project Start 01-AUG-1999; Project End 31-JUL-2004 Summary: Muscle wasting, which occurs mainly by an activation of the ubiquitin- proteasome degradative pathway, is a prominent, debilitating feature of many disease states, including diabetes mellitus and renal failure. Recently, using a newly established cell-free system, we have been able to demonstrate that rates of ubiquitin (Ub) conjugation increase in atrophying muscles from septic; tumor-bearing, diabetic and uremic rats, and that a subset of Ub conjugating enzymes, the N-end rule pathway, is responsible for most of the enhanced Ub conjunction in these atrophying muscles. This is an interesting, unexpected discovery because the N-end rule pathway has been viewed as a minor ubiquitination system that was only involved in the elimination of certain abnormal polypeptides. These results raise the possibility that in cachexia, muscle proteins may be modified to become substrates for this pathway. We propose to use our newly developed cell-free system to further characterize this process. We will measure the abundance and activity of the N-end rule pathway enzymes (E1, E2/14K, and E3alpha) to identify the ones which are responsible for the enhanced proteolysis, and identify the substrates in muscle for these enzymes. In collaborative studies, we will genetically produce animals in which these enzymes are deleted to directly show their requirement in muscle atrophy. Finally, since most of the loss of muscle protein during muscle atrophy is from myofibrillar components, we will begin to study how the myofibril may serve as a source of substrates of the Ub-proteasome pathway by developing an assay for myofibril disassembly. Defining the components of the Ub- proteasome pathway and myofibril disassembly which are modulated in diabetes and renal failure should not only help to illuminate the regulation of muscle protein turnover, but also may allow the development of inhibitors that could combat the morbidity of these catabolic diseases. These studies will be performed in the laboratory of Dr. Alfred Goldberg, a leader in the fields of muscle proteolysis and the Ub- proteasome pathway. The applicant is a graduate of the M.D./Ph.D. program at UCLA, completing a Nephrology fellowship at the Beth Israel Deaconess Medical Center and Harvard Medical School. His long-term goal is to develop a research program centered on problems of protein folding and degradation relevant to kidney disease. This proposal offers the unique opportunity for the applicant to obtain further cell biology training, gaining experience in animal physiology, DNA technology, and biochemistry, while studying clinically relevant problems in renal disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: MOLECULAR GENETICS OF MUSCLES SPECIALIZATION Principal Investigator & Institution: Williams, R S.; Professor of Medicine; Medicine; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002; Project Start 01-APR-1991; Project End 31-MAR-2006 Summary: (Applicant's abstract): In the previous project period, we proposed that calcineurin and CaMK serve as nodal points in signal transduction pathways by which specific patterns of motor nerve activity lead to changes in gene expression that establish specialized metabolic and physiologic properties in adult skeletal myofibers. Our basic mechanistic model has been supported by evidence from our own lab, and from others, but features of the model remain conjectural or controversial, and the mechanisms we have described so far provide only a partial view of the relevant biological processes. In the next project period, we propose new experiments that seek to achieve a more complete understanding of the molecular basis for fiber type determination in mammalian skeletal muscles. To this end, we will address the following specific aims: 1) To define the set of specific molecular signals that are necessary and sufficient to

Studies 45 promote complete fiber type transformation in skeletal muscles of adult transgenic mice; 2) To define quantitative relationships between specific patterns of neural activity and the activation state of specific signaling cascades in skeletal myofibers of intact animals; 3) To define other signaling molecules and pathways pertinent to transcriptional regulation of fiber type-specific genes. These aims are distinctive within the field of muscle biology for several reasons. Activity-dependent inter-conversion of specialized skeletal muscle subtypes was observed many decades ago, but identifying the molecular mechanisms that underlie this physiologically important response has been an elusive goal. Our recent hypothesis that calcineurin is important to the process has stimulated a fresh look at the problem. The subsequent experiments we propose are hypothesis-driven and focused, and major conclusions will be buttressed by results from both reductionisticand integrative approaches. We have incorporated new experimental methods so as to capitalize on recent technological advances. Finally, the knowledge to be gained may provide opportunities for development of new therapeutic measures to alter the specialized properties of skeletal myofibers, for the benefit of patients with primary and secondary myopathies or with metabolic diseases in which skeletal muscle plays an important role. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: MOLECULAR PHYSIOLOGY OF RECOVERY FROM MUSCLE ATROPHY Principal Investigator & Institution: Pavlath, Grace K.; Associate Professor; Pharmacology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-MAY-2006 Summary: A loss of skeletal muscle functional capacity occurs in disease, disuse and aging mostly attributable to a loss of muscle mass. Such losses of muscle mass contribute to weakness, impaired mobility and/or respiratory function, low quality of life and high health care costs. The overall goal of this proposal is to delineate cellular and molecular mechanisms that regulate growth of atrophied muscles. The relative importance of muscle precursor cell (mpc) pathways vs. myofiber pathways can vary depending on the type of muscle growth and may differ for the growth of an atrophied myofiber. Determining how much of the recovery from atrophy is dependent on mpc is important for designing therapeutic strategies to treat muscle atrophy. This proposal has 3 integrated parts: (1) To delineate the contribution of mpc and other muscle progenitor cells to growth of atrophied muscle (Aims 1 and 2). We will define the timing of mpc proliferation and fusion with myofibers during growth. Subsequently, we will analyze growth in muscles lacking mpc due to local irradiation. Finally, we will determine if the abundance and/or in vitro properties of newly identified muscle progenitor populations change in response to muscle atrophy or growth. (2) To enhance mpc proliferation and fusion using the drug curcumin as a means of stimulating recovery from atrophy (Aim 3). We have previously shown that curcumin effectively enhances the growth of regenerating muscles and now extend these studies to growth of atrophied muscle; (3) To study molecular signals that are activated during the growth of atrophied muscles (Aims 4 and 5). We will delineate the contribution of a known signaling pathway (calcineurin) as well as identify new molecules using microarray analysis, which may play a role in regulating muscle growth. The experiments in this proposal will reveal new information about growth of atrophied muscle and possibly new avenues of rehabilitative therapy for manipulating this growth process in disease, disuse and aging. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

46 Muscles • Project Title: MUSCLE ACTIVITY INITIATION DURING HEMIPARETIC LOCOMOTION Principal Investigator & Institution: Brown, David A.; Programs in Physical Therapy; Northwestern University Office of Sponsored Research Chicago, Il 60611 Timing: Fiscal Year 2002; Project Start 10-SEP-2000; Project End 31-MAY-2004 Summary: (adapted from Investigator's abstract) During locomotion in persons with post-stroke hemiparesis, muscle activity is initiated at inappropriate points in the cycle. As a consequence, movements are less-forceful and are slower, and movement function is impaired. The investigators propose that an interaction between two key underlying mechanisms, heightened motoneuron excitability and abnormal position-dependent modulation of motoneuron excitability, result in inappropriately-timed muscle activity. With their earlier work, the investigators have shown that paretic uniarticular knee muscles and biarticular hip and knee muscles are inappropriately activated at an earlier phase in the pedaling cycle. Since these muscles are lengthening at these points in the cycle and, since this effect is speed-dependent, they first propose that heightened motoneuron excitability results in muscle being activated when it is stretched at a specific threshold length and velocity. They will systematically vary the ranges of length and velocity of uniarticular knee muscles during cyclical leg motion to identify threshold muscle stretch parameters that trigger inappropriate initiation of uniarticular muscle activity. They will also systematically vary the ranges of length and velocity of uni- and biarticular muscles crossing the hip to identify muscle stretch parameters that, secondarily, contribute to inappropriate initiation of uniarticular knee muscle activity. They will use a computer model of the musculoskeletal system to calculate each muscle's length and velocity characteristics from kinematic patterns and develop a comprehensive statistical model of the relative contributions from multiple muscle stretch parameters. Also, normally during cycling, uniarticular knee extensors are activated during knee extension, regardless of hip position. However, preliminary work in post-stroke subjects has demonstrated abnormal activation that is dependent on hip position. They propose that the position of the hip can abnormally modulate motoneuron excitability and, hence, influence timing of muscle activity in uniarticular knee extensor muscles. They will systematically vary the relative position of the hip versus knee using a unique linkage attached to the feet. This experiment will result in kinematic patterns that generate more appropriate timings of uniarticlar knee extensors. The intent is that the experimental apparatus and principles developed within this study will form the basis of a new therapeutic modality that targets deficits in locomotor control, post-stroke, and with other neurologic conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: MYOFILAMENT PROTEIN ISOFORMS IN NEUROMUSCULAR REFLEX Principal Investigator & Institution: Jin, J-P P.; Physiology and Biophysics; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2003; Project Start 20-JUN-2003; Project End 31-MAY-2006 Summary: (provided by applicant): Neuromuscular reflex plays a central role in the maintenance of muscle tone and hypertonia forms a basis of muscle contracture. As a sensory organ for muscle length in the peripheral neuromuscular reflex loop, muscle spindle produces positive feedback (la and II afferent) to simulate alpha-motor neuron activity. The sensitivity of a spindle is filtered by the tension of intrafusal muscle fibers under gamma-efferent regulation. Much attention has been paid to the spindle function

Studies 47 in muscle function and spasticity and the contractility of intrafusal fibers is an essential link in the reflex loop. The intrafusal fibers contain unique myosin isoforms as compared with the extrafusal fibers, but little is known for their Ca 2+ regulation and contractile features. The regulation of intrafusal myofilament protein isoform expression during muscle development, adaptation and diseases is largely unknown. Based on our previous studies, we plan to investigate the role of myofilament protein isoforms in neuromuscular reflex. Our research plan is focused on testing a hypothesis in which the changes in fiber type-specific myofilament protein isoforms, especially the actin filament-associated regulatory protein troponin T (TnT), in intrafusal fibers may play a role in the pathophysiology of muscle contracture. It has been found that spastic muscles have increased type I (slow) fibers. Cerebral palsy, joint immobilization and tenotomy, three very different original conditions which cause muscle contracture, have a common consequence that is a fixed shortening of the resting muscle length. We have found an increased expression of slow myosin in a tenotomy model and the expression of myosin and thin filament regulatory protein isoforms is coordinated in the muscle. As an acidic TnT isoform, an up-regulation of slow TnT would increase the sensitivity of myofilaments to Ca2+ activation. The increase in intrafusal fiber Ca2+ responsiveness will increase spindle tension and sensitivity, which in turn increases the positive feedback to stimulate alpha-motor neuron to activate the extrafusal fibers and result in hypertonia. To test this hypothesis will help to understand the pathophysiology of muscle contracture. Three specific aims will be pursued in this pilot study: I. To examine the thin filament regulatory protein isoforms expressed in intrafusal fibers in adult and developing muscles. II. To investigate whether fixed shortening of muscle length originated from different conditions induces similar changes in the expression of intrafusal myofilament protein isoforms. III. To test whether elevated slow TnT expression in transgenic mouse muscles will produce increased Ca2+ sensitivity of intrafusal fibers and increased alpha-motor neuron activity. To explore this largely unknown area of neuromuscular reflex, this research initiative will lay groundwork for understanding the molecular mechanism of muscle contracture and improving treatment of this disabling condition. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: NEURAL CONTROL OF GRASPING Principal Investigator & Institution: Santello, Marco; Exercise Science; Arizona State University P.O. Box 873503 Tempe, Az 852873503 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: Neurological and musculo-skeletal diseases severely impair the complex coordination of finger motion and forces that characterizes our ability to grasp and manipulate objects. Knowledge of the physiological control mechanisms of prehension is essential for an understanding of the pathologies that affect hand function. The long- term objective of the present proposal is to characterize the normal patterns of muscle activation responsible for the control of grasping movements, in particular the strategies used by the nervous system to coordinate the large number of muscles of the hand. This objective will be pursued by studying the simultaneous activation of multiple hand muscles and the coordination of grip forces. The present proposal has three specific aims: to characterize the organization of hand muscle activity as a function of hand and wrist posture (Aim number 1); to determine whether motor unit synchronization is dependent on task constraints (object's size and center of mass location; Aim number 2) and grip type (power vs. precision grip, and object shape; Aim number 3). The proposed studies are based on the hypothesis, supported by previous work, that the coordination

48 Muscles of multiple grip forces is based on synergies reducing the number of degrees of freedom that has to be controlled independently. We will determine how the activity of multiple hand muscles is coordinated as a function of finger/wrist posture and task constraints. Hand muscle activity will be measured by intramuscular electromyographic recording as (a) interference multi-unit EMG and (b) single motor unit activity. Contact forces exerted by each finger will be measured in three dimensions by force sensors. The issues examined by this basic research are relevant to efforts in rehabilitation and restoration of hand function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: NEURAL CONTROL OF MUSCLE ACTIVITY Principal Investigator & Institution: Fetz, Eberhard E.; Professor; Physiology and Biophysics; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 30-SEP-1978; Project End 31-JUL-2006 Summary: We plan to investigate the neural mechanisms controlling voluntary hand and arm movement in primates. The functional roles of premotor (PreM) cells in motor cortex and spinal cord will be directly compared. PreM cells with a correlational linkage to forelimb motoneurons will be identified by post-spike effects in spike-triggered averages of EMG activity. The activity of PreM cells and multiple muscles will be documented during multidirectional wrist movements. Monkeys will operate a multi- jointed manipulandum that will allow wrist movements in three directions: flexion- extension, radial-ulnar deviation and pronation-supination. In addition a grip handle will transduce force during a power grip. This repertoire of movements will activate muscles in different synergistic combinations and resolve whether PreM cells and non- PreM cells are organized primarily in terms of muscles or movement parameters. The directional tuning of forearm muscles will be compared with the tuning curves of PreM cells and non-PreM cells. We anticipate finding functionally significant differences between motor cortex cells and spinal interneurons with regard to their relation to muscles and movements. Spinal cord interneurons have been studied largely in immobilized animals; our study will provide new information about the involvement of interneurons in preparation and execution of voluntary movements. These interneurons will be identified by their synaptic inputs from different forelimb muscles and from functionally identified cortical sites. We will also systematically map the movements of arm and hand evoked by electrical stimulation of spinal cord sites; the modulations of these responses during an instructed delay task will reveal the interaction of intraspinally evoked responses with preparation and execution of voluntary movements. Activity of dorsal root afferent fibers also will be recorded during an instructed delay task to document the afferent input to the central nervous system during movement. The axonal excitability of afferent fibers will be tested to investigate task-related modulation of presynaptic inhibition. These studies of the primate motor system will provide unique information essential to understanding and effectively treating clinical motor disorders, like cerebral palsy, stroke and spinal cord injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: NEURAL FACTORS AND UPPER AIRWAY MUSCLE DEVELOPMENT Principal Investigator & Institution: Millhorn, David E.; Joseph Eichberg Prof. & Chairman; Molecular and Cellular Physio; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221

Studies 49 Timing: Fiscal Year 2002; Project Start 10-JUL-2000; Project End 31-MAY-2004 Summary: Breathing is a highly regulated process that requires precise coordination among the muscles that cause ventilation and those responsible for maintenance of upper airway patency. Failure to properly activate the upper airway dilator muscles in response to an increase in inspiratory drive can result in obstruction of the upper airways. High fidelity synaptic signaling across the neuromuscular junction is required for precise regulation of upper airway patency that corresponds to the level of inspiratory drive. The major synaptic component of the neuromuscular junction is the nicotinic acetylcholine receptor (nAChR), a ligand (ACh)- gated channel that is composed of four homologous trans-membrane subunits (alpha2, beta, epsilon, gamma) arranged in a pentamer. During early postnatal development the nAChR undergoes a structural modification which impacts on its ability to respond to ACh released from motoneurons. In the neonate, the nAChR contains a gamma- instead of the epsilon- subunit. The nAChR-gamma exhibits a lower single channel conductance than the adult nAChR-epsilon. Thus, muscles that express more nACh-gamma and less nAChR- epsilon might be prone to hypotonicity and less responsive to synaptic input. We hypothesize that discordant regulation of the nAChR-gamma and nAChR-epsilon isoforms could lead to reduced upper airway patency and airway obstruction There is growing evidence that opposing kinase and phosphatase pathways in muscle regulate the nAChR-gamma to nAChR-epsilon transition during early postnatal development. Moreover, recent findings indicate that both the kinase and phosphatase activities are regulated by \"trophic\" factors released from the motoneurons. The proposed research will investigate the role of the tetradecapeptide somatostatin (SST) in the regulation of tyrosyl phosphatase (PTPase) activities in muscle. Preliminary results show that SST, which is expressed developmentally in the motoneurons that innervate the upper airways, prevents induction of -subunit gene expression by the kinase pathway. The specific aims are: 1) Identify and characterize the protein tyrosyl phosphatases that are activated by SST and cause inhibition of epsilon-subunit gene expression; 2) Determine the mechanism by which SST-induced PTPases oppose kinase pathways to prevent activation of epsilon-subunit gene expression; and 3) Determine the effect of continuous expression of the SST-SSTR-PTPase pathway on epsilon-subunit gene expression in genetically engineered mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: NEURAL MECHANISMS IN MUSCLE FATIGUE Principal Investigator & Institution: Enoka, Roger M.; Professor; Kinesiology & Appld Physiology; University of Colorado at Boulder Boulder, Co 80309 Timing: Fiscal Year 2002; Project Start 15-APR-2002; Project End 31-MAR-2005 Summary: The endurance capacity of muscle varies with the task that is performed. We found that the endurance time for a submaximal isometric contraction with the elbow flexor muscles was twice as long when the wrist was attached to a force transducer compared with when it supported an equivalent inertial load. Although the subject sustained a constant force when the wrist was restrained by a force transducer and maintained a constant elbow angle when supporting the inertial load, the resultant muscle torque and the rate of increase in the average EMG were identical for the two tasks. Nonetheless, additional results suggested that the descending drive to the motor neurons was greater during the constant-position contraction. We hypothesize that endurance time of the elbow flexor muscles is less for a constant- position contraction compared with a constant-force contraction due to greater excitatory descending drive to the motor neurons and greater inhibitory feedback from the muscles. According to

50 Muscles this hypothesis, the difference in endurance time for the two tasks is attributable to differences in the input received by the spinal motor neurons. We propose three specific aims (Aims 1 to 3) to examine the, descending- drive component of the hypothesis and two aims (Aims 4 and 5) to assess the inhibitory-feedback component. The hypothesis predicts that motor unit activity will be greater during the constant-position contraction (Aim 1) and that endurance time will be briefer when the gain of the position-feedback signal is increased (Aim 2) and vibration is applied to the active muscles (Aim 3). Furthermore, the hypothesis predicts that the decline in maximum discharge rate of motor units in the contralateral muscles (Aim 4) and that the increase in mean arterial pressure (Aim 5) will be greater after the constant-position contraction. We are not aware of another study that has examined the contribution of neural mechanisms to the fatigue experienced during constant-force and constant-position isometric contractions. The outcomes will provide novel information on the physiological adjustments that occur during isometric contractions, which are the most common form of muscle activity, and will have direct application to the design of work tasks in ergonomics and the prescription of physical activities in rehabilitation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: NEUROMUSCULAR CONTROL OF THE PHARYNGEAL AIRWAY Principal Investigator & Institution: Fregosi, Ralph F.; Associate Professor; Physiology; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2002; Project Start 10-APR-1998; Project End 31-MAR-2004 Summary: (Adapted from the applicant's abstract): The long-term objective of this proposal is to test the hypothesis that the muscles that protrude and retract the tongue (genioglossus and hypoglossus/styloglossus muscles, respectively) are co-activated during inspiration, and that co-contraction contributes significantly to the maintenance of pharyngeal airway patency. The conceptual model is that co-contraction during inspiration stiffens the tongue as the antagonist muscles work against one another, thereby minimizing backward displacement of the tongue and subsequent occlusion of the pharynx. Significant new data showing respiratory-related co-activation of the protrudor and retractor muscles in animal models, as well as recent evidence showing improved inspiratory airflow with co-activation in human subjects with obstructive sleep apnea, provide strong support for this conceptual framework. Accordingly, the following Specific Aims are designed to rigorously test the co-activation hypothesis using an anesthetized rat model: Aim 1 is to demonstrate that the protrudor and retractor muscles of the tongue are co-activated during breathing and that they respond similarly to changes in respiratory related stimuli. Aim 2 is to show that co-activation of the extrinsic tongue muscles will improve pharyngeal airway mechanics more than the independent activation of either the protrudor or retractor muscles. Aim 3 is to demonstrate that the initial operating length of the tongue muscles will influence: a) the magnitude of respiratory related tongue movements, b) the ability of the tongue muscles to modulate pharyngeal airway flow mechanics, c) the fatigability of the tongue muscles. These experiments will lay the foundation for new and improved treatment strategies for persons with obstructive sleep apnea or with other conditions that are caused by malfunction of the tongue motor system. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies 51 • Project Title: NEUROMUSCULAR STRATEGIES FOR HUMAN TONGUE MOVEMENT Principal Investigator & Institution: Sokoloff, Alan J.; Physiology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 31-MAY-2006 Summary: The tongue is essential in normal oromotor function, and is of pre-eminent importance in the production of human speech. Tongue dysfunction is associated with many human clinical syndromes. Yet the design of effective treatments for recovery from tongue dysfunction is hindered by our limited understanding of the neuromuscular bases for tongue motor control. Most critically, we lack information on the organization of the fundamental output elements of the tongue motor system, i.e., tongue muscles, tongue muscle compartments and tongue motor units. The long term goals of this study are to determine the neuromuscular organization of these functional output elements in the human tongue motor system and to improve clinical treatments for recovery from tongue dysfunction. To achieve these goals this study applies anatomical and physiological techniques directly to investigations of the human and non-human primate tongue. The results of these investigations will meet three general aims. First, the architecture of human tongue muscles and the pattern of their motor innervation will be studied to determine the neuroanatomical bases of muscle biomechanical diversity in the human tongue. Second, the identity and distribution of muscle fiber types in the human tongue will be determined to test the hypothesis of parallel anatomical systems for human tongue movement. Third, the morphology and physiology of tongue motor units and muscle compartments will be determined in the non-human primate to allow physiological correlation of anatomical organization. These studies will provide the first detailed understanding of the functional output elements of the human and non-human primate tongue. This understanding is essential if we are to develop accurate models of tongue motor control and if we are to design rational interventions for recovery of tongue function in human disease Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: NEUROMUSCULAR SYNAPTOGENESIS IN ZEBRAFISH Principal Investigator & Institution: Balice-Gordon, Rita J.; Associate Professor; Neuroscience; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2005 Summary: (provided by applicant): The goal of this proposal is to isolate vertebrate genes that play a role in neuromuscular synapse formation and maintenance, using zebrafish as a model system. Previous fish mutagenesis screens have not focused on mutants that affect neuromuscular synaptogenesis, in part because these synapses need to be labeled with antibodies or toxins that specifically label different synaptic components and visualized using light microscopy at relatively high magnification. Over the last year, my lab has participated in a pilot mutagenesis screen conducted by Drs. Mary Mullins and Michael Granato in the Dept. of Cell and Developmental Biology at the University of Pennsylvania. My lab developed an assay for neuromuscular synapses in zebrafish utilizing antibodies against synaptic vesicles to mark presynaptic terminals, fluorescent conjugated alpha-bungarotoxin to label acetylcholine receptor (AChR) clusters, and high resolution fluorescence microscopy in intact fish at 48 hours post fertilization (hpf). Preliminary results demonstrate that we have identified several mutants with defects in different aspects of neuromuscular synaptogenesis at 48 hpf, and that some of these mutants also have motility defects. These mutants fall into three

52 Muscles overlapping categories: aberrant synapse formation (too many, too few or mislocalized pre- and/or postsynaptic specializations); normal synapse formation, followed by synapse loss and/or redistribution; and aberrant primary and/or secondary motor axon branching within body wall musculature, resulting in aberrant endplate bands within individual muscles. Based on our success with this small, pilot screen, we propose to first, define the primary defect in 2-3 of the isolated mutants by analyzing synaptic structure and function; second, to determine the genetic map position of mutated genes for 2-3 mutants using complementation, mapping using an established set of molecular markers, and linkage analyses; and third, to isolate new mutations in genes required for neuromuscular synapse formation and maintenance by continuing and expanding our screen of mutant fish. Taken together, these approaches will allow us to study the genetic, molecular and cellular mechanisms of these processes in vertebrates. This R21 proposal will allow us to use mutagenesis in zebrafish to identify some of the genes required for neuromuscular synapse formation and maintenance, and expand the repertoire of tools available in my lab to address these fundamental questions in zebrafish and mice in the future. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: PRECISE CONTOL OF TONGUE MOVEMENT Principal Investigator & Institution: Goldberg, Stephen J.; Professor; Anatomy and Neurobiology; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2002; Project Start 01-JUN-1994; Project End 31-MAY-2006 Summary: The normal development of the complex neuromuscular system used to control tongue movement is critical to the immediate survival of all terrestrial mammals. Voluntary control in this motor system involves a sequence of neural and muscular events beginning in the motor cortex. Coordinated tongue movements are needed for eating (mastication and swallowing), drinking, licking (suckling), breathing, grooming and vocalization. Clinically, and in contrast to a normal developmental progression, premature human infants often need to be fed intravenously or with a nasogastric tube for extended periods of time (weeks or months) to insure their survival. Attempts to begin bottle feeding these infants can result in apnea, bradycardia, hypoxia, fatigue and agitation and there can also be the long term consequence of delayed oral feeding milestones which results in longer hospital stays. A later impact on motor speech has also been documented. It may be that the interrupted normal maturation of the neuromuscular control system for appropriate suckling plays an important role here. In addition, infants born at term who also need non-oral nutrition due to system disorders or surgical interventions may also exhibit delayed oral feeding. We propose, therefore, to continue our studies of rat hypoglossal nucleus anatomy and tongue muscle contractile measures with a new emphasis on system development. We also propose to add morphological and biochemical studies of individual developing tongue muscles. The normal development of this system, and its cortical control, will then be compared and contrasted to that in rat pups who have been fed, for varying postnatal times, using a gastric cannula. Some animals will experience a near total absence of suckling while others will have their normal suckling sequence interrupted. This has been termed \"artificial rearing\" and is modeled on the human infant interventions mentioned above. New preliminary data indicates that artificial rearing from postnatal days 4 to 13 results in striking changes in tongue contractile strength, speed, endurance, muscle fiber diameter and a persistence of developmental myosin heavy chain (MHC) isoforms, similar to changes observed in other skeletal muscles after a period of disuse. These studies should help to lay a firm foundation for an understanding of how the

Studies 53 hypoglossal motor system develops, especially since many aspects of its normal development have simply not yet been studied. In addition, we hypothesize that the neuroanatomical organization within the hypoglossal nucleus, muscle morphology plus MHC expression, muscle contractile characteristics and afferent input from the motor cortex are altered in animals that have been artificially reared. The degree to which each of these components is altered needs to be ascertained for a clearer view of this motor system and to delineate those postnatal time periods that are the most critical for normal development. It is also hoped, for the long run, that these basic findings can have an application for a speedier and more complete rehabilitation of human infants that are necessarily deprived of normal suckling and eating. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: PRE-PATTERNING OF SKELETAL MUSCLE Principal Investigator & Institution: Burden, Steven J.; Professor; Pharmacology; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2002; Project Start 15-MAY-2001; Project End 31-MAR-2005 Summary: (From the Applicant's Abstract): Current ideas of synapse formation suggest that muscle is patterned by signals, such as agrin, provided by motor neurons. Our recent studies, however, have revealed that muscle is pre-patterned in the absence of innervation. We found that motor axons in top 2b mutant embryos reach their targets but fail to grow or branch within limb or diaphragm muscles. To our surprise, we found that AChRs are clustered in the central region of muscle, despite the absence of motor axons within the muscle. These results suggest that the expression pattern of AChRs in skeletal muscles is determined, at least in part, by mechanisms that are autonomous to muscle and suggest that muscle is pre-patterned, independent from signals provided by motor neurons. The experiments described in this proposal are designed to determine how pre-patterning of muscle is established, whether muscle pre-patterning might regulate where axons terminate and form synapses and how innervation might regulate muscle pre-patterning. We will determine (1) whether motor innervation requires neural or muscle expression of top 2b, (2) whether signals from motor axons are required to pre-pattern AChRs in skeletal muscle, (3) whether MuSK or agrin are required to establish muscle pre-patterning, (4) whether additional skeletal muscle proteins are pre-patterned in muscle, (5) whether genes encoding synaptic proteins are pre-patterned in muscle, (6) whether pre-patterned molecules might have a role in specifying the site of motor innervation, (7) whether motor axons or electrical activity suppress muscle pre-patterning, and (8) whether a distinct myoblast lineage might be a source of the pre-pattern. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: PROGESTERONE /MELATONIN AS NEUROPROTECTANTS IN NERVE INJ Principal Investigator & Institution: Yu, Wan-Hua A.; City College of New York 138Th St and Convent Ave New York, Ny 10031 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2007 Summary: Motor neurons of adult animals, despite resistance to axotomy-induced cell death, undergo apoptotic cell death after nerve injury with removal of axon associated Schwann cells, indicating that neurotrophic factors from central glial cells may not be adequate to support the survival of injured neurons. This proposal aims to test the hypothesis that glial synthesis of neurotrophic factors can be up-regulated by steroid

54 Muscles hormones, and that death of injured neurons is preventable by agents which scavenge free radicals and remove reactive oxygen species. Adult rat hypoglossal nerve innervating the tongue muscles will be lesioned on one side by crush (for reversible injury), ligation (to permanently disconnect neurons from target muscles but retain the proximal nerve segment), and avulsion (to deprive neurons of Schwann cell-derived neurotrophic factors). The vagus nerve will be crushed or transected to include parasympathetic motor neurons for comparison. Since progesterone (PG) and melatonin (MT) possess antioxidant activities; and in cerebral ischemia and truamatic injuries, reduce tissue damage, attenuate brain edema and cell loss, and facilitate functional recovery; and glial cells have PG receptors, nerve lesioned rats will receive PG injection daily via s.c. route, MT by osmotic pump infusion, combined treatment of the two agents, PG antagonist RU486 to block endogenous PG activities, and no treatment as control. Specific questions to be addressed are: (1) Will PG increase the synthesis of brain-derived neurotrophic factor (BDNF) and glial cell-line derived neurotrophic factor (GDNF)? (2) Will PG and MT prevent the loss of neurons after nerve avulsion? (3) What is the status of PG receptors in motor neurons before and after axotomy? Will PG affect the expression of PG receptors ininjured neurons? (4) Will a \"death receptor\" FAS be induced in neurons after nerve avulsion? Will PG and MT block the induction or reduce the expression of FAS and p75 in injured neurons? To answer these questions, tissue sections will be prepared for neuronal cell counting, and for immunostaining of BDNF, GDNF, PG receptors, FAS and p75, and quantify their levels by computerized image analysis. These studies will provide insight into the cellular and molecular events responsible for the initiation and activation of apoptotic pathways in injured neurons, and offer therapeutic potential for treating traumatic injuries and other neuropathological conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: REDOX MECHANISMS OF RESPIRATORY MUSCLE STRESS ADAPTATION Principal Investigator & Institution: Clanton, Thomas L.; Professor; Internal Medicine; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2002; Project Start 01-DEC-1994; Project End 31-JAN-2005 Summary: During intense exercise, skeletal muscles must withstand stress in the form of heat, tissue hypoxia, reactive oxygen, steep osmotic gradients, elevated tissue pressure, sheer stress and over-stimulation. Few cells of the body could survive such punishment and yet skeletal muscles survive and adapt to it. To accomplish this, they must be pre-programmed in some primordial way to sense when the environment is threatening and make rapid adaptations in contractile and metabolic activity to reduce the threat to survival. We hypothesize that reactive oxygen is an important signal used for this purpose, particularly under conditions of metabolic stress, such as high energy demand (over-stimulation), low energy supply (hypoxia) or overheating (thermal stress). In this funding period, we will investigate the mechanisms by which reactive oxygen participates in muscle adaptation to stress. The study will focus on isolated, perfused mouse diaphragm. SPECIFIC AIM 1 will test the hypothesis that reactive oxygen is formed as an acute response to hypoxia, heat stress and over-stimulation (resulting in fatigue) and that conditions of disordered O2 supply and demand are necessary prerequisites for this response. Both tissue fluorescence and confocal imaging techniques will be used in these experiments. SPECIFIC AIM 2 will test the hypothesis that reactive oxygen plays an important role as a signaling agent to modify metabolic pathways during stress in such a way as to favor of accumulation of metabolites,

Studies 55 preservation of ATP and reduction of creatine phosphate. This will be tested by blocking the effects or reactive oxygen with antioxidants and by using transgenic species with antioxidant over-expression. Measures phosphate metabolism, mitochondrial function, creatine kinase function and activity of other metabolic enzymes will be assessed. SPECIFIC AIM 3 will test the hypothesis that reactive oxygen plays a role in acute changes in the cytoskeleton during stress that promote an increase in muscle \"stiffness\" and favor preservation of muscle structural integrity. Biophysical measurements of the viscoelastic properties of muscle will be tested before and during stress. These studies should provide new information regarding the adaptive mechanisms muscle in stressful environments. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: REGULATION OF ALS AND ITS ROLE IN THE IGF SYSTEM Principal Investigator & Institution: Boisclair, Yves R.; Animal Science; Cornell University Ithaca Office of Sponsored Programs Ithaca, Ny 14853 Timing: Fiscal Year 2003; Project Start 26-SEP-1997; Project End 31-MAR-2007 Summary: (provided by applicant): Gene deletion studies have demonstrated the importance of IGF-I and II (IGFs), particularly during fetal life when local IGFs production predominates. After birth, the liver becomes the most important site of IGFs synthesis, resulting in the development of a substantial plasma reservoir. This reservoir is dependent on the postnatal production of the acid labile subunit (ALS), a protein that recruits IGFs and IGF Binding Protein-3 in long-lived ternary complexes. The significance of this reservoir has been uncertain until we showed that ALS and the plasma IGF-I reservoir are required for early postnatal growth and bone development. We now will extend these studies to normal and diseased states of later postnatal life. This is relevant to malnutrition and catabolic illnesses in which decreased plasma IGF-I is associated with erosion of lean mass. Despite this association, IGF-I-based therapies have had limited success, reflecting the need for their incorporation into ternary complexes for effectiveness. Three specific aims wilt be pursued to address the role of ALS and the circulating IGFs reservoir during diseased states. AIM A: IGF-I is a potent positive regulator of skeletal muscle mass. Null ALS mice will be subjected to challenges known to induce changes in plasma IGF-I and to alter the mass of skeletal muscles (i.e., sudden increase in GH, nutritional deficiency or sepsis). AIM B: Humans have 3 times as much plasma IGF-II than IGF-I. In contrast, mice have little IGF-II and null ALS mice have normal carbohydrate homeostasis. To determine the role of ALS in containing the metabolic effects of IGF-II, we will study null ALS mice over-expressing human IGF-II. AIM C: GH stimulates ALS synthesis by increasing transcription. In vitro, this effect is conveyed by STAT5, but the importance of this mechanism remains to be established in vivo. Using null STAT5 mice and liver cells, we will evaluate the contribution of direct and indirect mechanisms mediating the effects of GH on ALS synthesis. Studying the GH-regulation of ALS transcription will provide clues to mechanisms responsible for development of hepatic GH resistance during catabolic diseases. Overall, these studies will significantly advance our understanding of the roles played by ALS and the circulating IGF reservoir in diseases of postnatal life. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: REGULATION OF PROTEIN TURNOVER IN SEPSIS Principal Investigator & Institution: Vary, Thomas C.; Professor; Cellular/Molecular Physiology; Pennsylvania State Univ Hershey Med Ctr 500 University Drive Hershey, Pa 170332390

56 Muscles Timing: Fiscal Year 2002; Project Start 01-JUL-1989; Project End 31-JUL-2003 Summary: The objectives of the studies described herein are to identify the loci responsible for the inhibition of protein synthesis in skeletal muscle during sepsis and to establish the mechanism(s) by which the inhibition can be reversed in order to develop treatment strategies to combat the severe muscle wasting associated with the septic process. Sustained muscle wasting contributes to the morbidity and mortality associated with sepsis. The defect in protein synthesis is localized to an impaired translation of mRNA at the level of peptide-chain initiation. Translation initiation is regulated at two steps: formation of the 43S pre-initiation complex (controlled by eukaryotic initiation factor 2 (eIF2) and eIF2B); and the binding of mRNA to the 40S ribosome (controlled by elF4E). We have identified a decreased activity of eIF2B as one defect in peptide-chain initiation and have shown that the muscle content of eIF2B protein is diminished 40 percent by sepsis. Therefore, reduced expression of eIF2B appeared a likely cause of the sepsis-induced inhibition of peptide-chain initiation in muscles of septic rats. However, protein synthesis can be stimulated 2-fold by perfusion of muscles from septic rats with buffer containing either IGF-I or elevated concentrations of amino acids by accelerating peptide-chain initiation without increasing the muscle content of eIF2B. Thus, effects of a reduced eIF2B expression on protein synthesis can be overridden, but the mechanisms responsible remain unknown. The hypothesis to be tested is that altered regulation of eIF2B and/or eIF4E mediates the changes in protein synthesis in sepsis. The specific aims of the studies proposed for the next project period are: (1) to evaluate the role of altered phosphorylation of eIF2B activity in controlling translation initiation during sepsis; (2) to investigate the effect of sepsis on eIF4E by measuring the amount of eIF4E found in the inactive 4E-BPI eIF4E complex and the active eIF4G eIF4E complex in muscle; (3) to investigate the mechanisms by which IGF-I stimulates translation initiation and contrast the response of skeletal muscle protein synthesis to IGF-I with that of insulin during sepsis; (4) to investigate the mechanisms by which amino acids stimulate translation initiation, and hence protein synthesis, during sepsis; and (5) to investigate the mechanisms by which chronic infusion of TNF or IL-1 cause an inhibition of protein synthesis in skeletal muscle. The research design will be to correlate changes in eukaryotic factor activity with rates of protein synthesis to establish which control mechanisms are important for regulating protein synthesis in skeletal muscle during sepsis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: REGULATION OF SMOOTH MUSCLE ACTOMYOSIN BY CALPONIN Principal Investigator & Institution: Haeberle, Joe R.; Associate Professor; Molecular Physiol & Biophysics; University of Vermont & St Agric College 340 Waterman Building Burlington, Vt 05405 Timing: Fiscal Year 2002; Project Start 01-APR-1995; Project End 31-JUL-2004 Summary: The proposed studies constitute part of a larger effort to understand how the contraction of smooth muscle is regulated at the level of contractile proteins, actin and myosin. The focus of this proposal is to elucidate the mechanism by which the putative regulatory protein calponin interacts with the actin filament to modulate contraction. In particular, thee studies will attempt to determine if calponin regulates a well described state of smooth muscle contraction called a \"latch- state\". The latch-state allows smooth muscles to remain contracted for long periods with relatively low expenditure of chemical energy. The high-economy of smooth muscle contraction is essential for normal physiologic function. In spite of the central importance of this contractile state

Studies 57 for normal function of smooth muscle, the molecular basis for the regulation of the latch-state is unknown. Our central hypothesis is that calponin slows the rate of cross- bridge dissociation from actin, and this leads to activation of unphosphorylated cross bridges via a thin filament-linked mechanism. To test this hypothesis we will measure 1) actin filament sliding velocity, 2) changes in the level of force exerted on regulated actin filaments by a field of immobilized myosin molecules, 3) the force, displacement (step size), and attachment time for single myosin molecules interact with single actin filaments, and 4) the rate of myosin dissociation from actin using stopped-flow techniques. These measurements will provide insights into the physiologic parameters of isometric force and unloaded shortening velocity that characterize the contractile state of intact smooth muscles. These assays, in conjunction with recent x-ray diffraction data and high resolution electron microscopic images of actin myosin, tropomyosin, and calponin allow us to formulate and test specific molecular models for how calponin might interact with actin, tropomyosin, and/or myosin. The proposed studies will begin to address the issue of how calponin might interact with actin, tropomyosin, and/or myosin. The proposed studies will begin to address the issue of how calponin-mediated regulation interacts with the now well established myosin phosphorylation regulatory system. A major goal of the proposed studies will be to elucidate the role of calponin in thin-filament linked regulation of unphosphorylated myosin (i.e. the latch-state). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: RESPIRATORY ACTIVITIES OF INTRINSIC TONGUE MUSCLES Principal Investigator & Institution: Bailey, Elizabeth F.; Physiology; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL-2005 Summary: (provided by applicant): Tongue movement depends on the actions of both intrinsic (origin and insertion in the tongue) and extrinsic (attached to bone and inserted into the tongue) muscles. These muscles play a key role in swallowing, breathing, chewing, and speaking. Contraction of the extrinsic muscles is generally considered to change tongue position (protrusion or retrusion), whereas contraction of the intrinsic tongue muscles changes tongue shape. To date, research that examines the respiratory- related effects of tongue function in mammals has focused exclusively on the respiratory control and function of the extrinsic tongue muscles. The respiratory-related control and function of the intrinsic tongue muscles and their bearing on extrinsic tongue muscle activity are still unknown. Recent findings indicate that the intrinsic tongue muscles may contribute to tongue protrusion and retraction, and facilitate the actions of the extrinsic tongue muscles in swallowing. In light of these findings, our objective is to characterize the respiratory-related activities of the intrinsic tongue muscles in vivo. The specific goals of the present application are to test the following hypotheses: (1) intrinsic tongue muscles are co-activated with extrinsic tongue muscles during resting tidal breathing; (2) intrinsic and extrinsic tongue muscle activities are modulated in parallel by central and peripheral chemoreceptors and airway mechanoreceptors; and (3) the EMG of intrinsic and extrinsic tongue muscles exhibit similar onset times and burst characteristics during perturbations of chemoreceptor and mechanoreceptor feedback. Experiments will be conducted on urethane anesthetized, spontaneously breathing male Sprague-Dawley rats. Simultaneous EMG recordings of the hyoglossus, internal intercostal muscles and superior longitudinal muscles will be obtained under each of the following conditions: (1) hypoxia, hypercapnia, and asphyxia, to assess the effects of central and peripheral chemoreceptor stimulation of intrinsic tongue muscle activities; (2) before and after superior laryngeal nerve section, and before and after lingual nerve

58 Muscles section, to quantify the influence of upper airway mechanosensory modulation of intrinsic tongue muscle activities; (3) with and without single-breath airway occlusion, to quantify the influence of phasic lung volume changes on drive to intrinsic tongue musculature. The results of this work will enhance our understanding of the functions of the tongue musculature and provide broad insights into the modulation of tongue muscle activities in breathing and other behaviors such as chewing and swallowing. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: RESPIRATORY RELATED MOTOR OUTPUT TO UPPER AIRWAY MUSLCES Principal Investigator & Institution: Kuna, Samuel T.; Associate Professor of Medicine; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-JUL-1981; Project End 31-MAR-2004 Summary: (Adapted from the Applicant's Abstract): The purpose of this proposal is to perform experiments in decerebrate cats to examine four specific aims: 1. To determine the neural input from the Kolliker-Fuse nucleus (KFN) to pharyngeal respiratory muscle motoneurons located in the hypoglossal nucleus (HGN). In addition, to neural pathways, neuromediator activity of the KLN will be explored. 2. To determine the effect of airway length on the mechanical effects of pharyngeal constrictor muscle contraction. It is hypoothesized that upper airway shortening may alter the mechanical effect of contraction of these muscles, such that they will have dilatory instead of constricting action. 3. To determine the effect of vagal afferent activity on pharyngeal muscle constrictor action. It is proposed that the pharyngeal muscles that are usually pharyngeal constrictors may become dilator muscles during hypercapnia in the absence of afferent vagal feedback. 4. To determine the changes in regional structure during contracture of various pharyngeal muscles by the use of retrograde fiberoptic imaging in a closed upper airway. This work is an expansion of work conducted to date by the PI, who has recently relocated to the University of Pennsylvania. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: SARCOLEMMAL ORGANIZATION OF EXTRACULAR MUSCLE Principal Investigator & Institution: Porter, John D.; Professor; Ophthalmology; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2005 Summary: Extraocular muscle (EOM) is specifically tailored to serve a diverse repertoire of eye movement control systems. Many aspects of the molecular biology, cell biology, morphology, and function of EOM are very different from the well-describe skeletal muscles of the limb and axial skeleton. Genotype and/or phenoptypic differences in the EOMs may either predispose or protect them in disease. Thus, knowledge of EOM biology is critical in design of theoretical and practical models of eye movements and in preventing or treating disorders. of eye alignment or movement. We currently have almost no knowledge of the cell/molecular substrate for stabilizing the EOM membrane, or sarcolemma, and for formation and maintenance of specializations at the neuromuscular function. What we do know strongly suggests that the transmembrane protein complex that plays these roles in skeletal muscle may exhibit adaptations in EOM. We propose to test the hypothesis that the unique phenotype, and functional properties, of EOM require muscle group-specific adaptations at the level of the intricate complex of proteins that spans the sarcolemma to stabilize during muscle contraction and to organize the neuromuscular junction. First, we will determine the

Studies 59 spatial/temporal relationships in maturation EOM and visuomotor systems. Data will establish similarities and differences between EOM and the pattern that has been well described in other muscles. Second, we will investigate the regulatory mechanisms for the specializations in the transmembrane protein complex at neuromuscular junctions in EOM. These studies will allow use to identify the extent to which EOM utilizes general muscle regulatory mechanisms and identify any protein complex in EOM using natural mutant and gene knockout models that generate loss of function in most muscles. Our pilot data establish that EOM responds to loss of components of the transmembrane protein system in ways that other skeletal muscles do not. Proposed studies will begin to understand the molecular mechanisms used by EOM in sarcolemmal organization for the day-to-day function of these novel muscles. An overall knowledge of the properties and regulation of the EOM sarcolemma will be important for understanding and treating ocular motility disorders in myasthenia gravis, congenital fibrosis of EOM, and strabismus. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: SMOOTH MUSCLE THIN FILAMENT Principal Investigator & Institution: Graceffa, Philip J.; Boston Biomedical Research Institute 64 Grove St Watertown, Ma 02472 Timing: Fiscal Year 2002; Project Start 20-AUG-2001; Project End 31-JUL-2005 Summary: (provided by the applicant): Smooth muscles, which surround the periphery of hollow organs, contract to change organ shape or maintain tension to fix the shape and thereby control the flow of vital fluids, which are essential to the normal functioning of the cardiovascular, respiratory, digestive, and reproductive systems. If the regulation of smooth muscle contraction does not function properly, it could contribute to such diseases as high blood pressure, asthma, and premature birth. The goal of our work is to understand the molecular basis of the normal regulation of contraction. Smooth muscle contraction is primarily regulated by the Ca2+ controlled phosphorylation of myosin in the thick filament. However there is not a strict coupling between phosphorylation levels and the level of the resulting contractile force. Evidence indicates that there is additional regulation in the actin thin filament possibly involving tropomyosin (Tm). However the mechanism of this function is poorly understood. The long-range goal of this project is to uncover the molecular mechanisms whereby Tm, in concert with other thin filament proteins, regulates smooth muscle contraction. The main hypothesis of this proposal is that thin filament regulation occurs mainly by controlling the movement of Tm on the thin filament by myosin in the thick filament and by the other thin filament proteins, caldesmon and calponin, which are in turn regulated by phosphorylation and Ca2+binding proteins. This will be tested by monitoring Tm's position, and movement by measuring the Tm-actin distances as a function of myosin, caldesmon and calponin by fluorescence resonance energy transfer and correlated with actomyosin ATPase activity, an in vitro analogue of contraction. The results of these studies, which will be conducted on reconstituted thick and thin filaments, will help to further our understanding of the switching on/off of smooth muscle contraction and of smooth muscle's unique ability, especially vascular muscle, to maintain tension, and thus organ shape, at the cost of very little energy. These studies will compare myosin from vascular and gastrointestinal smooth muscles in order to better understand the ability of vascular muscle to maintain this tension. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

60 Muscles • Project Title: SPATIAL AND TEMPORAL CONTROL OF TARGETED LIMB MOVEMENTS Principal Investigator & Institution: Cordo, Paul J.; Senior Scientist; None; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 01-DEC-1983; Project End 31-MAY-2007 Summary: The long-range goal of this project is to determine how the human central nervous system (CNS) coordinates voluntary movement and ultimately to use this information to develop treatments for motor disorders, such as stroke. The goal of the research proposed in this application is to determine how proprioception at the receptor level-in this case, the muscle spindle-leads to perception. The central hypothesis to be investigated is that, in active movement, the primary source of proprioceptive input is muscle spindles in the lengthening, \"antagonist\" muscles, rather than muscle spindles in the contracting, \"agonist\" muscles. Three specific aims are addressed: Specific Aim 1 is to contrast the information signaled by agonist and antagonist muscle spindles to determine which of these populations provides the CNS with the most accurate information about limb position and movement. Unlike agonist muscle spindles, little is known about how antagonist muscle spindles respond to active joint rotation. We will characterize how agonist and antagonist muscle spindles signal joint position and movement to test the hypothesis that the CNS uses the input from both populations, but that the information provided by antagonist muscle spindles is the most accurate. Specific Aim 2 is to investigate how antagonist muscle spindles encode position and movement variables, to inform the CNS of the location and movement of the limbs in space. The proposed experiments are designed to test the hypothesis that, during a movement, antagonist muscle spindles signal the CNS information about the starting position, movement velocity, and limb position during movement by three distinctive features within the firing pattern. Specific Aim 3 is to characterize the influence of fusimotor input on antagonist muscle spindles. Past research on agonist muscle spindles has failed to explain why the CNS activates the fusimotor system during voluntary movement. The proposed experiments are designed to test the hypothesis that fusimotor input increases the precision with which antagonist muscle spindles signal limb position and movement during precise movements and during motor learning, but that fusimotor input does not decrease the precision of signaling from antagonist muscle spindles during loaded movements. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: SPATIAL AND TEMPORAL PROCESSING IN PROPRIOCEPTION Principal Investigator & Institution: Jones, Lynette A.; Mechanical Engineering; Massachusetts Institute of Technology Room E19-750 Cambridge, Ma 02139 Timing: Fiscal Year 2002; Project Start 16-FEB-2001; Project End 31-JAN-2005 Summary: (Adapted from the Investigator's Abstract) The proprioceptive system converts information from receptors in muscles, skin and joints for the purposes of perceiving both the internal state of the neuromuscular system (e.g. the position of limbs, the forces generated by muscles) and the properties of objects (e.g., weight, stiffness) encountered in the external world. There is considerable kinematic ambiguity in these afferent signals as mechanoreceptors in muscles, skin and joints do not simply encode a single stimulus but respond to a number of variables both mechanical and temporal. Despite this ambiguity, the proprioceptive system can still extract the necessary information, such as joint velocity or angular position, from the sensory input and use this both to control and perceive muscle force and limb movements. The long-

Studies 61 term goal of the present research is to understand The principles and mechanisms underlying these perceptual processes and to determine the commonalities in information processing shared by the proprioceptive system with other sensory modalities whose inputs arise externally. The present proposal uses human psychophysical techniques to address these issues in several series of experiments that will examine the nature and extent of spatial summation of forces in the hand using the contralateral limb-matching procedure, the temporal processing of limb movements and the motor and sensory mechanisms involved in perceiving derived percepts such as stiffness. The movement studies will initially focus on determining whether frequency selectivity, a property of many sensory modalities, characterizes proprioceptive processing. This will be measured in terms of tuning curves and peripheral filtering processes (i.e. critical bands). Related studies will determine what factors influence the perception of movement velocity under active and passive conditions, during fast and slow movements and when cutaneous signals are masked. The final series experiments will determine how subjects perceive properties such as stiffness, viscosity and inertia on the basis of muscle force and limb displacement signals, and whether, as predicted, the motor strategies used to derive this information differs for each of these variables. This research program will elucidate the basic operations of the human proprioceptive system, improve our understanding of normal perceptual functioning and provide a basis for interpreting neuromuscular and neurological disorders that impact human movement control. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: STRUCTURE AND FUNCTION OF SARCOPLASMIC RETICULUM Principal Investigator & Institution: Ikemoto, Noriaki; Senion Scientist; Boston Biomedical Research Institute 64 Grove St Watertown, Ma 02472 Timing: Fiscal Year 2002; Project Start 01-JUN-1976; Project End 31-MAR-2007 Summary: (provided by applicant): The overall goal of this project is to resolve the molecular mechanism of Excitation (E)-Contraction (C) Relaxation (R) coupling in normal and diseased muscles. Skeletal muscle-type E-C-R coupling appears to occur in several sequential steps. The proposed experiments aim to elucidate the mechanism for each of these steps. (1) Upon depolarization of the surface membrane (excitation of muscle cell), the activator domain of the dihydropyridine receptor II-III loop binds to, and its blocker domain dissociates from, the ryanodine receptor (RyR)/calcium release channel protein; T-tubule polarization reverses these processes (hypothesis). The investigator will test this model (and alternative models as well) by examining how the peptides corresponding to these domains (activator and blocker) compete with their in vivo counterparts during E-C coupling in triads and skinned or permeabilized fibers. To further define the mechanism, the pattern of peptide activation/inhibition will be correlated with the pattern of peptide binding. (2) The binding of these II-III loop domains to their specific binding sites on the RyR produces local conformational changes in the signal reception region. The investigator will localize the binding sites of these loop domains, and will monitor the dynamic conformational changes occurring in the signal reception region during E-C coupling using the site-specific fluorescence probe. (3) The conformational change in the signal reception region is coupled with a global conformational change in the RyR and calcium release (contraction). This process seems to involve interactions of a number of regulatory sub-domains within the RyR. Using a novel peptide probe technique, this investigator has uncovered several sub- domains involved in the regulation of the RyR calcium channel. Efforts will be made to uncover a sufficient number of sub-domains to deduce the global structure of the intra-

62 Muscles molecular communication network. (4) Soon after the induction of calcium release (contraction), the calcium ATPase is activated to facilitate re-uptake of the released calcium (relaxation). The investigator hypothesizes that the communication between the RyR and the calcium ATPase is mediated by the transient changes occurring in the luminal calcium. This will be tested by correlating the time course of the changes in the activity of the calcium ATPase with those in the luminal calcium concentration. This program will likely resolve the basic mechanisms governing individual steps of E-C coupling, and will provide a better understanding of abnormal channel regulation in skeletal and cardiac muscles. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: THE ALPHA-1C CALCIUM CHANNEL IN MUSCLE Principal Investigator & Institution: Palade, Philip T.; Professor; Physiology and Biophysics; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2002; Project Start 27-SEP-2000; Project End 31-JUL-2005 Summary: (Adapted from the applicant's abstract): L-type voltage-gated calcium channels also known as dihydropyridine receptors (DHPRs) are critical for excitation- contraction coupling in both skeletal and cardiac muscle. Each of these muscle types expresses its own isoform of the DHPR. The role of the alpha1C cardiac DHPR in cardiac muscle is unquestionable to both provide the influx of Ca2+ needed to trigger Ca2+ release from intracellular stores as well as to provide a means to refill those stores when they become depleted. In vascular smooth muscle these same channels are the site of action of nearly all Ca2+ channel blockers used therapeutically in the treatment of hypertension and heart disease. Recently certain adult skeletal muscles have been shown to exhibit not only the alpha1S skeletal isoform of the DHPR, but also the alpha1C cardiac isoform, although at lower levels of expression. This grant tests several hypotheses for the role of the cardiac DHPR in adult skeletal muscle. The hypotheses to be tested include refilling of partially depleted intracellular Ca2+ stores, forestalling fatigue, and serving to turn off other genes. Methods will include tension, (Ca2+)i and electrophysiology measurements and measurements of gene expression. The results may suggest additional roles for the alpha1C cardiac DHPRs in the heart as well as in many smooth muscles. This grant also seeks to determine how the steroid hormone dexamethasone, the protein kinase C inhibitor staurosporine, and electrical stimulation regulate the expression of the cardiac DHPR in muscle, and to determine the response elements for the transcription factors involved and for tissue-specific expression within the gene promoter. Additional methods will include traditional assays used for promoter work. These results will enhance understanding of the transcriptional regulation of this extremely important receptor for therapeutic agents in the treatment of hypertension and heart disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: THE ANATOMICAL BASIS OF HUMAN TONGUE BIOMECHANICS Principal Investigator & Institution: Sanders, Ira; Associate Professor; Otolaryngology; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 01-FEB-2001; Project End 31-JUL-2004 Summary: (provided by applicant): What is special about the human tongue that allows it to perform the movements that are unique to human speech and swallowing? The biomechanics of the tongue are dependent on its anatomy, and some of the most basic

Studies 63 facts of human tongue anatomy are unknown. It is hypothesized that the human tongue contains specialized anatomy related to the movements of human speech and swallowing. Studying this anatomy will increase our understanding of tongue movements; provide a normative baseline from which to compare pathological conditions, and provide the detail required for progress in surgical procedures on the tongue, including transplantation. The human tongue presents formidable challenges for the anatomist: the small muscle groups that interweave in complex ways are technically difficult to trace; it is often difficult to identify specific muscles in histological sections; and many techniques routinely used in animal studies cannot be used on human post mortem tissue. However, based on experience studying the human larynx, a systematic approach is proposed with a variety of techniques that have all been successfully tested in the preliminary work. Tongue anatomy will simultaneously be studied on the gross anatomical, microscopic and molecular level using the following methods: 1) high-resolution magnetic resonance microscopy of tongue tissue to study 3- D structural detail; 2) Sihler's stain, a process that renders whole tongue specimens translucent while counterstalning the nerve supply and outlines of muscle groups; 3) serial sectioning of whole tongues followed by staining to show details of muscle structure and insertion into connective tissue; 4) micro dissection of muscle fibers followed by silver and acetylcholinesterase staining to study details of muscle fiber size and shape, motor endplate types, and terminal axon branching; 5) myofibrillar ATPase, to type the muscle fibers of each muscle; 6) immunohistochemistry, to identify the myosin heavy chain (MHC) within tongue muscles; and 7) immunoelectrophoresis and immunoblotting, to confirm the immunohistochemistry. Preliminary work has supported the presence of specialized anatomy in the human tongue. Certaln muscles are significantly different in size and position when compared to other mammalian tongues. The genioglossus muscle, for example, is greatly enlarged while the inferior longitudinal is comparatively smaller. In addition, human tongue muscles have unusual internal structure: some appear to be compartmentalized into smaller groups of muscle fibers arranged in series. In the superior longitudinal muscle preliminary work suggests that these muscle compartments are surprisingly short and that the muscle fibers are interconnected in complex webs. Overall, the human tongue has the highest proportion of slow twitch muscle fibers yet reported in any mammalian tongue, and these are arranged in a gradient with the higher proportions found medially and in the tongue base. Among these slow muscle fibers are large numbers of slow tonic muscle fibers, an extremely rare type of muscle fiber with unique contractile properties. In summary, the dearth of information about the human tongue appears to offer an opportunity to increase our understanding of the special nature of speech and swallowing as well as the pathophysiology of dysphagia and dysarthria. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: THE ELECTROPHYSIOLOGY OF MOTOR NEURON DISEASES Principal Investigator & Institution: Bromberg, Mark B.; Professor; Neurology; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2003 Summary: (provided by applicant): Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders of unknown etiology. They have in common death of lower motor neurons (LMN) causing muscle weakness, and both disorders are fatal. Mechanisms of LMN death differ for SMA and ALS. In SMA, LMN death may occur over a limited period of time. Unanswered is whether there is late or continued LMN loss. Recent genetic studies in SMA indicate a relationship between

64 Muscles survival motor neuron gene (SMN2) copy number and SMA type. Unanswered is the relationship between copy number and LMN number. In ALS, no single mechanism of LMN death explains known features, and a cascade of events ultimately leading to LMN death is likely. Unanswered in ALS is the natural pattern of progression of LMN loss from muscle to muscle. Although muscle weakness is the clinical manifestation of LMN loss for both disorders, the rate of loss of strength does not accurately reflect the rate of loss of LMNs. The discrepancy is due to the compensatory effects of reinnervation of denervated fibers by collateral sprouting from surviving motor nerve terminals. Similarly, routine electrophysiologic tests do not accurately measure LMN loss. Unanswered for both disorders is the dynamics of the compensatory process that determines the clinical state and level of function. Motor unit number estimation (MUNE) is a special electrophysiologic test that can directly assess the number of LMNs innervating a muscle. There are no data on the natural course of LMN loss for SMA, and little data for ALS. We propose to develop and refine MUNE and other electrophysiologic techniques to study, and follow the course of LMN loss and associated compensatory changes. For SMA, we will adapt MUNE techniques to study infants and children. For older SMA and ALS, we will refine MUNE techniques to optimize data collection. For SMA, we will correlate LMN loss with clinical type and SMN2 copy number. We will begin, in the two years of the grant-performing serial studies, to assess whether there is continued LMN loss. For ALS, we will determine and compare the rate and pattern of LMN loss in distal and proximal muscles. In older SMA and ALS, we will assess relationships between LMN loss and measures of collateral reinnervation and strength. We anticipate that MUNE and other electrophysiologic techniques will have direct applicability to the design of clinical trials for SMA and ALS, because these techniques can be used as informative end-point measures. To facilitate the use of MUNE in clinical trials, we will develop and refine the techniques in a form that can be used in any clinical center participating in trials. Currently, most MUNE techniques rely on proprietary software. We will develop software for use on PC-based computer systems, making them available to all laboratories. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: TRANSGENIC MICE WITH ALTERED CALCIUM HANDLING Principal Investigator & Institution: Kranias, Evangelia G.; Professor; Pharmacology & Cell Biophysics; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2003; Project Start 01-AUG-1997; Project End 31-JUL-2003 Summary: The sarcoplasmic recticulum (SR) is an internal membrane system in muscle, which functions as a Ca2+-sink during relaxation as as a Ca2+-source during contraction. Relaxation is mediated by the transport of Ca2+into the SR lumen by the Ca2+-ATPase (SERCA2), which is under regulation by phospholamban (PLB) in cardiac, slow-twitch skeletal and smooth muscles. Dephosphorylated PLB is an inhibitor of the affinity of the SR Ca2+-pump for Ca2+and phosphorylation relieves this inhibition. Alterations is in the expression levels of PLB or the SR Ca2+-ATPasehave been linked to altered Ca2+ homeostasis and deterioration of cellular function in several diseases. While transgenic mice have been rccently generated, which elucidated the functional role of altered PLB expression in vivo, focused on cardiac muscle and the physiological significance of PLB in other muscle and non-muscle tissues is not well understood. Thus, the objectives of the present proposal are to generate mouse models, with altered expressionof PLB or the SR Ca2+-ATPase to better define the function of each of these two key Ca2+-handling protein in vivo. Specifically, we will generate mice: a) overexpressing PLB and its phosphorylation mutants in either smooth or soleus muscle.

Studies 65 Studies in these models coupled with studies in the PLB knockout mouse will elucidate the functional role of PLB in smooth and soleus muscles and define the second messanger pathways regulating these muscles through phosphorylation of PLB; b) overexpressing PLB in multiple tissues and under the control of an inducible promoter to achieve tight temporal and quantitative control of PLB expression in a reversible manner. These models will permit evaluation of the role of temporal alterations in PLB expression levels on cellular function; and c) overexpressing each of the SERCA2 isoforms (SERCA2a or SERCA2b) or conditionally ablating SERCA2 expression in a tissue specific manner. The models with altered SERCA2 expression levels will elucidate the role of this protein in the intact animal. Overall, the proposed animal models will provide valuable and unique systems for the biomedical community at large to carry out further studies on elucidating the functional role of PLB and SERCA2 in intracellular calcium handling in health and disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: TROPHIC MANIPULATIONS OF THE OCULOMOTOR SYSTEM Principal Investigator & Institution: Von Bartheld, Christopher S.; Associate Professor; Physiology and Cell Biology; University of Nevada Reno 204 Ross Hall Mailstop 325 Reno, Nv 89557 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-JUL-2005 Summary: (Adapted from applicant's abstract): Strabismus is a misalignment of the visual axis, which can lead to severe deficiencies such as loss of central vision from one eye, known as amblyopia. Strabismus is relatively common in the general population with estimates of 5-6 percent. The etiology of strabismus is multifactorial. Current therapies for restoration of visual alignment include muscle weakening by surgical recession or pharmacological denervation with botulinum toxin and muscle tightening by surgical resection. In the proposed research project, the trophic regulation between eye muscles an innervating oculomotor neurons will be explored with the long-term goal to supplement surgical treatment of strabismus with a pharmacological treatment targeted at trophic interactions. Injections of trophic factors or trophic antagonists into selected eye muscles may restore balanced eye movements by mimicking intrinsic trophic mechanisms. The proposed studies will test in an animal model how trophic manipulations of oculomotor neurons and eye muscles can adjust the strength of these muscles, increase the survival of oculomotor neurons during development, increase numbers of collateral axonal branches of oculomotor neurons, and maintain axon collaterals and endplates. Studies will determine which trophic factors are produced in the eye muscles, which functions they have on muscle mass, muscle strength, nerve sprouting, and maintenance of axons or endplates. Additional studies will determine whether the muscle-derived factors are transported retrogradely to the oculomotor neurons and support the survival of these neurons. The time course of trophic interactions between eye muscles and their nerves will be explored with the goal to understand and manipulate the trophic responses which are induced by denervation with botulinum toxin or in chronically paralyzed muscle such as the avian genetic mutant, crooked neck dwarf (cn/cn). These studies will focus on four trophic factors, brain-derived neurotrophic factor (BDNF), glial cell-line-derived neurotrophic factor (GDNF), and the insulin-like growth factors (IGF I, II), and, added in the resubmission, cardiotrophin-1 (CT-1). Additional trophic factors will be screened for their potential to modify the strength of eye muscles. A combined pharmacological, molecular, physiological and morphological approach including the ultrastructural level will provide a meaningful assessment of the prospects for a trophic, pharmacological

66 Muscles treatment of strabismus and other eye muscle disorders as a supplement to current resection and denervation procedures. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen • Project Title: VULNERABILITY OF MOTOR NERVE TERMINALS IN AN ALS MODEL Principal Investigator & Institution: Barrett, Ellen F.; Professor; Physiology and Biophysics; University of Miami-Medical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2006 Summary: (provided by applicant): Motor nerve terminals are especially vulnerable to ischemic stress. The proposed experiments will test the hypothesis that even at early ages motor terminals in mice that overexpress a mutant human superoxide dismutase I (SODIG93A, a model of familial amyotrophic lateral sclerosis) are more vulnerable to stress than terminals in mice that overexpress wild-type human superoxide dismutase (hSOD1). We will test three stresses that might sometimes be encountered by motor terminals in vivo: (1) hindlimb ischemia/reperfusion stress in vivo, (2) hypoxia/ reoxygenation stress in vitro, and (3) in vivo intense stimulation of a single motor nerve. Structural integrity of the stressed motor terminals will be assessed by a fluorescence endplate occupancy assay, testing the extent to which labeled skeletal muscle endplates in fast and slow muscles are occupied by an innervating motor nerve terminal. Preliminary results indicate that both the ischemic and stimulation stresses increase endplate denervation. The function of motor terminals will be assessed during and/or after the stress by measuring resting and stimulation-induced changes in cytosolic and mitochondrial [Ca2+] and mitochondrial membrane potential using fluorescent indicators, and by measuring quantal transmitter release using electrophysiological recording. Preliminary results show disruptions in all these functional parameters during the hypoxia/ reoxygenation stress. Other experiments will test whether stresses that damage motor terminals also produce immunohistochemical signs of damage in the parent motoneurons. We will also test whether agents shown to be neuroprotective for motoneurons (e.g. vascular endothelial growth factor, VEGF; insulin-like growth factor, IGF-1) can protect motor nerve terminals during these stresses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “muscles” (or synonyms) into the search box. This search gives you access to full- text articles. The following is a sample of items found for muscles in the PubMed Central database: 3 Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html. 4 With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.

Studies 67 • 14-3-3[tau] associates with and activates the MEF2D transcription factor during muscle cell differentiation. by Choi SJ, Park SY, Han TH.; 2001 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=55772 • 20-Hydroxyeicosatetraenoic acid mediates calcium/calmodulin-dependent protein kinase II-induced mitogen-activated protein kinase activation in vascular smooth muscle cells. by Muthalif MM, Benter IF, Karzoun N, Fatima S, Harper J, Uddin MR, Malik KU.; 1998 Oct 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22894 • A Calcineurin-NFATc3-Dependent Pathway Regulates Skeletal Muscle Differentiation and Slow Myosin Heavy-Chain Expression. by Delling U, Tureckova J, Lim HW, De Windt LJ, Rotwein P, Molkentin JD.; 2000 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86143 • A conserved CATTCCT motif is required for skeletal muscle-specific activity of the cardiac troponin T gene promoter. by Mar JH, Ordahl CP.; 1988 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=281980 • A Gene Therapy Strategy Using a Transcription Factor Decoy of the E2F Binding Site Inhibits Smooth Muscle Proliferation in vivo. by Morishita R, Gibbons GH, Horiuchi M, Ellison KE, Nakajima M, Zhang L, Kaneda Y, Ogihara T, Dzau VJ.; 1995 Jun 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41600 • A novel E box/AT-rich element is required for muscle-specific expression of the sarcoplasmic reticulum Ca2+-ATPase (SERCA2) gene. by Baker DL, Dave V, Reed T, Misra S, Periasamy M.; 1998 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=147358 • A protein kinase B-dependent and rapamycin-sensitive pathway controls skeletal muscle growth but not fiber type specification. by Pallafacchina G, Calabria E, Serrano AL, Kalhovde JM, Schiaffino S.; 2002 Jul 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=123120 • A Role for Nitric Oxide in Muscle Repair: Nitric Oxide --mediated Activation of Muscle Satellite Cells. by Anderson JE.; 2000 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=14889 • A serum response factor-dependent transcriptional regulatory program identifies distinct smooth muscle cell sublineages. by Kim S, Ip HS, Lu MM, Clendenin C, Parmacek MS.; 1997 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=232076 • A single MEF-2 site is a major positive regulatory element required for transcription of the muscle-specific subunit of the human phosphoglycerate mutase gene in skeletal and cardiac muscle cells. by Nakatsuji Y, Hidaka K, Tsujino S, Yamamoto Y, Mukai T, Yanagihara T, Kishimoto T, Sakoda S.; 1992 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=360362

68 Muscles • Abnormal Junctions Between Surface Membrane and Sarcoplasmic Reticulum in Skeletal Muscle with a Mutation Targeted to the Ryanodine Receptor. by Takekura H, Nishi M, Noda T, Takeshima H, Franzini-Armstrong C.; 1995 Apr 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42170 • Absence of the [beta] subunit (cchb1) of the skeletal muscle dihydropyridine receptor alters expression of the [alpha]1 subunit and eliminates excitation-contraction coupling. by Gregg RG, Messing A, Strube C, Beurg M, Moss R, Behan M, Sukhareva M, Haynes S, Powell JA, Coronado R, Powers PA.; 1996 Nov 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19477 • Abundant expression of parathyroid hormone-related protein in primary rat aortic smooth muscle cells accompanies serum-induced proliferation. by Hongo T, Kupfer J, Enomoto H, Sharifi B, Giannella-Neto D, Forrester JS, Singer FR, Goltzman D, Hendy GN, Pirola C, et al.; 1991 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=295751 • Actinin-Associated LIM Protein-Deficient Mice Maintain Normal Development and Structure of Skeletal Muscle. by Jo K, Rutten B, Bunn RC, Bredt DS.; 2001 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86714 • Activation and Cellular Localization of the Cyclosporine A-sensitive Transcription Factor NF-AT in Skeletal Muscle Cells. by Abbott KL, Friday BB, Thaloor D, Murphy TJ, Pavlath GK.; 1998 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25565 • Activation of Protein Kinase C[zeta] Induces Serine Phosphorylation of VAMP2 in the GLUT4 Compartment and Increases Glucose Transport in Skeletal Muscle. by Braiman L, Alt A, Kuroki T, Ohba M, Bak A, Tennenbaum T, Sampson SR.; 2001 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=99955 • Activation of Ras and the Mitogen-Activated Protein Kinase Pathway Promotes Protein Degradation in Muscle Cells of Caenorhabditis elegans. by Szewczyk NJ, Peterson BK, Jacobson LA.; 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=133852 • Adeno-associated virus site-specifically integrates into a muscle-specific DNA region. by Dutheil N, Shi F, Dupressoir T, Linden RM.; 2000 Apr 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18323 • Adenovirus-mediated over-expression of the cyclin/cyclin-dependent kinase inhibitor, p21 inhibits vascular smooth muscle cell proliferation and neointima formation in the rat carotid artery model of balloon angioplasty. by Chang MW, Barr E, Lu MM, Barton K, Leiden JM.; 1995 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=185876 • Adenylate kinase1 gene deletion disrupts muscle energetic economy despite metabolic rearrangement. by Janssen E, Dzeja PP, Oerlemans F, Simonetti AW, Heerschap A, Haan AD, Rush PS, Terjung RR, Wieringa B, Terzic A.; 2000 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=305872

Studies 69 • Administration of endotoxin, tumor necrosis factor, or interleukin 1 to rats activates skeletal muscle branched-chain alpha-keto acid dehydrogenase. by Nawabi MD, Block KP, Chakrabarti MC, Buse MG.; 1990 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=296413 • Alpha 1-adrenergic receptor stimulation of sarcomeric actin isogene transcription in hypertrophy of cultured rat heart muscle cells. by Long CS, Ordahl CP, Simpson PC.; 1989 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=303787 • Alteration of Myosin Cross Bridges by Phosphorylation of Myosin-Binding Protein C in Cardiac Muscle. by Weisberg A, Winegrad S.; 1996 Aug 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38584 • Altered Extracellular Signal-Regulated Kinase Signaling and Glycogen Metabolism in Skeletal Muscle from p90 Ribosomal S6 Kinase 2 Knockout Mice. by Dufresne SD, Bjorbaek C, El-Haschimi K, Zhao Y, Aschenbach WG, Moller DE, Goodyear LJ.; 2001 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=88782 • Altered Skeletal Muscle Phenotypes in Calcineurin A[alpha] and A[beta] Gene- Targeted Mice. by Parsons SA, Wilkins BJ, Bueno OF, Molkentin JD.; 2003 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156151 • AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. by Zong H, Ren JM, Young LH, Pypaert M, Mu J, Birnbaum MJ, Shulman GI.; 2002 Dec 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=138551 • An alternative, nonkinase product of the brain-specifically expressed Ca2+/calmodulin-dependent kinase II alpha isoform gene in skeletal muscle. by Bayer KU, Lohler J, Harbers K.; 1996 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=230975 • An in vitro assay reveals essential protein components for the \"catch\" state of invertebrate smooth muscle. by Yamada A, Yoshio M, Kojima H, Oiwa K.; 2001 Jun 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34405 • An intronic enhancer containing an N-box motif is required for synapse- and tissue- specific expression of the acetylcholinesterase gene in skeletal muscle fibers. by Chan RY, Boudreau-Lariviere C, Angus LM, Mankal FA, Jasmin BJ.; 1999 Apr 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16383 • An N-terminal fragment of titin coupled to green fluorescent protein localizes to the Z-bands in living muscle cells: overexpression leads to myofibril disassembly. by Turnacioglu KK, Mittal B, Dabiri GA, Sanger JM, Sanger JW.; 1997 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=276120 • Analysis of SM22[alpha]-Deficient Mice Reveals Unanticipated Insights into Smooth Muscle Cell Differentiation and Function. by Zhang JC, Kim S, Helmke BP, Yu WW, Du KL, Lu MM, Strobeck M, Yu QC, Parmacek MS.; 2001 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=99586

70 Muscles • Analysis of the rabbit cardiac/slow twitch muscle sarcoplasmic reticulum calcium ATPase (SERCA2) gene promoter. by Sukovich DA, Shabbeer J, Periasamy M.; 1993 Jun 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=309608 • Association of calcium channel [alpha]1S and [beta]1a subunits is required for the targeting of [beta]1a but not of [alpha]1S into skeletal muscle triads. by Neuhuber B, Gerster U, Doring F, Glossmann H, Tanabe T, Flucher BE.; 1998 Apr 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20205 • Association of titin and myosin heavy chain in developing skeletal muscle. by Isaacs WB, Kim IS, Struve A, Fulton AB.; 1992 Aug 15; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=49737 • Caenorhabditis elegans UNC-98, a C2H2 Zn Finger Protein, Is a Novel Partner of UNC-97/PINCH in Muscle Adhesion Complexes. by Mercer KB, Flaherty DB, Miller RK, Qadota H, Tinley TL, Moerman DG, Benian GM.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=194897 • Calcineurin controls nerve activity-dependent specification of slow skeletal muscle fibers but not muscle growth. by Serrano AL, Murgia M, Pallafacchina G, Calabria E, Coniglio P, Lomo T, Schiaffino S.; 2001 Nov 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=60832 • Cardiac actin is the major actin gene product in skeletal muscle cell differentiation in vitro. by Bains W, Ponte P, Blau H, Kedes L.; 1984 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=368933 • CArG elements control smooth muscle subtype --specific expression of smooth muscle myosin in vivo. by Manabe I, Owens GK.; 2001 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=199571 • Carvedilol, a Cardiovascular Drug, Prevents Vascular Smooth Muscle Cell Proliferation, Migration, and Neointimal Formation Following Vascular Injury. by Ohlstein EH, Douglas SA, Sung CP, Yue T, Louden C, Arleth A, Poste G, Ruffolo RR Jr, Feuerstein GZ.; 1993 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46893 • Caspase 3 activity is required for skeletal muscle differentiation. by Fernando P, Kelly JF, Balazsi K, Slack RS, Megeney LA.; 2002 Aug 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=123204 • Characterization of a rat myosin alkali light chain gene expressed in ventricular and slow twitch skeletal muscles. by Periasamy M, Wadgaonkar R, Kumar C, Martin BJ, Siddiqui MA.; 1989 Oct 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=334880 • Characterization of Muscle Sarcoplasmic and Myofibrillar Protein Hydrolysis Caused by Lactobacillus plantarum. by Fadda S, Sanz Y, Vignolo G, Aristoy MC, Oliver G, Toldra F.; 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=91531

Studies 71 • Characterization of the AB (AF-1) region in the muscle-specific retinoid X receptor- gamma: evidence that the AF-1 region functions in a cell-specific manner. by Dowhan DH, Muscat GE.; 1996 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=145623 • Common core sequences are found in skeletal muscle slow- and fast-fiber-type- specific regulatory elements. by Nakayama M, Stauffer J, Cheng J, Banerjee-Basu S, Wawrousek E, Buonanno A.; 1996 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=231230 • Consequences of DNA-Dependent Protein Kinase Catalytic Subunit Deficiency on Recombinant Adeno-Associated Virus Genome Circularization and Heterodimerization in Muscle Tissue. by Duan D, Yue Y, Engelhardt JF.; 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=152118 • Contraction Stimulates Translocation of Glucose Transporter GLUT4 in Skeletal Muscle Through a Mechanism Distinct from that of Insulin. by Lund S, Holman GD, Schmitz O, Pedersen O.; 1995 Jun 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41592 • d-[alpha]-Tocopherol Inhibition of Vascular Smooth Muscle Cell Proliferation Occurs at Physiological Concentrations, Correlates with Protein Kinase C Inhibition, and is Independent of Its Antioxidant Properties. by Tasinato A, Boscoboinik D, Bartoli G, Maroni P, Azzi A.; 1995 Dec 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40322 • Development of a porcine skeletal muscle cDNA microarray: analysis of differential transcript expression in phenotypically distinct muscles. by Bai Q, McGillivray C, da Costa N, Dornan S, Evans G, Stear MJ, Chang KC.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=152649 • Developmental Expression of Spectrins in Rat Skeletal Muscle. by Zhou D, Ursitti JA, Bloch RJ.; 1998 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25216 • Dexamethasone enhances insulin-like growth factor-I effects on skeletal muscle cell proliferation. Role of specific intracellular signaling pathways. by Giorgino F, Smith RJ.; 1995 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=185771 • Differential Activation of Mitogen-Activated Protein Kinase in Response to Basic Fibroblast Growth Factor in Skeletal Muscle Cells. by Campbell JS, Wenderoth MP, Hauschka SD, Krebs EG.; 1995 Jan 31; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42722 • Differential Epitope Tagging of Actin in Transformed Drosophila Produces Distinct Effects on Myofibril Assembly and Function of the Indirect Flight Muscle. by Brault V, Sauder U, Reedy MC, Aebi U, Schoenenberger CA.; 1999 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25159

72 Muscles • Differential localization of HDAC4 orchestrates muscle differentiation. by Miska EA, Langley E, Wolf D, Karlsson C, Pines J, Kouzarides T.; 2001 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=55849 • Differential Requirement for the Nonhelical Tailpiece and the C Terminus of the Myosin Rod in Caenorhabditis elegans Muscle. by Hoppe PE, Andrews RC, Parikh PD.; 2003 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153131 • Direct Involvement of N-Cadherin --mediated Signaling in Muscle Differentiation. by Goichberg P, Geiger B.; 1998 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25598 • Disruption of Sur2-containing KATP channels enhances insulin-stimulated glucose uptake in skeletal muscle. by Chutkow WA, Samuel V, Hansen PA, Pu J, Valdivia CR, Makielski JC, Burant CF.; 2001 Sep 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=58803 • Distinct regulatory elements control muscle-specific, fiber-type-selective, and axially graded expression of a myosin light-chain gene in transgenic mice. by Rao MV, Donoghue MJ, Merlie JP, Sanes JR.; 1996 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=231388 • Doxorubicin selectively inhibits muscle gene expression in cardiac muscle cells in vivo and in vitro. by Ito H, Miller SC, Billingham ME, Akimoto H, Torti SV, Wade R, Gahlmann R, Lyons G, Kedes L, Torti FM.; 1990 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=54091 • Effect Of DNA-dependent protein kinase on the molecular fate of the rAAV2 genome in skeletal muscle. by Song S, Laipis PJ, Berns KI, Flotte TR.; 2001 Mar 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=31183 • Effect of extraction time and acid concentration on the separation of proglycogen and macroglycogen in horse muscle samples. by Brojer JT, Stampfli HR, Graham TE.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=227005 • Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts. by Stump CS, Short KR, Bigelow ML, Schimke JM, Nair KS.; 2003 Jun 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=164701 • Effect of thymol on kinetic properties of Ca and K currents in rat skeletal muscle. by Szentandrassy N, Szentesi P, Magyar J, Nanasi PP, Csernoch L.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=183846 • Elevated arginase I expression in rat aortic smooth muscle cells increases cell proliferation. by Wei LH, Wu G, Morris SM Jr, Ignarro LJ.; 2001 Jul 31; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=55408 • Elevated expression of monocyte chemoattractant protein 1 by vascular smooth muscle cells in hypercholesterolemic primates. by Yu X, Dluz S, Graves DT, Zhang L, Antoniades HN, Hollander W, Prusty S, Valente AJ, Schwartz CJ, Sonenshein GE.; 1992 Aug 1; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=49623

Studies 73 • Elevated Glucose and Angiotensin II Increase 12-Lipoxygenase Activity and Expression in Porcine Aortic Smooth Muscle Cells. by Natarajan R, Gu J, Rossi J, Gonzales N, Lanting L, Xu L, Nadler J.; 1993 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46630 • Elevated subsarcolemmal Ca2 + in mdx mouse skeletal muscle fibers detected with Ca2 +-activated K + channels. by Mallouk N, Jacquemond V, Allard B.; 2000 Apr 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18338 • Elimination of smooth muscle cells in experimental restenosis: targeting of fibroblast growth factor receptors. by Casscells W, Lappi DA, Olwin BB, Wai C, Siegman M, Speir EH, Sasse J, Baird A.; 1992 Aug 1; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=49665 • Endothelial cell expression of vasoconstrictors and growth factors is regulated by smooth muscle cell-derived carbon monoxide. by Morita T, Kourembanas S.; 1995 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=185974 • Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: Acetyl --CoA carboxylase inhibition and AMP-activated protein kinase activation. by Tomas E, Tsao TS, Saha AK, Murrey HE, Zhang CC, Itani SI, Lodish HF, Ruderman NB.; 2002 Dec 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=138607 • Enhancement of Muscle Gene Delivery with Pseudotyped Adeno-Associated Virus Type 5 Correlates with Myoblast Differentiation. by Duan D, Yan Z, Yue Y, Ding W, Engelhardt JF.; 2001 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=115001 • Epigallocathechin-3 Gallate Selectively Inhibits the PDGF-BB --induced Intracellular Signaling Transduction Pathway in Vascular Smooth Muscle Cells and Inhibits Transformation of sis-transfected NIH 3T3 Fibroblasts and Human Glioblastoma Cells (A172). by Ahn HY, Hadizadeh KR, Seul C, Yun YP, Vetter H, Sachinidis A.; 1999 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25235 • Epiregulin is a potent vascular smooth muscle cell-derived mitogen induced by angiotensin II, endothelin-1, and thrombin. by Taylor DS, Cheng X, Pawlowski JE, Wallace AR, Ferrer P, Molloy CJ.; 1999 Feb 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15542 • ErbB2 Is Required for Muscle Spindle and Myoblast Cell Survival. by Andrechek ER, Hardy WR, Girgis-Gabardo AA, Perry RL, Butler R, Graham FL, Kahn RC, Rudnicki MA, Muller WJ.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=133917 • Evidence for the load-dependent mechanical efficiency of individual myosin heads in skeletal muscle fibers activated by laser flash photolysis of caged calcium in the presence of a limited amount of ATP. by Sugi H, Iwamoto H, Akimoto T, Ushitani H.; 1998 Mar 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19317

74 Muscles • Expression and Partial Characterization of Kinesin-related Proteins in Differentiating and Adult Skeletal Muscle. by Ginkel LM, Wordeman L.; 2000 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15063 • Expression of bovine myf5 induces ectopic skeletal muscle formation in transgenic mice. by Santerre RF, Bales KR, Janney MJ, Hannon K, Fisher LF, Bailey CS, Morris J, Ivarie R, Smith CK 2nd.; 1993 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=364664 • Expression of high and low molecular weight caldesmons during phenotypic modulation of smooth muscle cells. by Ueki N, Sobue K, Kanda K, Hada T, Higashino K.; 1987 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=299689 • Expression of myogenic factors in denervated chicken breast muscle: isolation of the chicken Myf5 gene. by Saitoh O, Fujisawa-Sehara A, Nabeshima Y, Periasamy M.; 1993 May 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=309553 • Expression of the troponin complex genes: transcriptional coactivation during myoblast differentiation and independent control in heart and skeletal muscles. by Bucher EA, Maisonpierre PC, Konieczny SF, Emerson CP Jr.; 1988 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=365482 • Expression of utrophin A mRNA correlates with the oxidative capacity of skeletal muscle fiber types and is regulated by calcineurin/NFAT signaling. by Chakkalakal JV, Stocksley MA, Harrison MA, Angus LM, Deschenes-Furry J, St-Pierre S, Megeney LA, Chin ER, Michel RN, Jasmin BJ.; 2003 Jun 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=164666 • Expression profiling reveals altered satellite cell numbers and glycolytic enzyme transcription in nemaline myopathy muscle. by Sanoudou D, Haslett JN, Kho AT, Guo S, Gazda HT, Greenberg SA, Lidov HG, Kohane IS, Kunkel LM, Beggs AH.; 2003 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153613 • Extraocular muscle is defined by a fundamentally distinct gene expression profile. by Porter JD, Khanna S, Kaminski HJ, Rao JS, Merriam AP, Richmonds CR, Leahy P, Li J, Andrade FH.; 2001 Oct 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59827 • Flight muscle function in Drosophila requires colocalization of glycolytic enzymes. by Wojtas K, Slepecky N, von Kalm L, Sullivan D.; 1997 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=305727 • From intestine to muscle: Nuclear reprogramming through defective cloned embryos. by Byrne JA, Simonsson S, Gurdon JB.; 2002 Apr 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122901 • Full Functional Rescue of a Complete Muscle (TA) in Dystrophic Hamsters by Adeno-Associated Virus Vector-Directed Gene Therapy. by Xiao X, Li J, Tsao YP, Dressman D, Hoffman EP, Watchko JF.; 2000 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111478

Studies 75 • Functional muscle ischemia in neuronal nitric oxide synthase-deficient skeletal muscle of children with Duchenne muscular dystrophy. by Sander M, Chavoshan B, Harris SA, Iannaccone ST, Stull JT, Thomas GD, Victor RG.; 2000 Dec 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17659 • Functional Protection of Dystrophic Mouse (mdx) Muscles after Adenovirus- Mediated Transfer of a Dystrophin Minigene. by Deconinck N, Ragot T, Marechal G, Perricaudet M, Gillis JM.; 1996 Apr 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39651 • G protein-mediated inhibition of myosin light-chain phosphatase in vascular smooth muscle. by Kitazawa T, Masuo M, Somlyo AP.; 1991 Oct 15; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=52703 • Gene expression comparison of biopsies from Duchenne muscular dystrophy (DMD) and normal skeletal muscle. by Haslett JN, Sanoudou D, Kho AT, Bennett RR, Greenberg SA, Kohane IS, Beggs AH, Kunkel LM.; 2002 Nov 12; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137534 • Gene transfer establishes primacy of striated vs. smooth muscle sarcoglycan complex in limb-girdle muscular dystrophy. by Durbeej M, Sawatzki SM, Barresi R, Schmainda KM, Allamand V, Michele DE, Campbell KP.; 2003 Jul 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=166412 • Genetic Fate of Recombinant Adeno-Associated Virus Vector Genomes in Muscle. by Schnepp BC, Clark KR, Klemanski DL, Pacak CA, Johnson PR.; 2003 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149530 • Glucose transport in cultured human skeletal muscle cells. Regulation by insulin and glucose in nondiabetic and non-insulin-dependent diabetes mellitus subjects. by Ciaraldi TP, Abrams L, Nikoulina S, Mudaliar S, Henry RR.; 1995 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=185992 • GLUT4, AMP kinase, but not the insulin receptor, are required for hepatoportal glucose sensor --stimulated muscle glucose utilization. by Burcelin R, Crivelli V, Perrin C, Costa AD, Mu J, Kahn BB, Birnbaum MJ, Kahn CR, Vollenweider P, Thorens B.; 2003 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155044 • High-efficiency gene transfer into skeletal muscle mediated by electric pulses. by Mir LM, Bureau MF, Gehl J, Rangara R, Rouy D, Caillaud JM, Delaere P, Branellec D, Schwartz B, Scherman D.; 1999 Apr 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16320 • HIV envelope gp120 activates human arterial smooth muscle cells. by Schecter AD, Berman AB, Yi L, Mosoian A, McManus CM, Berman JW, Klotman ME, Taubman MB.; 2001 Aug 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=56929 • Human and murine dystrophin mRNA transcripts are differentially expressed during skeletal muscle, heart, and brain development. by Bies RD, Phelps SF, Cortez MD, Roberts R, Caskey CT, Chamberlain JS.; 1992 Apr 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=312263

76 Muscles • Human cytomegalovirus IE1 promoter/enhancer drives variable gene expression in all fiber types in transgenic mouse skeletal muscle. by Hallauer PL, Hastings KE.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=29077 • Hypoxia Extends the Life Span of Vascular Smooth Muscle Cells through Telomerase Activation. by Minamino T, Mitsialis SA, Kourembanas S.; 2001 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=100255 • Identification of a myocyte nuclear factor that binds to the muscle-specific enhancer of the mouse muscle creatine kinase gene. by Buskin JN, Hauschka SD.; 1989 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=362335 • Identification of the coupling between skeletal muscle store-operated Ca2 + entry and the inositol trisphosphate receptor. by Launikonis BS, Barnes M, Stephenson DG.; 2003 Mar 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151445 • Immune interferon inhibits proliferation and induces 2'-5'-oligoadenylate synthetase gene expression in human vascular smooth muscle cells. by Warner SJ, Friedman GB, Libby P.; 1989 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=303804 • Impairment of sympathetic activation during static exercise in patients with muscle phosphorylase deficiency (McArdle's disease). by Pryor SL, Lewis SF, Haller RG, Bertocci LA, Victor RG.; 1990 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=296590 • In vitro infection of smooth muscle cells by Chlamydia pneumoniae. by Knoebel E, Vijayagopal P, Figueroa JE 2nd, Martin DH.; 1997 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=176087 • In vivo and in vitro Analysis of Electrical Activity-Dependent Expression of Muscle Acetylcholine Receptor Genes Using Adenovirus. by Bessereau J, Stratford-Perricaudet LD, Piette J, Poupon CL, Changeux J.; 1994 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43146 • In Vivo Regulation of Human Skeletal Muscle Gene Expression by Thyroid Hormone. by Clement K, Viguerie N, Diehn M, Alizadeh A, Barbe P, Thalamas C, Storey JD, Brown PO, Barsh GS, Langin D.; 2002 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155277 • In vivo Suppression of Injury-Induced Vascular Smooth Muscle Cell Accumulation Using Adenovirus-Mediated Transfer of the Herpes Simplex Virus Thymidine Kinase Gene. by Guzman RJ, Hirschowitz EA, Brody SL, Crystal RG, Epstein SE, Finkel T.; 1994 Oct 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45096

Studies 77 • Inactivation of fatty acid transport protein 1 prevents fat-induced insulin resistance in skeletal muscle. by Kim JK, Gimeno RE, Higashimori T, Kim HJ, Choi H, Punreddy S, Mozell RL, Tan G, Stricker-Krongrad A, Hirsch DJ, Fillmore JJ, Liu ZX, Dong J, Cline G, Stahl A, Lodish HF, Shulman GI.; 2004 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=351314 • Induction by agrin of ectopic and functional postsynaptic-like membrane in innervated muscle. by Jones G, Meier T, Lichtsteiner M, Witzemann V, Sakmann B, Brenner HR.; 1997 Mar 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20144 • Inhibitors of soluble epoxide hydrolase attenuate vascular smooth muscle cell proliferation. by Davis BB, Thompson DA, Howard LL, Morisseau C, Hammock BD, Weiss RH.; 2002 Feb 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122346 • Insulin action on heart and skeletal muscle glucose uptake in essential hypertension. by Nuutila P, Maki M, Laine H, Knuuti MJ, Ruotsalainen U, Luotolahti M, Haaparanta M, Solin O, Jula A, Koivisto VA, et al.; 1995 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=185288 • Insulin and glucose 6-phosphate stimulation of Ca2+ uptake by skinned muscle fibers. by Brautigan DL, Kerrick WG, Fischer EH.; 1980 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=348397 • Insulin Control of Glycogen Metabolism in Knockout Mice Lacking the Muscle- Specific Protein Phosphatase PP1G/RGL. by Suzuki Y, Lanner C, Kim JH, Vilardo PG, Zhang H, Yang J, Cooper LD, Steele M, Kennedy A, Bock CB, Scrimgeour A, Lawrence JC Jr, DePaoli-Roach AA.; 2001 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86899 • Insulin increases near-membrane but not global Ca2 + in isolated skeletal muscle. by Bruton JD, Katz A, Westerblad H.; 1999 Mar 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=15933 • Insulin-induced cortical actin remodeling promotes GLUT4 insertion at muscle cell membrane ruffles. by Tong P, Khayat ZA, Huang C, Patel N, Ueyama A, Klip A.; 2001 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=209359 • Insulin-Like Growth Factor I Stimulates Myofibril Development and Decreases Smooth Muscle [alpha]-Actin of Adult Cardiomyocytes. by Donath MY, Zapf J, Eppenberger-Eberhardt M, Froesch ER, Eppenberger HM.; 1994 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43228 • Interference fine structure and sarcomere length dependence of the axial x-ray pattern from active single muscle fibers. by Linari M, Piazzesi G, Dobbie I, Koubassova N, Reconditi M, Narayanan T, Diat O, Irving M, Lombardi V.; 2000 Jun 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16527

78 Muscles • Intravenous administration of phosphorylated acid alpha-glucosidase leads to uptake of enzyme in heart and skeletal muscle of mice. by Van der Ploeg AT, Kroos MA, Willemsen R, Brons NH, Reuser AJ.; 1991 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=296338 • Invertebrate connectin spans as much as 3.5[micro]m in the giant sarcomeres of crayfish claw muscle. by Fukuzawa A, Shimamura J, Takemori S, Kanzawa N, Yamaguchi M, Sun P, Maruyama K, Kimura S.; 2001 Sep 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=125597 • Isoproterenol Stimulates Rapid Extrusion of Sodium from Isolated Smooth Muscle Cells. by Moore ED, Fay FS.; 1993 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=47287 • Long-term systemic therapy of Fabry disease in a knockout mouse by adeno- associated virus-mediated muscle-directed gene transfer. by Takahashi H, Hirai Y, Migita M, Seino Y, Fukuda Y, Sakuraba H, Kase R, Kobayashi T, Hashimoto Y, Shimada T.; 2002 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=129774 • Lymphocyte antigen Leu-19 as a molecular marker of regeneration in human skeletal muscle. by Schubert W, Zimmermann K, Cramer M, Starzinski-Powitz A.; 1989 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=286453 • M-CAT binding factor, a novel trans-acting factor governing muscle-specific transcription. by Mar JH, Ordahl CP.; 1990 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=360969 • Mice Lacking Skeletal Muscle Actin Show Reduced Muscle Strength and Growth Deficits and Die during the Neonatal Period. by Crawford K, Flick R, Close L, Shelly D, Paul R, Bove K, Kumar A, Lessard J.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=133984 • Mitochondrial DNA deletion mutations are concomitant with ragged red regions of individual, aged muscle fibers: analysis by laser-capture microdissection. by Cao Z, Wanagat J, McKiernan SH, Aiken JM.; 2001 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=60181 • Modulation of L-type Ca2+ current but not activation of Ca2+ release by the gamma1 subunit of the dihydropyridine receptor of skeletal muscle. by Ahern CA, Powers PA, Biddlecome GH, Roethe L, Vallejo P, Mortenson L, Strube C, Campbell KP, Coronado R, Gregg RG.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=37314 • Molecular Dissection of DNA Sequences and Factors Involved in Slow Muscle- Specific Transcription. by Calvo S, Vullhorst D, Venepally P, Cheng J, Karavanova I, Buonanno A.; 2001 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=100012 • Molecular genetics of muscle development andneuromuscular diseases Kloster Irsee, Germany, September 26 --October 1, 1999. by Brand T, Butler-Browne G, Fuchtbauer EM, Renkawitz-Pohl R, Brand-Saberi B.; 2000 May 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=305694

Studies 79 • Molecular organization of transverse tubule/sarcoplasmic reticulum junctions during development of excitation-contraction coupling in skeletal muscle. by Flucher BE, Andrews SB, Daniels MP.; 1994 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=301134 • Monoclonal antibody specific for the transverse tubular membrane of skeletal muscle activates the dihydropyridine-sensitive Ca2+ channel. by Malouf NN, Coronado R, McMahon D, Meissner G, Gillespie GY.; 1987 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=305238 • Mouse Limb Muscle is Determined in the Absence of the Earliest Myogenic Factor myf-5. by Tajbakhsh S, Buckingham ME.; 1994 Jan 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43026 • Mouse Pop1 Is Required for Muscle Regeneration in Adult Skeletal Muscle. by Andree B, Fleige A, Arnold HH, Brand T.; 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=134701 • Multiple defects in muscle glycogen synthase activity contribute to reduced glycogen synthesis in non-insulin dependent diabetes mellitus. by Thorburn AW, Gumbiner B, Bulacan F, Brechtel G, Henry RR.; 1991 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=296335 • Multiple thyroid hormone-induced muscle growth and death programs during metamorphosis in Xenopus laevis. by Das B, Schreiber AM, Huang H, Brown DD.; 2002 Sep 17; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=129427 • Muscle degeneration without mechanical injury in sarcoglycan deficiency. by Hack AA, Cordier L, Shoturma DI, Lam MY, Sweeney HL, McNally EM.; 1999 Sep 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17950 • Muscle LIM Proteins Are Associated with Muscle Sarcomeres and Require dMEF2 for Their Expression during Drosophila Myogenesis. by Stronach BE, Renfranz PJ, Lilly B, Beckerle MC.; 1999 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25449 • Muscle-regulated expression and determinants for neuromuscular junctional localization of the mouse RI[alpha] regulatory subunit of cAMP- dependent protein kinase. by Barradeau S, Imaizumi-Scherrer T, Weiss MC, Faust DM.; 2001 Apr 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33159 • Muscle-specific inactivation of the IGF-I receptor induces compensatory hyperplasia in skeletal muscle. by Fernandez AM, Dupont J, Farrar RP, Lee S, Stannard B, Le Roith D.; 2002 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150853 • Muscle-specific PPAR[gamma]-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones. by Norris AW, Chen L, Fisher SJ, Szanto I, Ristow M, Jozsi AC, Hirshman MF, Rosen ED, Goodyear LJ, Gonzalez FJ, Spiegelman BM, Kahn CR.; 2003 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=171387

80 Muscles • Myf5 is a direct target of long-range Shh signaling and Gli regulation for muscle specification. by Gustafsson MK, Pan H, Pinney DF, Liu Y, Lewandowski A, Epstein DJ, Emerson CP Jr.; 2002 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=155306 • Myocardin Is a Critical Serum Response Factor Cofactor in the Transcriptional Program Regulating Smooth Muscle Cell Differentiation. by Du KL, Ip HS, Li J, Chen M, Dandre F, Yu W, Lu MM, Owens GK, Parmacek MS.; 2003 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150745 • Myocardin is a master regulator of smooth muscle gene expression. by Wang Z, Wang DZ, Pipes GC, Olson EN.; 2003 Jun 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=165841 • Myocyte-Specific Enhancer Factor 2 Acts Cooperatively with a Muscle Activator Region to Regulate Drosophila Tropomyosin Gene Muscle Expression. by Lin M, Nguyen HT, Dybala C, Storti RV.; 1996 May 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39328 • MyoD is functionally linked to the silencing of a muscle-specific regulatory gene prior to skeletal myogenesis. by Mal A, Harter ML.; 2003 Feb 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149902 • Neural agrin controls acetylcholine receptor stability in skeletal muscle fibers. by Bezakova G, Rabben I, Sefland I, Fumagalli G, Lomo T.; 2001 Aug 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=55554 • NMR Studies of Muscle Glycogen Synthesis in Insulin-Resistant Offspring of Parents with Non-Insulin-Dependent Diabetes Mellitus Immediately after Glycogen- Depleting Exercise. by Price TB, Perseghin G, Duleba A, Chen W, Chase J, Rothman DL, Shulman RG, Shulman GI.; 1996 May 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39245 • Obscurin Is a Ligand for Small Ankyrin 1 in Skeletal Muscle. by Kontrogianni- Konstantopoulos A, Jones EM, van Rossum DB, Bloch RJ.; 2003 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151585 • Ontogenesis and localization of Ca2+ channels in mammalian skeletal muscle in culture and role in excitation-contraction coupling. by Romey G, Garcia L, Dimitriadou V, Pincon-Raymond M, Rieger F, Lazdunski M.; 1989 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=287034 • Opposing mitogenic and anti-mitogenic actions of parathyroid hormone-related protein in vascular smooth muscle cells: A critical role for nuclear targeting. by Massfelder T, Dann P, Wu TL, Vasavada R, Helwig JJ, Stewart AF.; 1997 Dec 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28357 • Origin of neointimal endothelium and [alpha]-actin --positive smooth muscle cells in transplant arteriosclerosis. by Hillebrands JL, Klatter FA, van den Hurk BM, Popa ER, Nieuwenhuis P, Rozing J.; 2001 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=209313 • Overexpression of myogenin in muscles of transgenic mice: interaction with Id-1, negative crossregulation of myogenic factors, and induction of extrasynaptic

Studies 81 acetylcholine receptor expression. by Gundersen K, Rabben I, Klocke BJ, Merlie JP.; 1995 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=230968 • Overexpression of the LAR (leukocyte antigen-related) protein-tyrosine phosphatase in muscle causes insulin resistance. by Zabolotny JM, Kim YB, Peroni OD, Kim JK, Pani MA, Boss O, Klaman LD, Kamatkar S, Shulman GI, Kahn BB, Neel BG.; 2001 Apr 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33185 • Pharmacogenetic heterogeneity of transgene expression in muscle and tumours. by Lefesvre P, Attema J, van Bekkum D.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=194725 • Platelet-Derived Growth Factor Stimulates the Secretion of Hyaluronic Acid by Proliferating Human Vascular Smooth Muscle Cells. by Papakonstantinou E, Karakiulakis G, Roth M, Block LH.; 1995 Oct 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40906 • Precise determination of mitochondrial DNA copy number in human skeletal and cardiac muscle by a PCR-based assay: lack of change of copy number with age. by Miller FJ, Rosenfeldt FL, Zhang C, Linnane AW, Nagley P.; 2003 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156738 • Prevention of cardiomyopathy in mouse models lacking the smooth muscle sarcoglycan-sarcospan complex. by Cohn RD, Durbeej M, Moore SA, Coral-Vazquez R, Prouty S, Campbell KP.; 2001 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=199179 • Prions in skeletal muscle. by Bosque PJ, Ryou C, Telling G, Peretz D, Legname G, DeArmond SJ, Prusiner SB.; 2002 Mar 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122606 • Promotion of Vascular Smooth Muscle Cell Growth by Homocysteine: A Link to Atherosclerosis. by Tsai J, Perrella MA, Yashizumi M, Hsieh C, Haber E, Schlegel R, Lee M.; 1994 Jul 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=44203 • Proteolytic disruption of laminin-integrin complexes on muscle cells during synapse formation. by Anderson MJ, Shi ZQ, Zackson SL.; 1996 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=231499 • Radial and longitudinal diffusion of myoglobin in single living heart and skeletal muscle cells. by Papadopoulos S, Endeward V, Revesz-Walker B, Jurgens KD, Gros G.; 2001 May 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33311 • Rapid neural regulation of muscle urokinase-like plasminogen activator as defined by nerve crush. by Hantai D, Rao JS, Festoff BW.; 1990 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=53806

82 Muscles • Rates of ubiquitin conjugation increase when muscles atrophy, largely through activation of the N-end rule pathway. by Solomon V, Baracos V, Sarraf P, Goldberg AL.; 1998 Oct 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22877 • Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. by Jackson KA, Majka SM, Wang H, Pocius J, Hartley CJ, Majesky MW, Entman ML, Michael LH, Hirschi KK, Goodell MA.; 2001 Jun 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=209322 • Regulation of Myosin Heavy Chain Expression during Rat Skeletal Muscle Development In Vitro. by Torgan CE, Daniels MP.; 2001 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34600 • Regulation of skeletal muscle stiffness and elasticity by titin isoforms: a test of the segmental extension model of resting tension. by Wang K, McCarter R, Wright J, Beverly J, Ramirez-Mitchell R.; 1991 Aug 15; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=52241 • Relationship of insulin-like growth factor II gene expression in muscle to synaptogenesis. by Ishii DN.; 1989 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=287027 • Release of Hepatocyte Growth Factor from Mechanically Stretched Skeletal Muscle Satellite Cells and Role of pH and Nitric Oxide. by Tatsumi R, Hattori A, Ikeuchi Y, Anderson JE, Allen RE.; 2002 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117951 • Requirement for Down-Regulation of the CCAAT-binding Activity of the NF-Y Transcription Factor during Skeletal Muscle Differentiation. by Gurtner A, Manni I, Fuschi P, Mantovani R, Guadagni F, Sacchi A, Piaggio G.; 2003 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=165670 • Rescue of dystrophin expression in mdx mouse muscle by RNA /DNA oligonucleotides. by Rando TA, Disatnik MH, Zhou LZ.; 2000 May 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25834 • Restoration of insulin-sensitive glucose transporter (GLUT4) gene expression in muscle cells by the transcriptional coactivator PGC-1. by Michael LF, Wu Z, Cheatham RB, Puigserver P, Adelmant G, Lehman JJ, Kelly DP, Spiegelman BM.; 2001 Mar 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=31136 • Role of Guanine Nucleotide-Binding Proteins--ras-Family or Trimeric Proteins or both--in Ca2+ Sensitization of Smooth Muscle. by Gong MC, Iizuka K, Nixon G, Browne JP, Hall A, Eccleston JF, Sugai M, Kobayashi S, Somlyo AV, Somlyo AP.; 1996 Feb 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40082 • Role of HuR in Skeletal Myogenesis through Coordinate Regulation of Muscle Differentiation Genes. by Figueroa A, Cuadrado A, Fan J, Atasoy U, Muscat GE, Munoz-Canoves P, Gorospe M, Munoz A.; 2003 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=162217

Studies 83 • Role of platelets in smooth muscle cell proliferation and migration after vascular injury in rat carotid artery. by Fingerle J, Johnson R, Clowes AW, Majesky MW, Reidy MA.; 1989 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=298292 • Role of the arginine-nitric oxide pathway in the regulation of vascular smooth muscle cell proliferation. by Ignarro LJ, Buga GM, Wei LH, Bauer PM, Wu G, del Soldato P.; 2001 Mar 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=31203 • Role of the short isoform of myosin light chain kinase in the contraction of cultured smooth muscle cells as examined by its down-regulation. by Bao J, Oishi K, Yamada T, Liu L, Nakamura A, Uchida MK, Kohama K.; 2002 Jul 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=123179 • Rostrocaudal gradient of transgene expression in adult skeletal muscle. by Donoghue MJ, Merlie JP, Rosenthal N, Sanes JR.; 1991 Jul 1; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=51975 • Sarcoglycan, the heart, and skeletal muscles: new treatment, old drug? by Towbin JA, Bowles NE.; 2001 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=199185 • Sarcolemmal Organization in Skeletal Muscle Lacking Desmin: Evidence for Cytokeratins Associated with the Membrane Skeleton at Costameres. by O'Neill A, Williams MW, Resneck WG, Milner DJ, Capetanaki Y, Bloch RJ.; 2002 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117318 • Sarcomere length-dependence of activity-dependent twitch potentiation in mouse skeletal muscle. by Rassier DE, MacIntosh BR.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=140028 • Sarcospan-Deficient Mice Maintain Normal Muscle Function. by Lebakken CS, Venzke DP, Hrstka RF, Consolino CM, Faulkner JA, Williamson RA, Campbell KP.; 2000 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=85350 • Scorpion toxins targeted against the sarcoplasmic reticulum Ca(2+)-release channel of skeletal and cardiac muscle. by Valdivia HH, Kirby MS, Lederer WJ, Coronado R.; 1992 Dec 15; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=50723 • Single-cell transplantation determines the time when Xenopus muscle precursor cells acquire a capacity for autonomous differentiation. by Kato K, Gurdon JB.; 1993 Feb 15; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=45862 • Skeletal muscle dysfunction in chronic obstructive pulmonary disease. by Jeffery Mador M, Bozkanat E.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59579 • Skeletal muscle engraftment potential of adult mouse skin side population cells. by Montanaro F, Liadaki K, Volinski J, Flint A, Kunkel LM.; 2003 Aug 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=170919

84 Muscles • Skeletal muscle membrane lipid composition is related to adiposity and insulin action. by Pan DA, Lillioja S, Milner MR, Kriketos AD, Baur LA, Bogardus C, Storlien LH.; 1995 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=185990 • Smooth muscle cell --extrinsic vascular spasm arises from cardiomyocyte degeneration in sarcoglycan-deficient cardiomyopathy. by Wheeler MT, Allikian MJ, Heydemann A, Hadhazy M, Zarnegar S, McNally EM.; 2004 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=351323 • Spontaneously hypertensive rat vascular smooth muscle cells in culture exhibit increased growth and Na+/H+ exchange. by Berk BC, Vallega G, Muslin AJ, Gordon HM, Canessa M, Alexander RW.; 1989 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=303754 • Stability of the human dystrophin transcript in muscle. by Tennyson CN, Shi Q, Worton RG.; 1996 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=146056 • Stable expression of calpain 3 from a muscle transgene in vivo: Immature muscle in transgenic mice suggests a role for calpain 3 in muscle maturation. by Spencer MJ, Guyon JR, Sorimachi H, Potts A, Richard I, Herasse M, Chamberlain J, Dalkilic I, Kunkel LM, Beckmann JS.; 2002 Jun 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124391 • Stearoyl-CoA desaturase 1 deficiency elevates insulin-signaling components and down-regulates protein-tyrosine phosphatase 1B in muscle. by Rahman SM, Dobrzyn A, Dobrzyn P, Lee SH, Miyazaki M, Ntambi JM.; 2003 Sep 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=196935 • Subcellular analysis of Ca2+ homeostasis in primary cultures of skeletal muscle myotubes. by Brini M, De Giorgi F, Murgia M, Marsault R, Massimino ML, Cantini M, Rizzuto R, Pozzan T.; 1997 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=276065 • Subcellular localization of myosin light chain kinase in skeletal, cardiac, and smooth muscles. by Cavadore JC, Molla A, Harricane MC, Gabrion J, Benyamin Y, Demaille JG.; 1982 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=346443 • Substance P Responsiveness of Smooth Muscle Cells is Regulated by the Integrin Ligand, Thrombospondin. by Dahm LM, Bowers CW.; 1996 Feb 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40070 • Surfactant-induced sealing of electropermeabilized skeletal muscle membranes in vivo. by Lee RC, River LP, Pan FS, Ji L, Wollmann RL.; 1992 May 15; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=49115

Studies 85 • Sustained secretion of human alpha-1-antitrypsin from murine muscle transduced with adeno-associated virus vectors. by Song S, Morgan M, Ellis T, Poirier A, Chesnut K, Wang J, Brantly M, Muzyczka N, Byrne BJ, Atkinson M, Flotte TR.; 1998 Nov 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24382 • Tagging muscle cell lineages in development and tail regeneration using Cre recombinase in transgenic Xenopus. by Ryffel GU, Werdien D, Turan G, Gerhards A, Goosses S, Senkel S.; 2003 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153756 • Telomerase reverse transcriptase promotes cardiac muscle cell proliferation, hypertrophy, and survival. by Oh H, Taffet GE, Youker KA, Entman ML, Overbeek PA, Michael LH, Schneider MD.; 2001 Aug 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=56957 • Temporal correlation between maximum tetanic force and cell death in postischemic rat skeletal muscle. by Suzuki H, Poole DC, Zweifach BW, Schmid-Schonbein GW.; 1995 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=186000 • The \"glycogen shunt\" in exercising muscle: A role for glycogen in muscle energetics and fatigue. by Shulman RG, Rothman DL.; 2001 Jan 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=14608 • The Cell Adhesion Molecule M-Cadherin Is Not Essential for Muscle Development and Regeneration. by Hollnagel A, Grund C, Franke WW, Arnold HH.; 2002 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=133893 • The development expression of the rat alpha-vascular and gamma-enteric smooth muscle isoactins: isolation and characterization of a rat gamma-enteric actin cDNA. by McHugh KM, Lessard JL.; 1988 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=365625 • The distribution of blood flow, oxygen consumption, and work output among the respiratory muscles during unobstructed hyperventilation. by Robertson CH Jr, Pagel MA, Johnson RL Jr.; 1977 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=333330 • The serum response factor coactivator myocardin is required for vascular smooth muscle development. by Li S, Wang DZ, Wang Z, Richardson JA, Olson EN.; 2003 Aug 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=170924 • The Thrombospondin Receptor CD47 (IAP) Modulates and Associates with [alpha]2[beta]1 Integrin in Vascular Smooth Muscle Cells. by Wang XQ, Frazier WA.; 1998 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25313 • The transduction properties of intercostal muscle mechanoreceptors. by Holt GA, Johnson RD, Davenport PW.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137590

86 Muscles • The Whistle and the Rattle: The Design of Sound Producing Muscles. by Rome LC, Syme DA, Hollingworth S, Lindstedt SL, Baylor SM.; 1996 Jul 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38881 • Theiler's murine encephalomyelitis virus-induced cardiac and skeletal muscle disease. by Gomez RM, Rinehart JE, Wollmann R, Roos RP.; 1996 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=190990 • Topology of the Ca2 + release channel of skeletal muscle sarcoplasmic reticulum (RyR1). by Du GG, Sandhu B, Khanna VK, Guo XH, MacLennan DH.; 2002 Dec 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=139211 • Transcription Enhancer Factor 1 Binds Multiple Muscle MEF2 and A/T-Rich Elements during Fast-to-Slow Skeletal Muscle Fiber Type Transitions. by Karasseva N, Tsika G, Ji J, Zhang A, Mao X, Tsika R.; 2003 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=165722 • Transdifferentiation of Chicken Embryonic Cells into Muscle Cells by the 3' Untranslated Region of Muscle Tropomyosin. by L'Ecuyer TJ, Tompach PC, Morris E, Fulton AB.; 1995 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41371 • Transfer of [beta]-Amyloid Precursor Protein Gene Using Adenovirus Vector Causes Mitochondrial Abnormalities in Cultured Normal Human Muscle. by Askanas V, McFerrin J, Baque S, Alvarez RB, Sarkozi E, Engel WK.; 1996 Feb 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40077 • Transformation by Rous sarcoma virus prevents acetylcholine receptor clustering on cultured chicken muscle fibers. by Anthony DT, Schuetze SM, Rubin LL.; 1984 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=345479 • Transgenic overexpression of caveolin-3 in skeletal muscle fibers induces a Duchenne-like muscular dystrophy phenotype. by Galbiati F, Volonte D, Chu JB, Li M, Fine SW, Fu M, Bermudez J, Pedemonte M, Weidenheim KM, Pestell RG, Minetti C, Lisanti MP.; 2000 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16926 • Trichinella spiralis-Infected Muscle Cells: Abundant RNA Polymerase II in Nuclear Speckle Domains Colocalizes with Nuclear Antigens. by Yao C, Jasmer DP.; 2001 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=98470 • Two Forms of Acetylcholine Receptor [gamma] Subunit in Mouse Muscle. by Mileo AM, Monaco L, Palma E, Grassi F, Miledi R, Eusebi F.; 1995 Mar 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42283 • Two mechanisms for termination of individual Ca2 + sparks in skeletal muscle. by Lacampagne A, Klein MG, Ward CW, Schneider MF.; 2000 Jul 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16629 • Type 3 ryanodine receptors of skeletal muscle are segregated in a parajunctional position. by Felder E, Franzini-Armstrong C.; 2002 Feb 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122253

Studies 87 • Vimentin mRNA Location Changes During Muscle Development. by Cripe L, Morris E, Fulton AB.; 1993 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46168 • Viral mediated expression of insulin-like growth factor I blocks the aging-related loss of skeletal muscle function. by Barton-Davis ER, Shoturma DI, Musaro A, Rosenthal N, Sweeney HL.; 1998 Dec 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=28090 • Voltage dependence of inositol 1,4,5-trisphosphate-induced Ca2+ release in peeled skeletal muscle fibers. by Donaldson SK, Goldberg ND, Walseth TF, Huetteman DA.; 1988 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=281839 • Voltage dependence of the pattern and frequency of discrete Ca2 + release events after brief repriming in frog skeletal muscle. by Klein MG, Lacampagne A, Schneider MF.; 1997 Sep 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23600 The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with muscles, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “muscles” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for muscles (hyperlinks lead to article summaries): • A delta-conotoxin from Conus ermineus venom inhibits inactivation in vertebrate neuronal Na+ channels but not in skeletal and cardiac muscles. Author(s): Barbier J, Lamthanh H, Le Gall F, Favreau P, Benoit E, Chen H, Gilles N, Ilan N, Heinemann SH, Gordon D, Menez A, Molgo J. Source: The Journal of Biological Chemistry. 2004 February 6; 279(6): 4680-5. Epub 2003 November 13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14615484 6 PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.

88 Muscles • A dynamic recurrent neural network for multiple muscles electromyographic mapping to elevation angles of the lower limb in human locomotion. Author(s): Cheron G, Leurs F, Bengoetxea A, Draye JP, Destree M, Dan B. Source: Journal of Neuroscience Methods. 2003 October 30; 129(2): 95-104. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14511813 • A Japanese family with FEOM1-linked congenital fibrosis of the extraocular muscles type 1 associated with spinal canal stenosis and refinement of the FEOM1 critical region. Author(s): Uyama E, Yamada K, Kawano H, Chan WM, Andrews C, Yoshioka M, Uchino M, Engle EC. Source: Neuromuscular Disorders : Nmd. 2003 August; 13(6): 472-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12899874 • A novel PHOX2A/ARIX mutation in an Iranian family with congenital fibrosis of extraocular muscles type 2 (CFEOM2). Author(s): Yazdani A, Chung DC, Abbaszadegan MR, Al-Khayer K, Chan WM, Yazdani M, Ghodsi K, Engle EC, Traboulsi EI. Source: American Journal of Ophthalmology. 2003 November; 136(5): 861-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14597037 • A retrospective analysis of the gluteal muscles contracture and discussion of the relative problems. Author(s): Liu G, Du J, Yang S, Zheng Q, Li J. Source: J Tongji Med Univ. 2000; 20(1): 70-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12845763 • Activation varies among the knee extensor muscles during a submaximal fatiguing contraction in the seated and supine postures. Author(s): Rochette L, Hunter SK, Place N, Lepers R. Source: Journal of Applied Physiology (Bethesda, Md. : 1985). 2003 October; 95(4): 1515- 22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12970375 • Activity patterns of leg muscles in periodic limb movement disorder. Author(s): de Weerd AW, Rijsman RM, Brinkley A. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2004 February; 75(2): 317- 9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14742617

Studies 89 • Adaptations in muscular activation of the knee extensor muscles with strength training in young and older adults. Author(s): Knight CA, Kamen G. Source: Journal of Electromyography and Kinesiology : Official Journal of the International Society of Electrophysiological Kinesiology. 2001 December; 11(6): 405-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11738953 • Altered aquaporin 4 expression in muscles of Fukuyama-type congenital muscular dystrophy. Author(s): Wakayama Y, Jimi T, Inoue M, Kojima H, Yamashita S, Kumagai T, Murahashi M, Hara H, Shibuya S. Source: Virchows Archiv : an International Journal of Pathology. 2003 December; 443(6): 761-7. Epub 2003 August 26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12942324 • An electromyographic analysis of the deep cervical flexor muscles in performance of craniocervical flexion. Author(s): Falla D, Jull G, Dall'Alba P, Rainoldi A, Merletti R. Source: Physical Therapy. 2003 October; 83(10): 899-906. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14519061 • An integrated AMLAB-based system for acquisition, processing and analysis of evoked EMG and mechanical responses of upper limb muscles. Author(s): Jaberzadeh S, Nazeran H, Scutter S, Warden-Flood A. Source: Australas Phys Eng Sci Med. 2003 June; 26(2): 70-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12956188 • Anatomical partitioning of three human forearm muscles. Author(s): Segal RL, Catlin PA, Krauss EW, Merick KA, Robilotto JB. Source: Cells, Tissues, Organs. 2002; 170(2-3): 183-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11731706 • Anterior and nasal transposition of the inferior oblique muscles. Author(s): Stager DR Jr, Beauchamp GR, Wright WW, Felius J, Stager D Sr. Source: J Aapos. 2003 June; 7(3): 167-73. Erratum In: J Aapos. 2003 December; 7(6): 450. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12825055 • Anticipatory activation of postural muscles associated with bilateral arm flexion in subjects with different quiet standing positions. Author(s): Fujiwara K, Toyama H, Kunita K. Source: Gait & Posture. 2003 June; 17(3): 254-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12770639

90 Muscles • Anticipatory postural adjustment in selected trunk muscles in post stroke hemiparetic patients. Author(s): Dickstein R, Shefi S, Marcovitz E, Villa Y. Source: Archives of Physical Medicine and Rehabilitation. 2004 February; 85(2): 261-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14966711 • Applied psychophysiology: beyond the boundaries of biofeedback (mending a wall, a brief history of our field, and applications to control of the muscles and cardiorespiratory systems). Author(s): Lehrer P. Source: Applied Psychophysiology and Biofeedback. 2003 December; 28(4): 291-304. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14686082 • Ask the doctor. I am a 64-year-old woman with high cholesterol caused by bad genes (familial hypercholesterolemia). Without medication, my cholesterol is above 450 mg/dL. So I am taking high-dose Lipitor (80 mg/day), WelChol, and Zetia to lower my cholesterol. I sometimes have pain and stiffness in my knees, and my shoulder, elbow, and wrist joints, plus the muscles in between, are stiff in the morning and hurt during the day. Two years ago I was diagnosed with bursitis in my hips. Could these problems be from the Lipitor? If so, is there another statin I could take that wouldn't do this? Author(s): Pasternak R. Source: Harvard Heart Letter : from Harvard Medical School. 2003 October; 14(2): 8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14576039 • Assessment of voluntary activation by stimulation of one muscle or two synergistic muscles. Author(s): Williams DM, Bilodeau M. Source: Muscle & Nerve. 2004 January; 29(1): 112-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14694506 • Atrophy of the abdominal wall muscles after extraperitoneal approach to the aorta. Author(s): Yamada M, Maruta K, Shiojiri Y, Takeuchi S, Matsuo Y, Takaba T. Source: Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter. 2003 August; 38(2): 346-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12891119 • Attitudinally correct designation of papillary muscles. Author(s): Frater RW. Source: J Heart Valve Dis. 2003 September; 12(5): 548-50. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14565703

Studies 91 • Beneficial effects of chronic low-frequency stimulation of thigh muscles in patients with advanced chronic heart failure. Author(s): Nuhr MJ, Pette D, Berger R, Quittan M, Crevenna R, Huelsman M, Wiesinger GF, Moser P, Fialka-Moser V, Pacher R. Source: European Heart Journal. 2004 January; 25(2): 136-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14720530 • Benign asymmetric hypertrophy of the masticator muscles. Author(s): Palacios E, Valvassori G, D'Antonio M. Source: Ear, Nose, & Throat Journal. 2000 December; 79(12): 915. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11191429 • Bilateral aberrant biceps brachii muscles with special reference to their common nerve trunks. Author(s): Kawashima T, Yoshitomi S, Ito M, Hoshino Y, Oh-Ishi E, Ikeda E, Igarashi M, Yoshimura Y, Sato F, Sasaki H. Source: Okajimas Folia Anat Jpn. 2003 October; 80(4): 77-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14964467 • Bilateral anomaly of anterior bellies of digastric muscles. Author(s): Peker T, Turgut HB, Anil A. Source: Surgical and Radiologic Anatomy : Sra. 2000; 22(2): 119-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10959680 • Bilateral cortical control of the human anterior digastric muscles. Author(s): Gooden BR, Ridding MC, Miles TS, Nordstrom MA, Thompson PD. Source: Experimental Brain Research. Experimentelle Hirnforschung. Experimentation Cerebrale. 1999 December; 129(4): 582-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10638432 • Bilateral inferior insertion of lateral rectus muscles associated with schizencephaly. Author(s): Wine SB, Saad N, Vella ME. Source: Clinical & Experimental Ophthalmology. 2000 February; 28(1): 69-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11345352 • Bilateral interactions during contractions of intrinsic hand muscles. Author(s): Zijdewind I, Kernell D. Source: Journal of Neurophysiology. 2001 May; 85(5): 1907-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11353007

92 Muscles • Bilateral posterior fixation sutures on the medial rectus muscles for correction of nonaccommodative esotropia with infantile onset criteria. Author(s): Rizk A. Source: Journal of Pediatric Ophthalmology and Strabismus. 1999 November-December; 36(6): 320-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11132663 • Bilateral recession of superior rectus muscles: its influence on A and V pattern strabismus. Author(s): Melek NB, Mendoza T, Ciancia AO. Source: J Aapos. 1998 December; 2(6): 333-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10532719 • Bilateral recurrent focal myositis of gastrocnemius muscles after BCG vaccination. Author(s): Manganelli S, De Stefano R, Malandrini A, Selvi E, Frati E, Gambelli S, Marcolongo R. Source: Rheumatology (Oxford, England). 2002 September; 41(9): 1074-6. Erratum In: Rheumatology (Oxford) 2002 December; 41(12): 1461. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12209048 • Binding of an ankyrin-1 isoform to obscurin suggests a molecular link between the sarcoplasmic reticulum and myofibrils in striated muscles. Author(s): Bagnato P, Barone V, Giacomello E, Rossi D, Sorrentino V. Source: The Journal of Cell Biology. 2003 January 20; 160(2): 245-53. Epub 2003 Jan 13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12527750 • Biomechanical model predicting electromyographic activity in three shoulder muscles from 3D kinematics and external forces during cleaning work. Author(s): Laursen B, Sogaard K, Sjogaard G. Source: Clinical Biomechanics (Bristol, Avon). 2003 May; 18(4): 287-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12689778 • Biomechanical model predicts directional tuning of spindles in finger muscles facilitates precision pinch and power grasp. Author(s): Biggs J, Horch K. Source: Somatosensory & Motor Research. 1999; 16(3): 251-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10527373