7
Skeletal Muscle

Introduction

Even though humans have not been reported to suffer permanent neuromuscular deficits from working in space for periods of a year or more, significant changes have been observed both in-flight and after return to Earth. These changes include muscle weakness, fatigue, incoordination, and delayed-onset muscle soreness. Loaded treadmill exercises reduce but do not prevent the loss of strength in the lower limbs, and bicycle ergometry is ineffective for preserving muscle mass. The increased fatigability, incoordination, and susceptibility to reloading injury are not remedied. Postflight recovery has not been analyzed adequately in either humans or animal models to determine the mechanisms, efficacy, and temporal progress of the rehabilitation. Muscle deterioration remains a major concern that warrants continued flight and ground studies to prepare for longer-duration missions. The goal is to maintain neuromuscular structure and function while minimizing the time required for countermeasures and enhancing the productivity of mission tasks. A consensus on the most appropriate types of countermeasures for prolonged spaceflight is far from being reached.1 2 3 There is general agreement that a multipronged approach, employing exercise plus other synergistic measures, is necessary. The other measures may include strategies such as the concomitant utilization of hormones, growth factors, drugs, and lower-body negative-pressure devices. To date, microgravity has been only minimally exploited as a unique tool for understanding the fundamental mechanisms that underlie its effects on neuromuscular function and provide the basis for development of effective countermeasures. The vast majority of spaceflight studies have been conducted pre- and postflight. Completion of the International Space Station and maintenance of a continuous human presence in space promise in-flight studies that will generate a wealth of new information on neuromuscular biology to advance basic knowledge and benefit humans in space and on Earth.

As currently understood, many effects on muscle can only be described as spaceflight-induced. Few changes can be confidently defined as resulting solely from microgravity. Humans continue to be



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--> 7 Skeletal Muscle Introduction Even though humans have not been reported to suffer permanent neuromuscular deficits from working in space for periods of a year or more, significant changes have been observed both in-flight and after return to Earth. These changes include muscle weakness, fatigue, incoordination, and delayed-onset muscle soreness. Loaded treadmill exercises reduce but do not prevent the loss of strength in the lower limbs, and bicycle ergometry is ineffective for preserving muscle mass. The increased fatigability, incoordination, and susceptibility to reloading injury are not remedied. Postflight recovery has not been analyzed adequately in either humans or animal models to determine the mechanisms, efficacy, and temporal progress of the rehabilitation. Muscle deterioration remains a major concern that warrants continued flight and ground studies to prepare for longer-duration missions. The goal is to maintain neuromuscular structure and function while minimizing the time required for countermeasures and enhancing the productivity of mission tasks. A consensus on the most appropriate types of countermeasures for prolonged spaceflight is far from being reached.1 2 3 There is general agreement that a multipronged approach, employing exercise plus other synergistic measures, is necessary. The other measures may include strategies such as the concomitant utilization of hormones, growth factors, drugs, and lower-body negative-pressure devices. To date, microgravity has been only minimally exploited as a unique tool for understanding the fundamental mechanisms that underlie its effects on neuromuscular function and provide the basis for development of effective countermeasures. The vast majority of spaceflight studies have been conducted pre- and postflight. Completion of the International Space Station and maintenance of a continuous human presence in space promise in-flight studies that will generate a wealth of new information on neuromuscular biology to advance basic knowledge and benefit humans in space and on Earth. As currently understood, many effects on muscle can only be described as spaceflight-induced. Few changes can be confidently defined as resulting solely from microgravity. Humans continue to be

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--> undernourished during flight, and this has global effects on the body—most especially muscle, which constitutes more than 30 percent of the body mass. In-flight studies so far have been inadequate to permit assignment of changes found during postflight sampling as resulting either from primary in-flight effects or secondary reentry or reloading alterations postflight. Dramatic secondary changes introduced during reentry and reexposure to unit gravity may alter or mask microgravity's primary effects. Despite this limitation, there are sufficient data from in-flight and simulated microgravity ground studies of humans and rats to put forth a plausible scenario of the adaptation of muscle to microgravity and readaptation to terrestrial gravity. This chapter discusses skeletal muscle biology in the context of whether or not we currently understand muscle physiology in sufficient detail to proceed with sending crews on long-term space missions, such as to Mars, and returning them to gravity without fear of serious clinical consequences. The answer is that we do not, but we can be ready in the next decade, given adequate ground-based and flight research opportunities. There are a number of key areas requiring attention. For example, muscle atrophy is induced by reduced contractile activity, unloaded contractions, and a shortened working range. Contractile proteins are selectively targeted for degradation through ubiquitination and the multicatalytic proteasome pathway. Stress hormones and undernutrition exacerbate a negative nitrogen balance due to loss of muscle protein. Lowered levels of bioactive growth hormone and diminished growth factors may be additional contributing factors (see Chapter 9). Changes in autonomic vasomotor regulation and blood volume affect muscle microcirculation. Musculovenous pumping is curtailed in quiescent muscles. The energy metabolism of muscle shifts from oxidative and lipid utilization toward reliance on glucose consumption. Novel patterns of central nervous system motor and reflex control of muscle are acquired. Most of these changes are appropriate adaptations to microgravity but are undesirable and debilitating in normal gravity. Most spaceflight investigations have focused on growing or mature animals. Preliminary spaceflight results and hindlimb unloading studies involving developing animals suggest that gravity loading may not only be necessary for the maintenance of mature skeletal muscle but may also be essential for differentiation of the developing neuromuscular system in a direction appropriate for functioning efficiently in terrestrial gravity. A period of unloading during spaceflight renders mature muscle susceptible to reloading injury. A major area of concern is that, while adaptation to microgravity is well tolerated, the stress of returning to gravity loading reveals serious impairments to normal functioning. The issue of neuromuscular deterioration involves multiple systems, which necessitates multifaceted solutions. Background Research Done on Muscle Biology Significant progress has been made in understanding the molecular basis of embryonic muscle cell differentiation. Sequential expression of regulatory factors of the MyoD family of myogenic proteins (MyoD, Myf5, MRF4, and myogenin) commits mesodermal cells to a myocyte lineage. 4 These proteins are members of the basic helix-loop-helix superfamily of transcription factors that, after forming heterodimers, bind to E-box sites on muscle-specific genes to activate transcription.5 Cells, programmed as myoblasts, migrate from somites to seed the body musculature; eventually, they cease proliferation and differentiate by coalescing to generate multinucleated myofibers that synthesize large quantities of muscle-specific proteins. Myocyte enhancer factor-2 (MEF2) transcription factors are necessary and interact synergistically with myogenic factors to maintain synthesis of muscle proteins.

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--> Growth factors regulate plasticity of the differentiating muscle. Insulin-like growth factors (IGFs) promote differentiation of myoblasts in response to injury, possibly through stimulating myogenin expression. Basic fibroblast growth factor represses differentiation and keeps myoblasts in the proliferative state. The mature fiber adapts its phenotype to optimize performance under conditions of altered workload, length, patterns of use, and humoral factors. Regulatory factors partition myofibers into multiple fast and slow fiber types. Primary slow fibers change from expression of embryonic to slow myosin heavy chain;6 7 secondary slow fibers produce embryonic, neonatal, fast, and slow myosins.8 9 There are several other proteins, such as the troponins and myosin light chains, which have fast and slow isoforms.10 DNA sequences with E-box and MEF2-like motifs upstream from the promoters (slow upstream regulatory elements) and intronic enhancers (fast intronic regulatory elements) are candidate factors for conferring fiber-type-specific expression. The phenotype of the secondary fibers is modulated by impulse patterns from the motor innervation.11 Thyroid hormone levels can also profoundly affect expression of myosin heavy and light chain isoforms.12 13 Mounting evidence indicates that cis- and trans-acting regulatory factors, as yet uncharacterized, control specific fiber-type differentiation at the transcriptional level.14 Myogenin mRNA levels are higher in slow fibers, and MyoD transcript levels are higher in fast fibers. 15 The characterization of cis- and trans-acting factors that regulate transcription of fiber-type-specific protein isoforms is an important area to pursue in understanding muscle plasticity. Whole-muscle physiological and biochemical studies have yielded insights into muscle adaptation but have stopped short of elucidating the unique repertoire of characteristics and functions at the single-fiber (cell) level. Transgenic animal studies have shown that c-ski proto-oncogene product induces hypertrophy of a subset of fast muscle fibers.16 The fast and slow phenotypes are altered by motor nerve impulse patterns and neurotrophic interactions, a cadre of hormones, and muscle cell working load and length. Previous Space- and Ground-based Research With the advent of the International Space Station and a permanent presence of humans in space, astronauts will spend longer periods in reduced gravity before returning to terrestrial gravity. Before this step can be accomplished with confidence, the deleterious effects that spaceflight and reloading upon return to Earth have on skeletal muscle must be better understood to ensure performance and prevent injury. The fact that many humans have successfully sojourned into space and returned without apparent persistent debilitation does not adequately diffuse the concern for ensuring healthy long-term space travel. A recent NASA panel on countermeasures concluded that many questions still have to be investigated so that researchers can identify efficacious countermeasure protocols. Exercise protocols appear to have a positive effect because the degree of muscle wasting correlates inversely with the amount of exercise, rather than directly with the duration of space travel.17 In addition, crew members increased their upper arm strength in microgravity by working against elastic cords. However, the tremendous compensatory and regenerative capacities of the neuromuscular system could have repaired and masked pathological changes during their recovery periods. If this is true, relying too heavily on such reserves may cause their capacity to be exceeded and culminate in permanent disabilities. This may be what happens in the so-called postpolio syndrome, in which individuals who have recovered from polio experience unexplained dramatic reductions in motor performance some 30 years later.18 To date, there have only been three studies of pre- and postflight muscle biopsies from astronaut crews of relatively short missions lasting 5, 11, and 17 days. Physiological, biochemical, and structural changes were studied at the cellular and molecular levels.19 20 21 22 Interpretation of the findings is complicated

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--> by factors that have continually plagued spaceflight studies and could have influenced the outcomes: the number of human subjects was small, and their preflight levels of exercise conditioning varied greatly. In addition to possible gender-unique responses, the test subjects participated in a wide range of in-flight payload activities that required variable and undocumented muscle use. Given the lack of specific details and high cost of time and effort, replaying the mission as a postflight ground control study in 1 g would be virtually impossible. This argues for better-controlled flight studies that may focus intensively on neuromuscular investigations for some future missions. Current understanding of the changes in skeletal muscles is derived from pioneering contributions of over two decades of pre- and postflight studies of rodents that were orbited 1 to 3 weeks in Russian biosatellites and U.S. space shuttles. A single in-flight tissue acquisition from adult rats was achieved as part of the 1993 Spacelab Life Sciences-2 (SLS-2) mission.23 A second on-orbit procurement of tissues from adult rats as well as developing postnatal rats flew in early 1998 as part of the Neurolab (Neurosciences Spacelab) mission. Data on ground-based rat hindlimb unloading and preliminary flight (NIH.R3 mission on STS-72) results indicate that gravity loading is required for normal development of the neuromuscular system of the weight-bearing soleus muscle, whereas loading is not critical for the non-weight-bearing extensor digitorum longus muscle. In the absence of weight-bearing, soleus muscle fibers failed to grow in size and differentiate normally into slow fibers, and elaboration of the motor nerve terminals was retarded. In addition, myoblast (satellite cell) proliferation was inhibited, producing a possible permanent deficit in the number of myonuclei per fiber.24 In a ground-based study, postnatal day-13 rats that were suspension unloaded until postnatal day 31 developed an abnormal hindlimb gait that persisted into adulthood.25 These findings suggest that neuromuscular development of terrestrial mammals requires timed environmental cues from gravity loading. A picture of microgravity-induced primary changes and reloading-induced secondary changes can be deduced from the collection of human spaceflight studies, ground-based simulations of spaceflight (including prolonged bed rest), and complementary investigations of rodents subjected to spaceflight or simulated microgravity unloading by hindlimb unloading (HU). HU involves harnessing rats to elevate the hindquarters and remove weight bearing (loading) from the muscles of the hindlimbs. 26 Primary In-Flight Changes Simple Deconditioning and Adaptation The primary effects of spaceflight and HU on rodent skeletal muscles have been established by in-flight dissection and by taking tissues in ground-based models before the affected muscles have reexperienced weight bearing.27 These changes are distinguished from secondary alterations that appear in muscle tissue obtained hours to days after return to Earth or let down from HU.28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 Broadly speaking, leg extensor muscles such as soleus and adductor longus lift the body against gravity (antigravity muscles). Antigravity slow-twitch muscles generally show the greatest deterioration following spaceflight and HU. These fibers have low-myosin ATPase activity and slow shortening contractions, and they are specialized for oxidative metabolism that provides fatigue resistance. In contrast, flexor muscles such as tibialis anterior and extensor digitorum longus, which contain mostly fast-twitch fibers, lack a weight-bearing function, are rapidly contracting, and are enriched with enzymes for anaerobic glycolysis. For human extensor muscles with a high proportion of fast fibers, spaceflight-induced atrophy of fast fiber types can be greater than that of slow fibers in the same muscle.51 In microgravity, novel motor patterns evolve as both humans and rats relegate the lower (hind) limbs to perching-type activities and rely on the forelimbs for translocation. Chronic electromyographic recordings of soleus

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--> muscles of HU adult male rats show an immediate and persistent 75 percent reduction in contractile activity.52 53 Suspended female rats exhibit a transient decrease in contractile activity, but in both sexes there is continuous unloading of soleus muscles.54 Neglect of the lower limbs during spaceflight correlates with the loss of proprioception in weightlessness and reliance on visual feedback of position. Early in-flight, humans lose anticipatory extensor muscle (electromyographic) activity in response to unannounced sudden falling. 55 Rats cease reaching for the floor when being set down. Both reflexes return quickly when the subjects are returned to gravity. Most of the primary changes represent simple deconditioning without pathology. These changes are appropriate adaptations for efficient functioning in a low-workload microgravity environment. Slow to fast transformation of muscle fiber type and decreased fiber size would be tolerable if astronauts did not have to return, rather abruptly, to gravity and use microgravity-weakened muscles to deal with heavy workloads. Thus, effective in-flight countermeasures should have the goal of maintaining the readiness of the skeletal muscle system to handle transitions without undue injury while delivering a high level of performance. Pathological Alteration and Metabolic Adaptation Not all of the expected primary changes in the muscles of humans exposed to microgravity will be free of pathology. Hindlimb unloading of adult rats for 10 days caused ischemic-like necrosis of fast-twitch, oxidative glycolytic fibers in the soleus.56 One interpretation is that the marked reduction in blood flow that occurs when a tonically active muscle becomes quiescent deprives highly oxidative fibers of sufficient blood-borne metabolites.57 This metabolic vulnerability may be transient, because during unloading, soleus fibers gradually acquire an increased capacity for glycolytic metabolism. The metabolically adapted cells are better equipped biochemically to derive energy anaerobically and tolerate ischemia.58 59 60 The reduced blood flow in and dehydration of the leg muscles cause enhanced heart rate responses. 61 The adaptation toward glycolysis is as yet unexplained and is accompanied by a compromised ability to oxidize long-chain fatty acids.62 This shift has the downside of rendering the muscle more fatigable, even though the capacity to transport glucose is enhanced. 63 64 The shift in metabolism is evident in the increased content of glycolytic energy-deriving enzymes, elevated storage of glycogen, and disappearance of peripheral mitochondria.65 66 67 68 69 Following bed rest, glycogen storage increased within the I bands and occupied spaces within myofibrils vacated by thin filaments lost during fiber atrophy.70 Astronauts and rats returning from a short-duration spaceflight of 1 to 2 weeks may experience muscle fatigue, weakness, incoordination, and delayed-onset muscle soreness.71 72 73 The greater reliance on glycolysis contributes to the reduced endurance and increased fatigability. Clearly the spaceflight-induced shift from fatty acid metabolism to glycolysis is an important issue in muscle metabolism that warrants continued investigation. Additional muscle biopsy studies are necessary to distinguish between simple deconditioning adaptive changes and pathological disruptions that invoke regenerative processes. Contractile Physiology, Contractile Proteins, and Myofilaments Muscle weakness following spaceflight and HU is consistent with the reported 20 to 50 percent decrease in muscle fiber cross-sectional area (CSA) and preferential loss of contractile proteins relative to cytoplasmic proteins.74 75 76 77 78 79 80 81 82 83 Surprisingly, significant atrophy was evident in human muscles after only 5 days in space.84 It has not been determined whether muscle deterioration reaches a plateau during long-duration spaceflight. Reduced output of muscle fiber force/CSA (specific tension) was found to be

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--> directly proportional to or greater than the reduction in CSA.85 86 87 88 89 In human bed-rest subjects, specific tension was not significantly less for soleus fibers after 17 days but was down by 40 percent for the quadriceps muscle by 6 weeks.90 91 Some reduction is expected when slow fibers shift toward fast ones because fast fibers reportedly generate lower specific tensions. More direct measures of single fiber tensions and diameters in isolated physiological preparations indicate no difference in slow and fast fiber-specific tensions, which range from 110 to 160 kN/m2. These physiological measurements may also be distorted by the correction factor of 20 percent swelling used for skinned fibers.92 93 94 Regardless, the longer-duration bed rest may have achieved a more complete fiber-type transformation. Fast fibers have more sarcoplasmic reticulum and thinner myofibrils to permit expedient and uniform exchange of Ca+2 ions during cycles of rapid contraction/relaxation.95 96 The soleus muscles of 7-day-HU rats exhibited dramatic (54 percent) increases in the velocity of shortening and a 17 percent decrease in specific tension.97 One explanation for the reduced tension is the disproportionate loss of thick (myosin-containing) filaments as documented ultrastructurally. 98 Accelerated loss of thick filaments is postulated to be the consequence of the foot-drop posture in the HU rat, which chronically shortens the working range of the soleus by ∼20 percent.99 Reorganization of sarcomeres in shortened muscles is necessary to reestablish optimal overlap (cross-bridge interaction) of thick and thin filaments for the midpoint of the abbreviated working range. Adjustment in the number of sarcomeres in series in fibers operates throughout the human's lifetime. The process is especially important for growth of fibers in length as the skeleton elongates. A second consequence of reduced packing density of contractile filaments is increased shortening velocity.100 This may account for single-fiber physiology and biochemistry measurements, which demonstrate speeding up of slow fibers without an associated elevation of fast myosin (heavy and light chain) expression.101 102 There is morphological and physiological evidence that the 20 percent reduction in thin filaments following a 17-day bed rest contributes to elevated shortening velocities of soleus fibers.103 A similar reduction was detected after a 17-day spaceflight.104 When floating in microgravity, humans are prone to foot-drop posture (ankle plantar flexion). This shortens the extensor compartment and appears to accelerate thick filament loss. The removal of weight bearing (unloading) appears to diminish thin filament concentration. Astronauts who exercise on bicycle ergometers and treadmills to preserve muscle strength and endurance also are counteracting the shortening adaptation. During these exercises, dorsiflexion of the foot stretches the soleus through its full range. Even the strength-testing sessions conducted during bed rest and in orbit, involving around 300 voluntary contractions of the foot against a strain gauge (dynamometer), may have blunted degenerative changes in soleus muscle fibers.105 106 107 The health benefits of stretching muscles through their full range are well known to physiotherapists. Brief exercise can be beneficial. 108 Preparation of the musculoskeletal system for reentry to a gravity environment through appropriate exercise and mechanical stimulation should be developed. Preservation of Function During Atrophy Muscle tissue is truly amazing in its ability to ameliorate the loss of function during atrophy. The elevated speed of shortening, resulting from decreased contractile-filament packing density and increased fast myosin expression, compensates for the reduced force by diminishing the loss in power output (power is the product of velocity times force).109 110 111 112 113 Another example is the increased capillary density and cross-sectional area of tissue that occurs when muscle fibers shrink more rapidly than the downsizing of the microvascular network.114 115 This theoretically compensates for lower blood flow and greater susceptibility to fatigue because the average diffusion distance is decreased from the capillary to the centers of muscle fibers. Muscle fatigability is also forestalled by the slower reduction in

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--> mitochondrial content relative to contractile protein loss. This conserves the normal concentration of intermyofibrillar mitochondria and associated oxidative enzymes.116 117 118 119 120 Reentry-And Reloading-Induced Secondary Changes Movements in Space and Upon Return to Earth In weightlessness, bipedal humans and quadrupedal rats both move about using the upper limbs or forelimbs.121 122 Because of the loss of proprioception in weightlessness and the dependence on visualizing limbs for positional information, it is not surprising that the less visible hindlimbs or lower limbs are used less frequently. A novel pattern of locomotion evolves that is appropriate and sufficient for directed movements in microgravity. The weightless astronaut soon ceases reflex stepping out with a foot when moving forward. Rats pull themselves around with their forelimbs, and the hindlimbs trail outstretched behind.123 Upon return to Earth, astronauts must reactivate 1-g motor skills such as recalling to step out to prevent falling when moving forward. Immediately upon their return to Earth, they are very unstable from a combination of orthostatic intolerance, altered otolith-spinal reflexes, reliance on weakened atrophic muscles, and inappropriate motor patterns.124 125 In the first few hours after landing, spaceflown rats do not extend their limbs and reach for the ground when lowered to the ground. This reflex, beneficial in 1 g, returns in a day.126 Spaceflown rats walked significantly more slowly than normal the first 2 days, but they moved as rapidly as ground controls by the third day. The jerky, stilted stepping of the hindlimbs quickly evolved to the smooth walking pattern of a terrestrially readapted rat.127 Unloading studies with immature rats indicate that gravity loading during the third and fourth weeks after birth is essential for normal development of 1-g locomotion.128 Early in-flight, humans subjected to sudden "drop tests" ceased anticipatory contractile (electromyographic) activity in extensor muscles.129 This reflex returned to normal within a day after landing. Thus, terrestrial motor skills are rapidly restored and performed forcefully. This occurs well before muscle-fiber regrowth in cross-sectional areas and during the period of slow muscle-fiber necrosis. It appears that the central nervous system undergoes significant reprogramming (plasticity) and performs compensatory activation of motor units that masks the deteriorated state of the neuromuscular system.130 131 132 133 There may also be rapid changes in the neuromuscular junctions. The physiological and morphological adaptations at the nerve/muscle synapse under conditions of reduced or elevated use have not been adequately examined.134 Compromised Microcirculation The headward fluid shift in microgravity and reduced muscle contractions (musculovenous pumping) during unloading result in reduced blood flow in the lower (hind) limbs.135 136 137 This is associated with the movement of blood proteins, such as albumin, into the interstitium. Without musculovenous pumping, extravasated proteins are recovered less well into the vascular system via postcapillary venules and lymphatics.138 139 140 At the shortest time examined after shuttle landing (0.5 hour after reentry plus 2 hours after wheel stop), the slow adductor longus muscles of rats already showed simple (noninflammatory) interstitial edema that was not evident in-flight.141 By 2 days postflight, the edema had advanced to inflammatory myopathy with more severe edema. The scenario of reloading-induced edema is mimicked by HU for 12.5 days and subsequent reloading of rat antigravity slow muscles. 142 Postflight pooling of blood in the lower limbs was not present in the legs of astronauts during quiet standing initiated about 4 hours after landing.143 144 This indicates that the pull of gravity (hydrostatic pressure)

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--> alone is not sufficient in the short term to cause fluid accumulation in relatively quiescent limbs. The onset and severity of interstitial edema in rats appears directly related to the intensity of postflight muscle contractile activity.145 146 147 148 149 150 The osmotic pressure of the extravascular proteins is thought to pull water into the interstitium when the microvascular network is reperfused with blood at high pressure and flow in response to resumption of strong muscle contractions. 151 152 If the muscle activity is sufficiently strenuous (a level that is undefined), interstitial edema increases and leads to ischemic-like tissue necrosis with mast cell degranulation and increased vascular permeability.153 At this stage, muscles exhibit inflammatory-like myopathy with infiltration of mononuclear cells.154 155 156 Neutrophils may exacerbate damage by activating complement-mediated membrane disruption and releasing reactive oxygen radicals.157 Muscles adapted to 1 g can also become edematous during intense exercise. 158 159 Perhaps adaptation to microgravity lowers a threshold for the onset of edema. It appears that underused microvessels adapt to low flow and pressure during spaceflight or HU and may become inherently "more leaky" during the rapid onset of high blood flow and pressure when gravity-loaded muscle contractions are resumed. 160 161 162 Furthermore, the unloading-induced shift to glycolytic metabolism away from oxidative metabolism results in a more robust stimulation of blood pressure during muscle contraction.163 The results suggest that avoiding strenuous muscle contractions during reacclimatization to gravity and possibly medicating before landing with drugs that block mast cell degranulation may minimize edema in returning astronauts. Possible countermeasures that should be investigated to minimize reentry and reloading-induced edema and ischemic tissue necrosis include flushing the interstitium of excess proteins by exercise-induced muscle contractions, combined with lower body negative pressure (LBNP) induction of microcirculation filling. LBNP is achieved by sealing the lower half of the body in a chamber in which air pressure is lowered to draw blood into the lower extremities. LBNP regimens and loaded treadmill exercises routinely performed by Russian cosmonauts are believed by them to be essential for successful readaptation to gravity after a year in space.164 However, these promising countermeasures, including stationary bicycle and rowing exercises used on other missions, require further controlled studies to verify their efficacy. This circulation-related problem emphasizes the point that muscle adaptation during spaceflight goes beyond changes restricted to muscle fibers (cells). In fact, nervous and cardiovascular system involvement in muscle performance serves as a reminder that we are sending organisms, not isolated organ systems, into space. Effective countermeasures will need to target multiple systems. Increased Susceptibility to Structural Damage Atrophic muscle fibers resulting from spaceflight and hindlimb unloading are structurally weaker and more susceptible to eccentric-like (lengthening) contraction-induced tearing of the contractile elements, the fiber cell membrane (sarcolemma), and associated connective tissue.165 166 167 168 169 The severity of the damage appears directly correlated to the magnitude of the reloading workload. These tissue changes are reminiscent of those associated with delayed-onset muscle soreness in 1-g-adapted human muscles after unaccustomed strenuous exercise (especially muscle lengthening) and in rat muscles electrically stimulated to generate forceful eccentric contractions.170 171 172 173 Some astronauts are aware that minimizing activities that eccentrically load their leg muscles, such as walking down stairs during the first days back on Earth, reduces the severity of delayed-onset soreness and stiffness.174 Adaptation to the lower workload history of microgravity or HU appears to render muscle tissue more prone to structural failure when reloaded, especially by lengthening contractions.175 176 177 178 179 180 This is partly explained by the relatively greater workload on the antigravity muscles because of fiber atrophy.181 182 A

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--> 50 percent loss of soleus mass is equivalent to increasing muscle loading by doubling the body weight. Further studies on Earth subjecting 1-g-adapted animals to hypergravity on a variable force centrifuge would be useful. In addition to the relative increase in workload, however, there still may be a lowering of a threshold for structural failure so that muscle fibers are damaged at a level of specific tension previously tolerated without injury.183 184 The disproportionate loss of actin thin filaments and increased tension per filament in human soleus muscles, after spaceflight and chronic bed rest, is one possible molecular mechanism of lowering the injury threshold. Another possibility is a disproportionate decrease in structural proteins (harnessing tension) relative to the contractile proteins (generating tension). 185 There is evidence for unlinking of the cytoskeleton (actin and intermediate filaments) and myofibrils to costameres.186 Postflight damage, sport-related injuries, and degeneration in muscular dystrophies share structural similarities.187 188 189 Skeletal muscles are capable of generating more force than the connective tissue (interstitium and myotendinous junctions) can tolerate without structural failure. 190 For both spaceflight and HU, the atrophic degenerative changes that have been documented at the myotendinous junctions and along the length of the fibers are consistent with a reduced margin of safety for structural integrity during weight-bearing contractions. 191 192 193 194 Structural proteins can fail within sarcomeres. This process has been thoroughly reviewed for 1-g-adapted muscles.195 Null allele mutations to eliminate selected sarcomeric proteins provide valuable insights into the mechanism of myofibril assembly.196 197 The sarcolemma (cell membrane and basal lamina) is another potentially weakened component. At costameres and myotendinous junctions, cytoskeletal actin and intermediate filaments normally transmit contractile force through linking proteins to integral membrane glycoproteins that bind to extracellular matrix ( integrins to fibronectin and dystrophin/dystroglycan to laminin-2).198 199 200 201 202 These sites may also function as receptors for sensing workload and generate intracellular signals through enzymes like focal adhesion kinase that affect the synthesis of myofibrillar proteins.203 Mechanosensing of workload by heart myocytes (likely to be analogous for skeletal muscle) involves autocrine/paracrine growth factors signal transduction, immediate-early genes, and multiple second messengers (phospholipase, eicosinoids, tyrosine kinases, RAF-1, MAP kinases, stretch-activated ion channels, and protein translation regulators).204 The in vitro model of applying stretch to skeletal muscle cells has shown a convincing correlation between active tension and prostaglandin release; these autocrine factors modulate protein degradation and synthesis.205 Absence of a single component protein of the dystrophin glycoprotein complex can result in greater susceptibility to contraction-induced sarcolemma tearing.206 207 208 This is seen in human dystrophies and mouse dystrophy mutants.209 Muscles of the mdx dystrophic mouse are more easily torn during contraction than the same muscles in normal animals.210 HU renders the atrophic soleus muscle more susceptible to contraction-induced muscle tearing.211 The nonatrophic extensor digitorum longus muscle in the same animals did not exhibit increased vulnerability.212 Fortunately, genetically normal muscle fibers rapidly repair sarcomere lesions by Z-line-like patching and restore segmental necrosis by membrane sealing and satellite cell regeneration.213 214 215 216 217 In human muscles, the number of satellite cell divisions normally may be limited. Dystrophic muscles are compromised in these reparative abilities and therefore undergo more extensive and persistent degeneration. Spaceflight-induced muscle atrophy may also compromise the healing capacity of injured muscles. 218 Investigations pursuing means of promoting repair processes with growth factors and pharmacological agents are needed to minimize the negative impact of muscle injury on astronaut performance.219 Extravehicular activities (space walks) require significant muscular effort, making astronauts vulnerable to muscular injury. This is an important consideration because repeated space walks are obvious requirements for space station construction. During manned exploration of the surface of Mars, performance could be negatively affected by

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--> such injuries, even those as commonplace as painful pulled back muscles or stiff neck muscles. Muscle soreness in astronauts needs to be examined rigorously. Recommendations The efficacy of muscle repair in microgravity should be more thoroughly examined at the sarcomere, myofiber, motor neuron, and tissue levels. Myotendinous junctions as structural failure sites warrant further study to prevent tendon rupture during transition to gravity reloading. Development of improved countermeasures is a high-priority goal, and should include the following: Consideration of the potential value of hormones, growth factors, second messengers, and drugs in the design of novel, more effective countermeasures; and Improved understanding of mechanisms of microcirculation failure, which is required for design of in-flight countermeasures for preventing reloading damage. The process of transitioning from microgravity to higher gravity without undue damage and loss of performance needs to be explored by examination of microgravity-adapted individuals transitioning to 1 g and 1-g-adapted individuals exposed to hypergravity by centrifugation. NASA should actively work with the scientific community and industry to develop equipment to reduce in-flight muscle stress and fatigue as well as instrumentation necessary for in-flight experimentation and monitoring of muscle function and health. Examples include the following: Rapid freezing apparatus to preserve biospecimens obtained in-flight for later biochemical and molecular assays; An ergonomic space suit for hand movements to reduce fatigue; and Dual-beam x ray and ultrasonography for noninvasive monitoring of muscle deterioration and real-time assessment of the efficacy of countermeasures. An astronaut's history of muscle use and condition needs to be better monitored before, during, and after flight to reduce uncontrolled parameters that introduce excessive intersubject variation for statistical detection of changes. Cellular And Molecular Mechanisms Up to now, researchers have only minimally exploited microgravity for advancing the understanding of muscle biology. Microgravity has proven an excellent tool for noninvasively perturbing the synthesis of muscle proteins in the search for molecular signals and gene regulatory factors influencing differentiation, growth, maintenance, plasticity, and atrophy of muscle. The relationships between blood flow history and interstitial edema and between workload history and structural failure are but two of the important problems that require serious attention. The roles of hormones and growth factors as well as of fiber-type-specific cis- and trans-acting factors in regulating gene expression, and the microgravityinduced alterations in their production, are other urgent issues. These types of studies will yield information that will advance basic knowledge of muscle biology and offer insights into countermeasure design. This knowledge is also likely to assist in the rehabilitation of diseased or injured muscles in humans on Earth, especially individuals in the more vulnerable aging population or those participating in strenuous sports. Microgravity can be exploited as a unique tool to perturb the normal adult and

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--> developing neuromuscular systems to derive insights into fundamental muscle function on Earth, as well as to define the epigenetic requirement of gravity for the maintenance and differentiation of the neuromuscular system. The past two decades of spaceflight research have yielded a description of the physiological effects of microgravity on multiple systems. The next generation of experiments must define the cellular and molecular mechanisms of microgravity-induced changes. The fundamental questions regarding control of muscle function, causes of atrophic changes, regulation of muscle phenotype, the mechanism of muscle plasticity in response to altered demands, and identification of optimal countermeasures will require rigorous ground-based research as well as spaceflight studies. The bed-rest paradigm for humans and the hindlimb unloading model for rats have provided high-fidelity ground-based models for many but not all aspects of spaceflight. These models can continue to produce significant information. Multidisciplinary approaches should be encouraged that probe the molecular changes in regulation of transcription and translation in individual muscle cells and the mechanisms whereby other organ systems (vascular, hormonal, neural) interact to bring about changes in gene expression and cellular function. However, no Earth-based model of microgravity is sufficiently faithful to escape some influences of the gravity vector. For example, gravity-induced postural distortion of the hindleg in hindlimb-suspension unloaded rats introduces a shortened working range for the soleus with associated changes in muscle structure and physiology. It will therefore be important to conduct in-flight experiments to test molecular and cellular mechanisms of response identified in ground-based models. Studies on regulation of gene expression will be increasingly important. Molecular tools are available to probe properties specific to a particular muscle fiber type; sensing of muscle length and load; and influence of autocrine, paracrine, and humoral factors. Transgenic mice with over- and underexpression of specific molecules thought to be involved in the adaptation process are invaluable research animals to incorporate into the ground and flight studies.220 221 The roles played by membrane receptors or ligands and cytoskeletal elements (costameres, dystrophin glycoprotein complex, integrins) in load bearing and length sensing need to be understood.222 Degradation of muscle proteins by ubiquitination and the proteolytic proteasome complex is a fundamental process of degrading contractile proteins during atrophy that requires further investigation. Factors responsible for the shift from lipid oxidation to glucose utilization need to be understood from the viewpoint of control of energy metabolism. Development from conception to the mature adult and the F1 generations are needed to determine whether critical periods require gravitation influences for normal gene expression. 223 As described in other chapters of this report, a key question is how cells detect the effects of gravity. The myotendinous junctions and costameres are the most likely sites at which loading imparts stresses on the connective tissues and tendons and the basement membrane, which signals through integral membrane proteins to the cytoskeleton and contractile proteins.224 225 226 These pathways will involve multiple second messengers, such as signaling through kinase activation and eicosinoids.227 Mechanisms of sensing working length remain undefined. Recommendations The highest priority for research projects should be those investigations designed to elucidate the cellular and molecular mechanisms underlying muscle weakness, fatigue, incoordination, and delayedonset muscle soreness. These deficits are associated with muscle cell atrophy, greater susceptibility of muscle fibers to contraction-induced destruction of fibers, and a compromised microcirculation leading to ischemic necrosis and secondary changes in muscle tissue. Ground-based models such as bed rest for humans and hindlimb unloading for rats should

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--> continue to be used for testing and refining hypotheses seeking to understand the fundamental mechanisms of how workload is transduced into molecular signals regulating muscle mass and protein isoform expression, as well as the cellular and molecular control myofilament assembly and length. Integrated studies employing multiple intraand interdisciplinary approaches are encouraged. Fundamental work is needed on myogenesis, fiber type differentiation, neuromuscular development, and spinal development using neonatal rodents as model systems. The mechanisms should be determined whereby muscle cells sense working length and the mechanical stress of gravity. Signal transduction pathways for growth factors, stretch-activated ion channels, regulators of protein synthesis, and interactions of extracellular matrix and membrane proteins with cytoskeleton should be investigated. In-flight and hindlimb unloading testing of genetically engineered murine models with gain and loss of function, up regulation and down regulation of key proteins, and release of candidate hormones and growth factors and their respective receptors should be exploited for probing basic mechanisms of neuromuscular function during adaptation to unique hypo- and hypergravity environments. References 1. Baldwin, K.M., White, T.P., Arnaud, S.B., Edgerton, V.R., Kraemer, W.J., Kram, R., Raab-Cullen, D., and Snow, C.M. 1996. Musculoskeletal adaptations to weightlessness and development of effective countermeasures. Med. Sci. Sports Exercise 10: 1247-1253. 2. Convertino, V.A. 1991. Neuromuscular aspects in development of exercise countermeasures. Physiologist 34: S125-S128. 3. Ferrando, A.A., Tipton, K.D., Bamman, M.M., and Wolfe, R.R. 1997. Resistance exercise maintains skeletal muscle protein synthesis during bed rest. J. Appl. Physiol. 82: 807-810. 4. Kablar, B., Krastel, K., Ying, C., Asakura, A., Tapscott, S., and Rudnicki, M. 1997. MyoD and Myf-5 differentially regulate the development of limb versus trunk skeletal muscle. Dev. Suppl. 124: 4729-4738. 5. Buonanno, A., and Rosenthal, N. 1996. Molecular control of muscle diversity and plasticity. Dev. Genet. 19: 95-107. 6. Hoh, J.F., and Hughes, S. 1989. Immunocytochemical analysis of the perinatal development of cat masseter muscle using anti-myosin antibodies. J. Muscle Res. Cell Motil. 10: 312-325. 7. Wright, C., Haddad, F., Qin, A.X., and Baldwin, K.M. 1997. Analysis of myosin heavy chain mRNA expression by RT-PCR. J. Appl. Physiol. 83: 1389-1396. 8. Hoh, J.F., and Hughes, S. 1989. Immunocytochemical analysis of the perinatal development of cat masseter muscle using anti-myosin antibodies. J. Muscle Res. Cell Motil. 10: 312-325. 9. Wright, C., Haddad, F., Qin, A.X., and Baldwin, K.M. 1997. Analysis of myosin heavy chain mRNA expression by RT-PCR. J. Appl. Physiol. 83: 1389-1396. 10. Schiaffino, S., and Salviati, F. 1998. Molecular diversity ofmyofibrillar proteins: isoforms analysis at the protein and mRNA level . Methods Cell Biol. 52: 349-369. 11. Hoh, J.F., and Hughes, S. 1989. Immunocytochemical analysis of the perinatal development of cat masseter muscle using anti-myosin antibodies. J. Muscle Res. Cell Motil. 10: 312-325. 12. Caiozzo, V.J. 1996. Thyroid hormone: Modulation of muscle structure, function, and adaptive responses to mechanical loading. Exercise Sport Sci. Rev. 24: 321-361. 13. Devor, S.T., and White, T.P. 1996. Myosin heavy chain of immature soleus muscle grafts adapts to hyperthyroidism more than to physical activity. J. Appl. Physiol. 80: 789-794. 14. Buonanno, A., and Rosenthal, N. 1996. Molecular control of muscle diversity and plasticity. Dev. Genet. 19: 95-107. 15. Buonanno, A., and Rosenthal, N. 1996. Molecular control of muscle diversity and plasticity. Dev. Genet. 19: 95-107. 16. Engert, J.C., Servaes, S., Sutrave, P., Hughes, S.H., and Rosenthal, N. 1995. Activation of a muscle-specific enhancer by the Ski proto-oncogene. Nucleic Acids Res. 23: 2988-2994. 17. Koslovskaya, I.B., Barmin, V.A., Stepantsov, V.I., and Kharitinov, N.M. 1990. Results of studies of motor functions in long-term spaceflights. Physiologist 33: S1-S3. 18. Thorteinsson, G. 1997. Management of postpolio syndrome. Mayo Clin. Proc. 72: 627-638.

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--> 19. Edgerton, V.R., Zhou, M.-Y., Ohira, Y., Klitgaard, H., Jiang, B., Bell, G., Harris, B., Saltin, B., Gollnick, P.D., Roy, R.R., Day, M.K., and Greenisen, M. 1995. Human fiber size and enzymatic properties after 5 and 11 days of spaceflight. J. Appl. Physiol. 78: 1733-1739. 20. Fitts, R.H., Widrick, J.J., Knuth, S.T., Blaser, C.A., Karhanek, M., Trappe, S.W., Trappe, T.A., and Costill, D.L. 1997. Force-velocity and force-power properties of human muscle fiber after spaceflight. Med. Sci. Sports Exercise 29: S190. 21. Trappe, S.W., Trappe, T.A., Costill, D.L., Lee, G.A., Widrick, J.J., and Fitts, R.H. 1997. Effect of spaceflight on human calf muscle morphology and function. Med. Sci. Sports Exercise 29: S190. 22. Zhou, M.-Y., Klitgaard, H., Saltin, B., Roy, R.R., Edgerton, V.R., and Gollnick, P.D. 1995. Myosin heavy chain isoforms of human muscle after short-term spaceflight. J. Appl. Physiol. 78: 1740-1744. 23. Riley, D.A., Thompson, J.L., Krippendorf, B.B., and Slocum, G.R. 1995. Review of spaceflight and hindlimb unloading induced sarcomere damage and repair. Basic Appl. Myology 5: 139-145. 24. Darr, K.C., and Schultz, E. 1989. Hindlimb suspension suppresses muscle growth and satellite cell proliferation. J. Appl. Physiol. 67: 1827-1834. 25. Walton, K., Heffernan, C., Sluice, D., and Benavides, L. 1997. Changes in gravity influenced rat postnatal motor system development: From simulation to spaceflight. Gravit. Space Biol. Bull. 10: 111-118. 26. Fitts, R.H., Metzger, J.M., Riley, D.A., and Unsworth, B.R. 1986. Models of skeletal muscle disuse: A comparison of suspension hypokinesia and hindlimb immobilization. J. Appl. Physiol. 60: 1946-1953. 27. Krippendorf, B.B., and Riley, D.A. 1993. Distinguishing unloading- versus reloading-induced changes in rat soleus muscle. Muscle Nerve 16: 99-108. 28. Edgerton, V.R., Zhou, M.-Y., Ohira, Y., Klitgaard, H., Jiang, B., Bell, G., Harris, B., Saltin, B., Gollnick, P.D., Roy, R.R., Day, M.K., and Greenisen, M. 1995. Human fiber size and enzymatic properties after 5 and 11 days of spaceflight. J. Appl. Physiol. 78: 1733-1739. 29. Riley, D.A., Slocum, G.R., Bain, J.L.W., Sedlak, F.R., Sowa, T.E., and Mellender, J.W. 1990. Rat hindlimb unloading: Soleus histochemistry, ultrastructure, and electromyography. J. Appl. Physiol. 69: 58-66. 30. Fitts, R.H., Widrick, J.J., Knuth, S.T., Blaser, C.A., Karhanek, M., Trappe, S.W., Trappe, T.A., and Costill, D.L. 1997. Force-velocity and force-power properties of human muscle fiber after spaceflight. Med. Sci. Sports Exercise 29: S190. 31. Trappe, S.W., Trappe, T.A., Costill, D.L., Lee, G.A., Widrick, J.J., and Fitts, R.H. 1997. Effect of spaceflight on human calf muscle morphology and function. Med. Sci. Sports Exercise 29: S190. 32. Zhou, M.-Y., Klitgaard, H., Saltin, B., Roy, R.R., Edgerton, V.R., and Gollnick, P.D. 1995. Myosin heavy chain isoforms of human muscle after short-term spaceflight. J. Appl. Physiol. 78: 1740-1744. 33. Baldwin, K.M., Herrick, R.E., and McCue, S.A. 1993. Substrate oxidation capacity in rodent skeletal muscle: Effects of exposure to zero gravity. J. Appl. Physiol. 75: 2466-2470. 34. Baranski, S., Baranska, W., Marciniak, M., and Ilyina-Kakueva, E.I. 1979. Ultrasonic (ultrastructural) investigations of the soleus muscle after spaceflight on the Biosputnik 936. Aviat. Space Environ. Med. 50: 930-934. 35. Ilyina-Kakueva, E.I., Portugalov, V.V., and Kirvenkova, N.P. 1976. Spaceflight effects on the skeletal muscle of rats. Aviat. Space Environ. Med. 47: 700,703. 36. Martin, I.P., Edgerton, V.R., and Grindeland, R.E. 1988. Influence of spaceflight on rat skeletal muscle. J. Appl. Physiol. 65: 2318-2325. 37. Riley, D.A., Ellis, S., Slocum, G.R., Satyanarayana, T., Bain, J.L.W., and Sedlak, F.R. 1987. Hypogravity-induced atrophy of rat soleus and extensor digitorum longus muscles. Muscle Nerve 10: 560-568. 38. Riley, D.A., Ilyina-Kakueva, E.I., Ellis, S., Bain, J.L.W., Slocum, G.R., and Sedlak, F.R. 1990. Skeletal muscle fiber, nerve, and blood vessel breakdown in spaceflown rats. FASEB J. 4: 84-91. 39. Riley, D.A., Ellis, S., Giometti, C.S., Hoh, J.F.Y., Ilyina-Kakueva, E.I., Oganov, V., Slocum, G.R., Bain, J.L.W., and Sedlak, F.R. 1992. Muscle sarcomere lesions and thrombosis after spaceflight and suspension unloading. J. Appl. Physiol. 73: S33-S43. 40. Riley, D.A., Thompson, J.L., Krippendorf, B.B., and Slocum, G.R. 1995. Review of spaceflight and hindlimb suspension unloading induced sarcomere damage and repair. Basic Appl. Myology 5: 139-145. 41. Riley, D.A., Ellis, S., Slocum, G.R., Sedlak, F.R., Bain, J.L.W., Krippendorf, B.B., Lehman, C.T., Macias, M.Y., Thompson, J.L., Vijayan, K., and DeBruin, J.A. 1996. In-flight and postflight changes in skeletal muscles of SLS-1 and SLS-2 spaceflown rats. J. Appl. Physiol. 81: 133-144. 42. Tischler, M.E., Henriksen, E.J., Munoz, K.A., Stump, C.S., Woodman, C.R., and Kirby, C.R. 1993. Spaceflight on STS-48 and Earth-based unweighting produce similar effects on skeletal muscle of young rats. J. Appl. Physiol. 74: 2161-2165.

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--> 43. Caiozzo, V.J., Haddad, F., Baker, M.J., Herrick, R.E., Prietto, N., and Baldwin, K.M. 1996. Microgravity-induced transformations of myosin isoforms and contractile properties of skeletal muscle. J. Appl. Physiol. 81: 123-132. 44. Diffee, G.M., Caiozzo, V.J., Herrick, R.E., and Baldwin, K.M. 1991. Contractile and biochemical properties of rat soleus and plantaris after hindlimb suspension. Am. J. Physiol. 260: C528-C534. 45. Diffee, G.M., Haddad, F., Herrick, R.E., and Baldwin, K.M. 1991. Control of myosin heavy chain expression: Interaction of hypothyroidism and hindlimb suspension. Am. J. Physiol. 261: C1099-C1106. 46. Krippendorf, B.B., and Riley, D.A. 1993. Distinguishing unloading- versus reloading-induced changes in rat soleus muscle. Muscle Nerve 16: 99-108. 47. Krippendorf, B.B., and Riley, D.A. 1994. Temporal changes in sarcomere lesions of rat adductor longus muscles during hindlimb reloading. Anat. Rec. 238: 304-310. 48. McDonald, K.S., Blaser, C.A., and Fitts, R.H. 1994. Force-velocity and power characteristics of rat soleus muscle fibers after hindlimb suspension. J. Appl. Physiol. 77: 1609-1616. 49. McDonald, K.S., Delp, M.D., and Fitts, R.H. 1992. Effect of hindlimb unweighting on tissue blood flow in the rat. J. Appl. Physiol. 72: 2210-2218. 50. Riley, D.A., Slocum, G.R., Bain, J.L.W., Sedlak, F.R., Sowa, T.E., and Mellender, J.W. 1992. Rat hindlimb unloading: Soleus histochemistry, ultrastructure and electromyography. J. Appl. Physiol. 69: 58-66. 51. Edgerton, V.R., Zhou, M.-Y., Ohira, Y., Klitgaard, H., Jiang, B., Bell, G., Harris, B., Saltin, B., Gollnick, P.D., Roy, R.R., Day, M.K., and Greenisen, M. 1995. Human fiber size and enzymatic properties after 5 and 11 days of spaceflight. J. Appl. Physiol. 78: 1733-1739. 52. Riley, D.A., Slocum, G.R., Bain J.L.W., Sedlak, F.R., Sowa, T.E., and Mellender, J.W. 1990. Rat hindlimb unloading: Soleus histochemistry, ultrastructure, and electromyography. J. Appl. Physiol. 69: 58-66. 53. Blewett, C., and Elder, G.C. 1993. Quantitative EMG analysis in soleus and plantaris during hindlimb suspension and recovery. J. Appl. Physiol. 74: 2057-2066. 54. Alford, E.K., Roy, R.R., Hodgson, J.A., and Edgerton, V.R. 1987. Electromyography of rat soleus, medial gastrocnemius, and tibialis anterior during hindlimb suspension. Exp. Neurol. 96: 635-649. 55. Young, L.R., Oman, C.M., Watt, D.G.D., Money, K.E., Lichtenberg, B.K., Kenyon, R.V., and Arrott, A.P. 1986. M.I.T./Canadian vestibular experiments on the Spacelab-1 mission: 1. Sensory adaptation to weightlessness and readaptation to one-g: An overview. Exp. Brain Res. 64: 291-298. 56. Riley, D.A., Slocum, G.R., Bain, J.L.W., Sedlak, F.R., Sowa, T.E., and Mellender, J.W. 1990. Rat hindlimb unloading: Soleus histochemistry, ultrastructure, and electromyography. J. Appl. Physiol. 69: 58-66. 57. McDonald, K.S., Delp, M.D., and Fitts, R.H. 1992. Effect of hindlimb unweighting on tissue blood flow in the rat. J. Appl. Physiol. 72: 2210-2218. 58. Baldwin, K.M., Herrick, R.E., and McCue, S.A. 1993. Substrate oxidation capacity in rodent skeletal muscle: Effects of exposure to zero gravity. J. Appl. Physiol. 75: 2466-2470. 59. Baranski, S., Baranska, W., Marciniak, M., and Ilyina-Kakueva, E.I. 1979. Ultrasonic (ultrastructural) investigations of the soleus muscle after spaceflight on the Biosputnik 936. Aviat. Space Environ. Med. 50: 930-934. 60. Riley, D.A., Ellis, S., Slocum, G.R., Satyanarayana, T., Bain, J.L.W., and Sedlak, F.R. 1987. Hypogravity-induced atrophy of rat soleus and extensor digitorum longus muscles. Muscle Nerve 10: 560-568. 61. Wilson, L.B., Dyke, C.K., Parsons, D., Wall, P.T., Pawelczyk, J.A., Williams, R.S., and Mitchell, J.H. 1995. Effect of skeletal muscle fiber type on the pressor response evoked by static contraction in rabbits. J. Appl. Physiol. 79: 1744-1752. 62. Baldwin, K.M., Herrick, R.E., and McCue, S.A. 1993. Substrate oxidation capacity in rodent skeletal muscle: Effects of exposure to zero gravity. J. Appl. Physiol. 75: 2466-2470. 63. Baldwin, K.M., Herrick, R.E., and McCue, S.A. 1993. Substrate oxidation capacity in rodent skeletal muscle: Effects of exposure to zero gravity. J. Appl. Physiol. 75: 2466-2470. 64. Tischler, M.E., Henriksen, E.J., Munoz, K.A., Stump, C.S., Woodman, C.R., and Kirby, C.R. 1993. Spaceflight on STS-48 and Earth-based unweighting produce similar effects on skeletal muscle of young rats. J. Appl. Physiol. 74: 2161-2165. 65. Edgerton, V.R., Zhou, M.-Y., Ohira, Y., Klitgaard, H., Jiang, B., Bell, G., Harris, B., Saltin, B., Gollnick, P.D., Roy, R.R., Day, M.K., and Greenisen, M. 1995. Human fiber size and enzymatic properties after 5 and 11 days of spaceflight. J. Appl. Physiol. 78: 1733-1739. 66. Martin, I.P., Edgerton, V.R., and Grindeland, R.E. 1988. Influence of spaceflight on rat skeletal muscle. J. Appl. Physiol. 65: 2318-2325.

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--> 67. Riley, D.A., Ellis, S., Slocum, G.R., Satyanarayana, T., Bain, J.L.W., and Sedlak, F.R. 1987. Hypogravity-induced atrophy of rat soleus and extensor digitorum longus muscles. Muscle Nerve 10: 560-568. 68. Riley, D.A., Ilyina-Kakueva, E.I., Ellis, S., Bain, J.L.W., Slocum, G.R., and Sedlak, F.R. 1990. Skeletal muscle fiber, nerve, and blood vessel breakdown in spaceflown rats. FASEB J. 4: 84-91. 69. Riley, D.A., Ellis, S., Giometti, C.S., Hoh, J.F.Y., Ilyina-Kakueva, E.I., Oganov, V., Slocum, G.R., Bain, J.L.W., and Sedlak, F.R. 1992. Muscle sarcomere lesions and thrombosis after spaceflight and suspension unloading. J. Appl. Physiol. 73: S33-S43. 70. Widrick, J.J., Romatowski, J.G., Bain, J.L.W., Trappe, S.W., Trappe, T.A., Thompson, J.L., Costill, D.L., Riley, D.A., and Fitts, R.H. 1997. Effect of 17 days of bed rest on peak isometric force and unloaded shortening velocity of human soleus fibers. Am. J. Physiol. 273: C1690-C1699. 71. Edgerton, V.R., and Roy, R.R. 1994. Neuromuscular adaptation to actual and simulated weightlessness. Pp. 33-67 in Advances in Space Biology and Medicine, Vol. 4 (S.L. Bonting, ed.). JAI Press, Greenwich, Conn. 72. Riley, D.A., Thompson, J.L., Krippendorf, B.B., and Slocum, G.R. 1995. Review of spaceflight and hindlimb suspension unloading induced sarcomere damage and repair. Basic Appl. Myology 5: 139-145. 73. Stauber, W.T., Clarkson, P.M., Fritz, V.K., and Evans, W.J. 1990. Extracellular matrix disruption and pain after eccentric muscle action. J. Appl. Physiol. 69: 868-874. 74. Edgerton, V.R., and Roy, R.R. 1994. Neuromuscular adaptation to actual and simulated weightlessness. Pp. 33-67 in Advances in Space Biology and Medicine, Vol. 4 (S.L. Bonting, ed.). JAI Press, Greenwich, Conn. 75. Koslovskaya, I.B., Barmin, V.A., Stepantsov, V.I., and Kharitinov, N.M. 1990. Results of studies of motor functions in long-term spaceflights. Physiologist 33: S1-S3. 76. Thornton, W.E., and Rummel, J.A. 1977. Muscular deconditioning and its prevention in spaceflight. Pp. 191-197 in Biomedical Results from Skylab (R.S. Johnston and L.F. Dietlein, eds.). NASA-SP-377. National Aeronautics and Space Administration, Houston, Tex. 77. Baranski, S., Baranska, W., Marciniak, M., and Ilyina-Kakueva, E.I. 1979. Ultrasonic (ultrastructural) investigations of the soleus muscle after spaceflight on the Biosputnik 936. Aviat. Space Environ. Med. 50: 930-934. 78. Ilyina-Kakueva, E.I., Portugalov, V.V., and Kirvenkova, N.P. 1976. Spaceflight effects on the skeletal muscle of rats. Aviat. Space Environ. Med. 47: 700,703. 79. Martin, I.P., Edgerton, V.R., and Grindeland, R.E. 1988. Influence of spaceflight on rat skeletal muscle. J. Appl. Physiol. 65: 2318-2325. 80. Riley, D.A., Ilyina-Kakueva, E.I., Ellis, S., Bain, J.L.W., Slocum, G.R., and Sedlak, F.R. 1990. Skeletal muscle fiber, nerve, and blood vessel breakdown in spaceflown rats. FASEB J. 4: 84-91. 81. Riley, D.A., Ellis, S., Giometti, C.S., Hoh, J.F.Y., Ilyina-Kakueva, E.I., Oganov, V., Slocum, G.R., Bain, J.L.W., and Sedlak, F.R. 1992. Muscle sarcomere lesions and thrombosis after spaceflight and suspension unloading. J. Appl. Physiol. 73: S33-S43. 82. Riley, D.A., Thompson, J.L., Krippendorf, B.B., Slocum, G.R. 1995. Review of spaceflight and hindlimb suspension unloading induced sarcomere damage and repair. Basic Appl. Myology 5: 139-145. 83. Riley, D.A., Ellis, S., Slocum, G.R., Sedlak, F.R., Bain, J.L.W., Krippendorf, B.B., Lehman, C.T., Macias, M.Y., Thompson, J.L., Vijayan, K., and DeBruin, J.A. 1996. In-flight and postflight changes in skeletal muscles of SLS-1 and SLS-2 spaceflown rats. J. Appl. Physiol. 81: 133-144. 84. Edgerton, V.R., Zhou, M.-Y., Ohira, Y., Klitgaard, H., Jiang, B., Bell, G., Harris, B., Saltin, B., Gollnick, P.D., Roy, R.R., Day, M.K., and Greenisen, M. 1995. Human fiber size and enzymatic properties after 5 and 11 days of spaceflight. J. Appl. Physiol. 78: 1733-1739. 85. Diffee, G.M., Caiozzo, V.J., Herrick, R.E., and Baldwin, K.M. 1991. Contractile and biochemical properties of rat soleus and plantaris after hindlimb suspension. Am. J. Physiol. 260: C528-C534. 86. McDonald, K.S., Blaser, C.A., and Fitts, R.H. 1994. Force-velocity and power characteristics of rat soleus muscle fibers after hindlimb suspension. J. Appl. Physiol. 77: 1609-1616. 87. Widrick, J.J., and Fitts, R.H. 1997. Peak force and maximal shortening velocity of soleus fibers after non-weight-bearing and resistance exercise. J. Appl. Physiol. 82: 189-195. 88. Widrick, J.J., Romatowski, J.G., Bain, J.L.W., Trappe, S.W., Trappe, T.A., Thompson, J.L., Costill, D.L., Riley, D.A., and Fitts, R.H. 1997. Effect of 17 days bedrest on peak isometric force and maximal shortening velocity of human soleus fibers. Am. J. Physiol. 273: C1690-C1699. 89. Larsson, L., Li, X., Berg, H.E., and Frontera, W.R. 1996. Effects of removal of weight-bearing function on contractility and myosin isoform composition in single human skeletal muscle cells. Pfluegers Arch. 432: 320-328.

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