Chapter 2 Neuromuscular Adaptation to Actual and Simulated Weightlessness

Chapter 2

NE UROMUSC ULAR ADAPTATI 0N TO ACTUAL A N D SIMULATED WEIGHTLESSNESS

V. Reggie Edgerton and Roland R . Roy

I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I1. Effects of Actual and Simulated Spaceflight on Skeletal Muscle . . . . . . .

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A . Changes in Force-Velocity Potential . . . . . . . . . . . . . . . . . . . . B . Changes In Endurance Properties . . . . . . . . . . . . . . . . . . . . . 111. Coordination of Movement During and Following Spaceflight . . . . . . . . . A . Principles of Motor Control . . . . . . . . . . . . . . . . . . . . . . . . . B . Effects of Spaceflight on the Control of Movement . . . . . . . . . . . . C . Control of Movement during Extravehicular Activity . . . . . . . . . . . D . Control of Movement upon Return to Earth . . . . . . . . . . . . . . . . E . Readaptation to Earth’s Gravity after Spaceflight . . . . . . . . . . . . . IV. Prevention of Spaceflight Effects . . . . . . . . . . . . . . . . . . . . . . . . V. Conclusions and Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Advnoce in Space Biology and Medicine V d u w 4. pages 3347 Copyrisht 0 1by JAI Press Inc AD ri@ts of reproduetioa in any form reserved

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1. INTRODUCTION For a productive and safe exploration of space by humans we need a clear understanding of how the nervous system controls movements under a wide variety of environmental conditions, particularly with respect to the range in gravitational fields that are encountered in space missions. Further, astronauts must maintain the functional integrity of the nwromuscular system in order to perform effectively in space exploration. This is not only essential for human productivity in space, but also for avoiding inappropriate movements at critical times that can affect astronaut safety and even survival. The present chapter will focus primarily on the effects of varying gravitational fields on the neuromuscular system and the functional implications of these effects on the neural control of movement. The factors that contribute to the functional integrity of movement can be viewed relatively simply at a conceptual level. For example, movements of a limb segment result from a modulation of force generated by select muscles or muscle components over some duration of time. Although many physical factors extrinsic to the neural and muscular systems affect movements, millisecond to millisecond control is determined by three decisions of the nervous system: (1) which motor units to activate, (2) when to activate each motor unit, and (3) what level of activation to achieve for each motor unit. The muscle response to neural control, likewise, can be conceptually simplified as the aggregate force, velocity. and endurance properties of the activated motor units. The maximum static or dynamic forces that will be produced an: determined by: ( I ) the number of muscle fibers per motor unit, (2) the total cross-sectionalarea of the fibers in each motor unit, and (3) the force efficiency of each motor unit, i.e., the force per unit of cross-sectional area.’ Similarly, the velocity of movement seems to be determined by the type of myosins that are expressed and maintained in the fibers; that is, “slow” or “fast’’ myosin in adult mus~les.2-~ and the number of sarcomeres arranged in series, (i.e.. the length of the fiber^).^" The endurance properties of motor units when recruited repetitively is a function of many interrelated factors. The simplified conceptual consideration that defines the resistance to fatigue of a unit is the ability of the muscle fibers and motoneurons to maintain homeostasis. This potential may be largely a reflection of the rate of utilization of energy relative to the rate at which it can be replaced and relocalized at the sites critical for contraction.The rate at which myosin hydrolyzes ATP. which can vary as much as l W f o l d , and the capacity of the cells to sustain oxidative phosphorylation seem to be two key factors in maintaining muscle fiber homeostasis. Although glycolysis is an essential element in maintaining homeostasis, the maximum glycolytic potential of muscle fibers is p r l y correlated with the fatigability of the muscle, at least as traditionally defined for motor units.’3

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11. EFFECTS O F ACTUAL A N D SIMULATED SPACEFLIGHT ON SKELETAL MUSCLE A clear undcrstanding of the force-velocity-endurance characteristics of muscles functioning at 1 G is fundamental to an undastanding of muscle function in routine activities when entering a 0 G environment, when landing on the Earth’s moon or Mars,and subsequently when returning to 1 G. It is also fundamentally important to understand the neural control features of movements at variable G levels. Data from actual spaceflight and from ground-based experiments designed to simulate the adaptations to the “weightlessness” environment; for example, bed rest and immersion in humans and hindlimb suspension for rats, have already facilitated planning for long-term spaceflight (see refs. 14-26 for reviews). Some of these findings will be discussed in this chapter. A. Cbanges in Force-Velo&y Potential

Spaceflight

Some muscles atrophy (i.e., lose mass) rapidly during spaceflight while others are relatively unaffected. The most marked loss of muscle tissue appears to occur in those muscles that have an antigravity function, e.g., the extensor muscles of the leg. It is likely that thc hip, back, and neck extensor muscles also atrophy,but further studies are needed to validate this assumption. To determine the spaceflight effects on skeletal muscle, torque-velocity tests of specific muscle groups have been the focus of srudy in both Russian and American missions, while some histochemical and morphological data have also been obtained. Based on gross anthropometric measurements of three astronauts in each Skylub mission, the size of the lower cxtremitics decreased by 7-1 1% in missions ranging in duration from 28 to 84 days, with 50% of the loss attributed to muscle Interestingly, the smallest atrophy and 50% attributed to cephalad fluid changes in leg volume were observed immediately postflight and after the longest flight, i.e.. the 84day mission. Urinary nitrogen, phosphate, amino acids, and 3-methylhistidine, all indirect indicators of a loss of muscle mass, wcre increased and there was a negative potassium balance following these Consistent with the loss in muscle mass, reductions in muscle strength during isometric and slow isokinetic, concentric contractions werc reported for the Skylab missions ( 2 8 4 4 days), with the effects being greater in the cxtensors than the flex0rs.2~ Cherepakhin and Pervushin?’ however, reported only a 1 and 6% reduction in calf circumference2 days after flight in the two Soyuz-9 crew members (1 8day flight). In addition, hand flexor strength was unchanged, while trunk extensor strength was reduced by 40 and 65 kg in these two cosmonauts. Astronauts from the Apoflo progmm ( 2 8 4 4 days) showed a significant loss of force output at the higher velocities of shonening, particularly among extensor

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muscles of the leg and trunk.n Although the flexor musculature of the legs and the arm flexors and extensors were also affected. the changes were less dramatic. For example, after 28 days of spaceflight, the hip and knee extensors were 22% weaker (tested at 0.78 rad sec-’) than before flight, while the hip and knee flexors were only 100/0 weaker.31 After the return from either a 14Cb or 175day space mission, the maximal torques at 1IO/sec for the calf muscles of a scientist pilot and a commander were reduced by more than half of the preflight values when tested on the second day po~tflight.’~ The differences, however, were less severe when the maximal torques wen: tested at lower velocities of movement. This suggests that the reduction in power was due to a loss of velocity as well as force potential of the muscle. Torque measurements for the thigh musculature showed a similar pattern as observed for the calf musculature; i.e., the largest decreases in torque were at the higher velocities. The changes, however, were less severe in the thigh than in the calf musculature. Another indication of muscle atrophy in the calf of the legs of the cosmonauts after a 175-day mission was the doubling of the electromyographic (EMG) amplitude to torque ratio. This elevation in EMG relative to torque production, however, was less evident in cosmonauts after a 14Cbday mission.’43’ In subsequent studies involving Salyur-6 and -7 and the Mir station, the results from long-term (60 to 366 days) and short-term flights (rendezvous missions of about 7 days) .were compared.3334The maximum torques of the plantar flexors in both short- and long-term flights were affected over the entire range of velocities tested. The maximum decline of strength fluetuated between 20 and 70% among subjects after either short- or long-term flights. The seventy of the decrement in torque-velocity performance immediately postflight was inversely related to the duration of the spaceflight.34It was also clear, however, that this inverse relationship was attributable to the effectiveness of the physical exercise utilized during the flight. As the Russians have increased the duration of their flights, they have gained a better understanding of the nature of the physical exercise necessary to minimizc the effects of spaceflight on neuromuscular performance. For example, one crew member from a 16Oday spaceflight lost -70% of his torque-velocity capacity over a range of velocities from 0 to 18Oo/sec. In contrast, one cosmonaut that endured a 366day flight and another a 33Oday flight showed reductions in their torquevelocity performances that ranged only from a few percent to slightly more than 20%. Of the 24 cosmonauts studied after 60 to 366 days of flight, two of the three individuals least affected with respect to motor effects endured flights greater than 350 days. In contrast to the plantar flexors, the maximum torques (at all speeds tested) of the dorsiflexors were affected significantly only after long-term flight. Postural strength, i.e.. hip extensor strength, was reduced by an average of 16% ( range 0 to 30%) for 11 cosmonauts after flights ranging from 2 to 5 days and measured 2 days po~tflight.~’ Gngorieva and Ko~lovskaya~~ reported a 30% decrease in the isokinetic (at all velocities tested) and isometric strength of the plantar flexors of healthy men after

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only 7 days of dry immersion, a ground-based model of weightlessness used extensively by the Russians. In contrast, the strength of the ankle dorsiflexors was reduced only during isometric contractions, and this decrease was less than that observed in the plantar flexors. The differences in the toques of the knee in cosmonauts before and after either a 140- or 175-day flight were less than those reported after 7 days of dry immersion." This lesser effect may reflect the success of the inflight exercise countermeasuresused by the cosmonauts. Ground-Based Studies

Five weeks of bed rest resulted in a 2% decrease in lean body mass and a concomitant 2% increase in fat content at constant body weight?6 The authors concluded that maintenance of body weight during long-duration bed rest or spaceflight may result from an accumulation of body fat. Leonard et aL30 used a variety of methods to assess the loss of lean body mass and fat components of the body weight in the three Skyiub missions. There was about a 4% reduction in body weight with lean body mass and fat losses each accounting for about one-half the change. There was no correlation between body weight loss and flight duration, indicating that adequate diet and appropriateexercise can control the weight loss. On the other hand, Convertino et reported that body weight decreased by 3% during a 36day bed rest period with the largest decrease occurring in the first 4 days. After 5 weeks of horizontal bed rest, the cross-sectionalarea of the major plantar flexors, i.e., soleus and gastrocnemius,had decreased by 12% based on magnetic resonance imaging of two contiguous 1-cm slices through the center of the gastrocn e m i ~ . ~Maximum ' isometric strength was decreased by 26%. In contrast, the cross-sectional area and maximum strength of the dorsiflexors were unaffected. Based on computed tomography of five cross-sectionsalong the length of the limb segment, Convertino et al?7reported an 8% decrease in muscle mass and a 9% increase in fat mass in the thigh and a 4 5 % decrease in the calf, after 30 days of bed rest. The average decrease in toque over a range of velocities of eccentric and concentric contractions was 19% for extensors and 6% for flex0rs.3~Muellera reported a 20%decrease in leg snength after only 2 weeks of bed rest. Gogia et a!l' found that the plantar flexor,dorsiflexor,knee extensor, knee flexor, and elbow flexor torques (at 6Wsec) were significantlydecreased after 5 weeks of horizontal bed rest. As noted in other studies, the extensors showed a larger decrement than the flexors. The only exception was the maintenance of strength in the elbow extensors, possibly because this muscle group was used for mobility while in bed. Bed rest in the head-down (-5') position for 120 days resulted in a progressive decrease in the strength-velocity properties of the triceps surae!* For example, at the end of the 4-month experimentalperiod the forces produced at 0.60,120, and 18Oo/sec tested by isokinetic dynamometry were reduced by 25 to 40%. the largest decrements found at the lowest velocities. Active countermeasures(hand and leg

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bicycling, high intensity loading of the calf muscles and/or breathing exercises for an hour per day) were reported to amelioratethe muscle atrophy in the triceps surae in about one-half of the subjects. Interestingly, passive stretching for about 40 midday maintained muscle strength in six Out of eight subjects. In general, the data obtained on the maximal torquewelocity capability of humans under carefully controlled conditions, before and after flight, have been limited by the small number of subjects, the individuality of the responses to spaceflight as well as the widely varying types of work schedules during flight. Although it appears that maximal extensor muscle torques are reduced more than flexors and that the arms are affected less than the legs, a clear conclusion on the magnitude of the effects and the time course of the changes as a result of spaceflight cannot be drawn based on published data to date. Animal Studies

There is a clearer understanding of the effect of short-duration spaceflighton the muscles of rats and nonhuman primates than of humans. In studies of the Rhesus, it has not been possible to differentiate the effects of 5 days43*44 or 14 days4’ of spaceflight from changes that may occur as a result of prolonged periods of chairing and the changes that occur with normal growth. Studies of rats in short duration flights show that extensor muscles atrophy more severely than flexors.” Those extensor muscles which consist of predominantly slow fibers atrophy more rapidly than extensor muscles that consist of predominantly fast fibers. The mean crosssectional area of muscle fibers of the slow soleus muscle of rats,for example, was reduced by 26% after a Cday flighta and by 36% after a 7-day pacef flight?^ A slightly greater atrophy was noted in the soleus of rats flown for 12.5 days on the Cosmos-1887 biosatellite?’ Similar degrees of atrophy wefe found following Cosmos flights lasting 22 d a ~ s . 4Figure ~ 1 summarizes the time course of these adaptations for the soleus muscle and clearly demonstrates that the atrophic response is similar for slow and fast fibers. Based on studies in rats, it is clear that severe muscle atrophy can occur within a few days, that extensor muscles atrophy more rapidly than flexor muscles, that slow contracting extensors atrophy more severely than fast extensors and that at some point soon after the beginning of flight the rate of atrophy is markedly reduced. The best ground-based animal models to study the effects of spaceflight on skeletal muscles have been those in which the whole body or the hindlimbs of animals, usually rats, are suspended (see refs. 15,25,26for recent reviews). In these experimental models, the limbs are chronically unweighted. The atrophic effects of hindlimb suspension are remarkably similar in degree, kind and in the specific hindlimb muscles being affected to those observed in spaceflight. The effects of space flight and hindlimb suspension are similar in many respects to the changes seen in paralyzed muscles, i.e., following long-term spinal cord transection or spinal

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Fkure 1. Summary of the time course of the atrophic response of the slow (open circles and dashed lines) and fast (closed circles and solid lines) fibers associated with spaceflight. Ground-based control values for each fiber type are represented as 100%. Data points are as follows: after 446, 747, 1448, 20.512', and 2249 days of flight.

isolation (see ref. 15 for a recent review) and following immobilization of the hind-limbs.50 Muscle Fiber Studies

One of the most direct and accurate approaches to assess the percentage muscle loss in spaceflight is to measure thc cross-sectional area of a population of muscle fibers. This can be done by studying muscles removed postflight or by needle biopsies from animals or humans. The muscle needle biopsy procedures are known to be acceptably safe for humans?' To determine the applicability of the data derived in flight from rats and monkeys to humans, it will be necessary to study human muscle after flights of similar durations.The rates of changes among species

V. RECCIE EDCERTON and ROLAND R. ROY

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Figure2. Mean cross-sectional area (CSA) of slow and fast fibers of the vastus lateralis muscle pre and post 5-11 days of flight for 8 crew members. (From ref. 52).

and muscles may vary significantly for a number of reasons. For example, the turnover rates of proteins undoubtedly are faster in small than in large animals and may differ among muscles. Strict comparisons of data obtained from rats, nonhuman primates and humans will be critical in efforts to validate the applicability of the results from animal studies to human adaptations in space. Direct evidence of the effects of spaceflighton muscle has been obtained recently from pre- and postflight biopsies of astronauts.52Muscle biopsies from five male and t h n x female Space Shuttle crew members, ranging in age from 33 to 46 years, have been studied.Muscle biopsies were obtained from the midportion of the vastus lateralis muscle with a 6-mm needle biopsy.53Five of the astronauts were on the same flight which lasted almost 11 days, while 3 other astronauts were on one of two 5-day flights. All crew members were evaluated and considered to be in good physical condition prior to flight, although their exercise habits varied. Preflight muscle biopsies wece taken 3-12 weeks prior to flight, while postflight samples were taken 2-3 hours after landing. Based on cross-sectionalarea measurements of single fibers,it appears that some atrophy occurred after 11 and perhaps even 5 days of weightlessness. %o of the

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TOTAL CSA (cm2 ) Figure 3. Relationship between maximum tetanic tension (Po) and total fiber crosssectional area (CSA) of 15 motor units from control carts (filled squares) and 9 motor units from spinal isolated carts (open cirdes). In the latter, chronic inactivity is produced by complete transection of the spinal cord at a low thoracic and a high sacral level plus bilateral dorsal rhizotomy. r, correlation coefficient. (Adapted from ref. 65).

three astronauts that flew for 5 days had significantly smaller fibers after flight than before. Within each subject, a similar amount of atrophy was observed for both slow and fast fibers. The mean decreases in fiber cross-sectional area for all astronauts were 15 and 22% for slow and fast fibers,respectively (Fig. 2). Since the cross-sectional area of the fibers of a muscle (or motor unit) is highly correlated with its maximal tetanic tension (Fig. 3), the present results suggest that the force potential of the vastus lateralis of the astronauts was significantly decreased within 5-11 days of spaceflight.

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The amount of atrophy differed considerably between crew members, which may be due to differences in physical activitiesexecuted during flight. For example, two of the astronauts that exercised on four or more occasions during the flight seemed to have little or no atrophy. On the other hand, in the one individual that exercised nine times during the 11-day flight the level of atrophy was one of the highest. This same individual, however, seemed to be the most affected by the flight, based on other physiological as well as subjective assessments immediately postflight. The effect of spaceflighton the types of myosin expressed in skeletal muscle was determined in various ways: ( I ) staining based on the sensitivity of myofibrillar ATPase to pH; (2) identification of the myosin heavy chain (MHC) isoforms in single fibers based on immunoreactivity to monoclonal antibodies; and (3) determination of the pH sensitivity of the myofibrillar ATPase activity of single fibers, which is rather closely correlated with the immunohistcchemical method based on the binding properties of antibodies specific for slow and fast MHC i s ~ f o r m s . ~ ~ ~ It appears that there was an increase in the number of fibers expressing fast MHC. In addition, most of the fibers that co-expressed fast and slow myosin were found in the biopsies taken after flight. The crew member showing most muscle fiber atrophy also showed the largest change in the percentage of fibers that co-expressed slow and fast MHC. In this person, slow and fast MHCs were co-expressed in only 1% of the fibers prior to flight and in 10% after the 11d a y flight. This individual was highly trained for endurance prior to flight. The importance of this observation is that the type of myosin expressed can apparently change much more rapidly than might be expected. Consistent with the trend towards more fibers expressing fast MHC after flight was the observation that the myofibrillar ATPase activity was also slightly increased.52 Similar results have been obtained from the soleus muscle of rats flown on the Space Shuttle (4 days% and 7 days47). Cosmos-1887 (12.5 daysa) and Cosmos2 0 4 4 ( 1 4 d a y ~ ~ ~In~ addition,H~lyetaI.~havereportedchanges ’). inthesensitivity of single fibers to calcium and strontium ion concenmtions in response to spaceflight. This is consistent with the interpretation that additional fibers express fast myosin isoforms after flight. Changes in expression of MHC isoforms in response to either spaceflight or hindlimb suspension have not been demonstrated clearly in muscles that consist predominantly of fast fibers. For example, the vastus lateralis of rats after a 12.5 day flight on Cosmos-1887did not show a significant increase in fast MHC expression?’ Normally there is a large range in the maximum shortening rates among fibers of the same m ~ s c l eThere . ~ ~ appears to be an increase in the maximum shortening velocity potential of fibers from predominantly slow muscles of rats following relatively short duration flights, but not from predominantly fast m u s ~ l e s 4 ~ ~ ~ ~ * Although the results from the astronaut biopsies noted above are consistent with the development of faster shortening velocities. it is unlikely that the magnitude of the changes in myosin would be detectable in tests of contractilefunction of whole

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muscles. It also seems unlikely that the performance potential of the a ~ t r o ~ u t s would be affected significantlyby the changes in myosin observed after only 5-1 1 days of flight.’* Is it reasonable to assume that during longer spaceflights changes in contractile speed will be more evident as a result of more fibers expressing fast myosin isoforms? Concomitantly, there may be an up-regulation of the proteins in the sarcoplasmicreticulum associated with fast fibers. Certainly one could assume that more, and perhaps all, fibers eventually could be reprogrammed so that the nuclei of slow fibers would begin to express only fast myosins and the other proteins usually co-regulated with fast myosin.62For example, there is some evidence that most, if not all, fibers in humans can express fast myosin after spinal cord i11jury.6~ Similarly, one year after low-thoracic spinalization in rats, virtually all fibers in the normally predominantly slow soleus muscle were fast, as shown by qualitative histochemical stainingfor myofibrillarATPase.64On the other hand, after 6 months of electrical silence of motoneurons by spinalization and deaffaentation, only about 25% of the slow fibers become reprogrammed to express fast myosin in muscles that normally are predominantly fast.5’-as*66 This value increases to 5096 in muscles that normally consist of predominantly slow fiber^?^.^ A similar limitation in reprogramming has been observed after cross-reinnervation of a predominantly slow muscle with the nerve from a predominantly fast m ~ s c l e . ~ ~ * ~ Perhaps only a limited number of fibers can be reprogrammed to express fast as well as slow myosin after prolonged spaceflight.

B. Changes In Endurance Properties It is generally expected that decreased use will make muscles more fatigable. However, this may not always be the case. For example. in response to hindlimb suspension it appears that the muscles which atrophy the most, i.e.. the predominantly slow muscles do not become more fatigable in response to the most commonly used tests of fatigability.50*69-72 Even after 6 months of total electrical silence, mixed fast muscles continue to have fast and slow motor units that are relatively resistant to fatigue:’ while predominantly slow muscles maintain about 50% of their slow fibersMand appear to maintain their resistance to fatigue even after 8 1nonths.7~ Fatigability is an extremely complex variable. In view of the variables assessed in the present study, fatigability can be addressed only in a relatively narrow perspective, particularly relative to in vivo function in everyday life where neurohumoral as well as muscular factors can contribute to fatigue. One estimate of fatigability is the activity ratio of metabolically supportiveenzymes,e.g., succinate dehydrogenase(SDH), relative to enzymes which reflect the rate of ATP utilization, e.g., ATPase. Since oxidative phosphorylation plays a more substantial role than glycolysis in the ability of a fiber to maintain homeostasis, it seems likely that the activity of SDH will be a more accurate indicator of metabolic support than that of

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glycolytic enzymes, such as alpha-glycerophosphate dehydrogenase (GPD) or lactate dehydrogenase(LDH). Biochemical assays related to fatigability have been conducted on single fibers in astronauts before and after spaceflight.SDH, a marker enzyme for the ability of fibers to utilize oxidative metabolic pathways, was unaffected in either slow or fast muscle fibersby flight. This finding is consistent with previously reported data for slow muscles of rats flown for 2 weeks5' on the Cosmos biosatellite and of rats hindlimb-suspended for up to 4 GPD activity, used as a glycolytic marker enzyme, also seemed to be unaffected, although the activity in the slow fibers was higher after flight in five of eight crew members. Although the effects of and hindlimb s ~ s p e n s i o non ~ the ~ ~glycolytic ~ ~ . ~ ~ capacity of individual fibers in rats have been variable (see ref. 15 for a discussion), the data suggest a general increase in glycolytic potential. Thus, the metabolic potential of fibers in rat and humans as indicated by an oxidative and a glycolytic marker enzyme seem to be stable for up to 2 weeks of spaceflight. While muscle fiber atrophy may have a direct effect on the force-generating potential of a muscle, it may also affect the fatigability of muscle fibers and motor units in two other important ways. First, resistanceto fatigue is likely to be increased by the smaller cross-sectional area of the fibers, because the diffusion distances between capillaries and the center of the fibers is reduced.79Secondly, the smaller cross-sectional areas result in higher capillary densities after spaceflight?**" On the other hand, susceptibility of an astronaut to fatigue upon return to Earth is likely to be enhanced whenever muscle atrophy occurs. For example, a routine postural task of a muscle may require the recruitment of about loo/o of the force potential (and cross-sectional area) of that muscle. If those same fibers can produce only half the normal force due to a 50% loss in cross-sectional area, then additional fibers must be recruited to complete the same task to compensatefor the 50%loss in mass. Because these additional fibersaremore fatigable(note that the least fatigable fibers are usually the first to be r e ~ r u i t e d ' ~ * ~routine . ~ ' ) , movements at 1 G upon return from prolonged periods at 0 G are likely to result in a more rapid onset of fatigue. The scenario described above is more likely to occur in the muscles of the legs. back and neck than in those of the arms. forearms and hands. If an astronaut works frequently in a spacesuit during extravehicular activity (EVA) over a period of several months, then the conditioned state for the arms and hands could bc higher after than before flight. The effective force that can be generated by the hand when wearing the gloves used in the EVA spacesuit is about one-half of the force generated without the glove. When the glove is pressurized to about 29 m a , * there is a further reduction in force generation. The main physiological consequence is that more than twice as many muscle fibers must be recruited to complete a task during EVA, a factor which may contribute to a rapid fatigue of the "grasping" muscles in the forearm. The effects of spaceflight on the endurance capability of a muscle group can thus be summarized as follows. It appears that the slow extensor muscles of the leg, back

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and neck may become more fatigable because of muscle atrophy and not because of any disproportionateloss of the supportive metabolic enzymes. In contrast, the musculature of the arms, forearms and hands are less likely to become more fatigable during spaceflight. Sustained EVAperformanceduring a mission may be difficult, not because of neuromuscular de-adaptation,but because of the functional limitations in the glove component of the prcssurized suit and the additional work load demanded of the forearms.

111. COORDINATION OF MOVEMENT DURING AND FOLLOWI NG SPACEF L I G HT A. Principles of Motor Control

Under normal environmental conditions, the central nervous system (CNS) has an amazing ability to precisely control routine movements, given the variety of conditions under which this control must be managed. Weightlessness seems to affect all physiological systems that play important roles in movement control in one or more ways. For example, accurate rapid and coordinated movements of the eyes is essential for optimal interaction with the control of body motion. Although the control of eye motion is largely spared the immediate task of dealing with varying gravitational forces, eye movements are affected in flight. These effects may occur indirectly through changes in visual, vestibular and proprioceptive function and through adaptation to m i c r ~ g r a v i t y . ~ ~ ’ The level of adaptation to altered G environments varies markedly from one muscle system to another.The facial muscles should experience minimal functional changes in response to variable gravitational forces. In contrast, the control strategies of the CNS for the musculatureof the arms and legs must be markedly changed. For example, when standing with the arms relaxed along the sides of the body, greater effort (force) is required to flex and extend the elbow at 1 G than would be the case at 0 G. With the same neural output at 0 G as at 1 G,to complete the same task at 0 G the hand would move faster and further during flexion, but there would be too little force during extension to return the hand to the side of the body. Similarly, the forces necessary to maintain an erect posture throughout the daily activities at 1 G must affect the CNS control system for the antigravity muscles (generally extensor muscles) more than any other muscle group. The work required of the flexors of the legs and arms may be more similar during spaceflight than in a 1 G environment. Flight experience has shown that immediately upon entering the Earth’s orbit, the more common mode of locomotion for the body involves the upper limbs, while the legs are used primarily to vary the position of the center of gravity to facilitate the orientation of the body segments. The fingas. hands, and upper arms then provide the means of moving the body from one location to another.

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Generally. it appears that when the gravitational environment is varied, each muscle group will adapt differently. As emphasized previously, the magnitude of the force generated by a muscle or group of muscles is proportional to the total cross-sectionalarea of the musculature that is activated by the nervous system”I2 Since the total cross-sectionalarea of a muscle is composed of thousands of muscle fibers, the precise forces needed 10 execute a movement is controlled by activating a selective and appropriate number of muscle fibers. Several hundred muscle fibers can be innervated by a single motoneuron (a motor unit) and each muscle may be innervated by 100 or more motoneurons. Thus, the level of force generated by any given muscle or muscle group is determined essentially by the number of motoneurons (motor units) activated.The neural control system is generally spared the problem of determining which of the many motoneurons should be activated to complete a task Rather, the CNS seems to decide what proportion or number of motor units must be activated to accomplish the desired task.” Since each network of motoneurons that innexvates a muscle or muscle group (motor pool) is organized so that in a movement the smaller motor units are recruited first and the larger ones are recruited last, the appropriate amount of force is produced by recruiting the appropriate number of motor units. The close association between order of recruitment and motor unit size f a n s the basis of the “sim principle” of recruit~nent,’~~’.~ which has been shown to be rcmarkably consistent for most conditions. Although the size of a motor unit can be estimated in a number of ways, the most relevant measures of the force potential of a unit are the number and size of muscle fibers per motoneuron, with the numtm of fibers (the innervation ratio) being the major determinant.’ An additional concept to consider in spaceflight is that since the activation and mechanical patterns of motor units affect their protein profile, chronic alterations in the mechanical load will result in predictable adaptations that will affect the muscleoutput, and thus the performance of motor tasks.The simplest condition for assessing the adaptation of muscle force is at zero velocity, i.e., under isometric conditions when neither shortening nor lengthening of the muscle occurs.In vivo, however, muscles function routinely in such a way that the muscle length and the load on the muscle may decrease or increase during a movement, depending on the external conditions. These rates of shortening(concentric)and lengthening (eccentric) usually are referred to as positive and negative velocities during which positive and negative work is done. An example of primarily negative work (eccentric contraction) is the work done by the quadriceps muscle group (primary knee extensors) when one jumps down or walks down stairs. On the other hand, during jumping up or walking up stairsmost of the work done by the quadricepsis positive, i.e., the muscles shorten when they are activated. In spite of the complexityof the interactionof force and velocity, the relationship between these variables at a given level of activation is predictable in many species of skeletal muscles, if the details of the muscle architecture and lever mechanics are known. It is apparent that many of the fundamental mechanisms of force

Neuromuscular Adaptation to Weightlessness

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Figure4. Mean angle specific (at 604 maximum voluntary torque output of the knee extensors during eccentric, isometric and concentric contractions (Adapted from ref. 126).

generation have been well preserved during the evolution of muscular systems. Note that the force potential is slightly higher when the activated muscle is lengthening than when contracting at zero velocity (Fig. 4). One should also note the hyperbolic drop in force as the velocity of shortening increases and the maximum rate of shortening occurs when there is the least resistance to oppose the contractile elements of the muscle. 6. Effects of Spaceflight on the Control of Movement A common response among crew members upon return to Earth has been a marked sense of ‘heaviness”of the head and body. It was noted in one report that for several days after return from a Skylab mission of 89 days, it was particularly difficult to get out of bed and move about in the morning while later in the day this sensation seemed less severe. Gibson,87a scientist pilot for Skylab4 (duration of 84 days), noted: “Also the brain was not coupled to the muscles in the same way as they were before we left: that is, we all felt very heavy. Every movement we made had to be worked at. Rolling over in bed, moving an arm,walking; they all had to be conscious efforts. And this lasted for a couple of days and was very much more severe at the beginning then at the end of those two days. We could go around corners fairly well, if we were careful. We tended to walk with our feet spread apart.

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I think that had we had any contingency on the return we would have been able to handle those which we had planned for but certainly we were a bit less able to handle them than when we left.” Similar descriptions have been reported by cosmonauts. The two crew members from Soyuz-9 (1 8-day flight) who had elevated tendon reflexes showed clear disturbances in gait 2-5 days after landing.88Their gait was characterized by stepping with the legs far apart and the torso shifted in the direction of the supporting leg. They had difficulty walking in a straight line and took short steps with their arms extended to improve their stability. The height to which the knee was elevated during stepping was reduced. The initial extensor phase of stepping was characterized by a “stamping” motion. This “stamping” gait was clearly evident 3 4 hours after landing, but had improved by the second day after flight. They compared the sensation with that of an acceleration of 2 G induced whileon Earth. In addition, theirperceptionofmuscularefforts and relative position of the limbs during walking was distorted. Detailed biomechanical analyses revealed numerous gait characteristics which remained p e r t u M for 2 days after flight. In spite of the consistent and dramatic descriptions by crew members of the effects of prolonged spaceflight on sensorimotor perception and function, it has been difficult to make direct obervations which explain these subjective phenomena. There is. however, a battery of measures that provide some clues as to the sites and kinds of changes that may be taking place in the neural components of the ncuromotor systems.The present chapter focusesprimarily on the neuromcchanical control by the spinal cord and associated output Characteristics of the muscular systems of the limb. The effects of spaceflight on vestibulwcular function and how this relates to head control as well as the control of precise movements that are not involved in postural-mobility functionswill not be addressed in this chapter. When humans enter a microgravity environment. there is an immediate and dramatic reduction in the activation of the extensor musculature required to maintain an upright posture at 1 G. The electrical activity (electromyography, EMG)of flexor and extensor muscles in the resting position of the neck, trunk, hip, knee, and ankle reflect a generalized flexor bias inflight compared to that at 1 G.32*8s91 This bias has been observed during spaceflight in astronauts when asked to stand upright, independently of whether or not their feet are anchored to a surface. Further, when they are asked to stand erect with a few degrees of forward tilt, the magnitude of the forward tilt may be as much as four times greater (12’ vs. 3’) at 0 G than at 1 G, indicating a relative decrease in extensor activity and/or increase in relative flexor activity. The sites and kinds of sensory information that trigger this exaggerated forward tilt are not known. It is likely that the flexor bias at 0 G results from a combination of less inhibition of extension and more facilitation of flexion from muscle and joint proprioceptors. In addition. at 1 G but not at 0 G, simple foot contact or pressure on the pads of the feet are likely sources of activation of extensor muscles.92These relatively flexed positions have been observed in

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49

cosmonauts and astronauts when they are free-floating and when their feet are anchored for body ~ t a b i l i t y . ' ~ * 'This ~ * ~residual ~ * ~ flexor bias, even after return to Earth,provides a clear indicator of a general adaptation strategy for organizing movements in a 0 G e n ~ i r o n m e n t . ~ ~ Although a flexor bias persists during flights, even after adaptation to 0 G, the activity levels of some of the extensor muscles progressively increase within a few ~ ~ recovery of extensor days of continued exposure to the 0 G e n v i r ~ n me n t.This activity and continued elevation of flexor activity has been clearly documented in ground-based models of w e i g h t l e s s n e s ~ .For ~ * example, ~ ~ ~ ~ extensor EMG activity essentially disappears immediately upon unloading of the hindlimbs in rats. Within hours, however, some EMG activity reappears during continued hindlimb suspension and by 7 days the total daily amount of activity is nearly normal. This pattern has been observed in both predominantly slow (e.g., soleus) and fast (e.g., medial gastrocnemus) ankle extensors. In contrast, the EMG activity of the tibialis anterior, an ankle flexor is significantly elevated throughout the suspension period.= The "recovery" to normal or near-normal levels of extensor EMG activity, while remaining "IInloaded", suggests that the CNS is "programmed" so that general extensor bias continues as it does at 1 G under normal gravitational loads. This apparent residual bias may have been permanently acquired during development as a result of the daily sensory cues of a 1-G environment. Alternatively. this extensor bias could be inherent in the design of the CNS. i.e., independent of any activity-dependent events associated with movement control in a 1-Genvironment. Some of the most fundamental and simplest neurophysiological functions are changed during spaceflight. The monosynaptic "stretch" (tendon) reflex is one of the simplest clinical tests of reflex function in the CNS, and the magnitude of this reflex can be used as an indicator of the spinal cord excitability. After only a few days of spaceflight,the magnitude of the reflex (amount of movement or muscular contraction) is reduced significantly." Also, there is an increased sensitivity (reduced threshold) to the tendon tap; i.e., within a few days of the initiation of spaceflight, a less brisk tendon tap will induce the monosynaptic reflex (Fig. 5). The amplitude of the tendon reflex remained depressed 2 days after a flight of only 4 days. Although the amplitude of the tendon tap reflex seemed to recover slightly during prolonged flight, it remained lower than preflight for flights lasting up to 175 days (Fig. 5). This depressed tendon reflex after a 175-day flight persisted for at least 11days postflight. In contrastto the reduction in the tendon reflex amplitude, noted in other missions, the amplitude of the patellar reflex was more than doubled in one crew member and more than tripled in another, 2 days after an 18day flight ( S O ~ U Z - ~This ) . ~ ' elevated reflex amplitude, however, had returned to preflight levels by 11 days postflight and the amplitude was markedly lower than preflight in both legs of both crew members 36 days postflight. An additional indicator of synaptic malleability is the disturbance in "crossed" reflexes. For example, the depression of the Achilles tendon reflex that normally occurs when the contralateral ankle is dorsiflexed, was not evident after 142-175 days of flight.

V. REGGIE EDGERTON and ROLAND R. ROY

50

0.04

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.

I

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Figure 5. Time course of the adaptations in the threshold and amplitude of the Achilles reflex after bed rest, spaceflight and dry immersion. (Adapted from refs. 14,16).

The level of excitabilityof h e spinal cord can also be estimated with an H-reflex test. This test consists of stimulating a peripheral nerve (e.g., the posterior tibial nerve) which then propagates an action potential to the spinal cord and activates, via hundreds of synapses, a population of motoneurons. The H-reflex amplitude is significantlyreduced after pacef flight.'^ This attenuation in the H-reflex is consistent with a reduced tendon reflex and a change (adaptation) in the neural networks of the spinal cord. It does not preclude, however, proprioceptiveadaptation in the periphery as well. For example, the reduced threshold for the monosynaptic reflex could be aperipheral andlor central phenomenon.The reduced monosynapticreflex threshold bears some analogy to the enhanced sensitivity of the bottom of the feet to vibration in cosmonautsafter flights lasting 3-5 m o n l h ~ . ' ~The * ' ~greater tremor-

Neuromuscular Adaptation to Weightlessness 0.6

W

tn

z

-

2In

05

-

2 s

0.4

-

= W

5

; W

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E 020.1

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BEFORE

AFER

F&re 6. Threshold response and correction time to a postural perturbation before and after a 7-day flight. (Adapted from ref. 16).

like activity observed postflight than preflight, when cosmonauts were asked to maintain an upright posture, is evidence of central adaptation. In addition, the time it took to make postural corrcctions while maintaining a standing posture was 2-3 times longer postflight than preflight (Fig. 6). The EMG response of the soleus and tibialis anterior to perturbations of the standing position was almost doubled in crews visiting Sufyut-6 for &14 days (mostly 7 days).14 Further, the response time to the perturbation was 3 times longer postflight than preflight. Severe postural disruptions after 4 1 0 days of spacefight on Space Shuttle have also been reported.98 A rapid recovery rate is evident immediately after flight, with 50% of the recovery occurring within the first 3 hours postflight followed by a slower recovery over the next 2 4 days. As was true for performance in a maximum torque-velocity test of the plantar flexors, the duration of the spaceflight has proven not to be an important factor in determining the

V. REGGIE EDGERTON and ROLAND R. ROY

52

severity of either a standing postural test or a postural perturbation test (Romberg Test). For example, the EMG amplitude response to postural perturbations immediately postflight in cosmonauts that had been on the Mir station for 326 days was similar to that preflight. In contrast, the EMG response was doubled in cosmonauts after either a 16oday or a 175-day spaceflight.% Another clear example of the modification in the input4utput ratio of the motor system was demonstrated after 7 days of dry immersion. Before immersion the subjects were able to increase the force in relatively constant increments up to about 50% of maximal voluntary contraction for about 10 successive trials. After immersion, the subjects overestimated the target force considerably even at the lower force levels, and the force differential became even more distorted at the higher torques (Fig. 7). These adverse postural effects have persisted for as long as 42 days after a 175-day flight.14All these effects demonstrate a negative impact on the preciseness of the control of movement when humans return from spaceflight, although little is known about the mechanism of these phenomena. Some of the adaptations in the motor responses noted above may reflect, at least in part, the effects of muscle atrophy. The reduced force potential could exacerbate the postural instabilityofastronauts, which is usually attributed to the neural control system upon return to 1G.This possibility seems particularly feasible since the fibers innervated by themtoneurons that have the largerrole in maintaining routine

0

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6

8

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TRIAL NUMBER

Figure 7. The ability of subjects to produce equal force increments in plantarflexion during successive trials without feedback before and after 7 days of dry immersion. (Adapted from ref. 16).

Neuromuscular Adaptation to Weightlessness

53

posture (i.e., the slow motor units) are the ones that seem to atrophy the most. Further, if the nervous system is not aware of the reduced muscle force potential and does not adjust the output signal accordingly, then the motor output will be reduced. This inappropriate neural input to output relationship will result in an exaggerated movement or sway during standing and may even result in the loss of balance. A study of subjects confined to 100 days of bed rest suggests that the absence of mobility and the general demands associated with the absence of postural maintenance has a dramatic effect on the performance of detailed motor tasks.99The subjects were required to perform coordinated and precise visual motor tasks under conditions very similar to the control systems of flight vehicles. Some subjects participated in physical exercises (“static and dynamic loads on the principal body muscle groups after each 4 days of adherence to a bed rest regime”) in an effort to prevent possible motor impairments. When comparing the performance before and after bed rest, the subjects that did not exercise had more than a 5-fold higher level of error in their performance of specific motor tasks.The decrement in performance was about 2.6-fold for those subjects that exercised during the bed rest period. In addition, the performance of the nonexercised subjects was much more variable than that of the exercised subjects. These data indicate that immobility at 1 G can have dramatic detrimental effects on the performance of skills that may be critical to maintain. In summary, during and after spaceflight the effectiveness of the neuromotor system is clearly compromised. There could be a degradation in functioning of the muscles, synapses within the spinal cord, reception of sensory information by the brain and, in some cases, interpretation and perception of the environment. Dysfunction at any one of these levels at some critical time during a flight could have a major impact on the success of a mission and the safety of the crew members. C. Control of Movement during Extravehicular Activity

Immediately upon entry into a 0 G environment, the neural control system must adapt to the reduced forces of gravity. One of the more obvious changes is the use of the arms rather than the legs to move the body from one position to another in the spacecraft. Whether propelling oneself with the legs or the arms, a low level of recruitment of motor units of a muscle group may be required. Perhaps the condition in spaceflight in which conml of movement is most critical for crew safety is during extravehicularactivity (EVA). There are several reasons for the danger associated with EVA. Other than the dangers of solar flares and the remote chance of collision with meteorites, the engineering of the EVA suit, the procedures for pressurizing the suit, and the specialized tools needed in EVA can have a high impact on the success of such missions. The spacesuit,of course, must be pressurized to a level sufficient to avoid the “bends”. This situation presents a very significant challenge to engineers primarily because of the required mobility

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V. REGGIE EDGERTON and ROLAND R. ROY

of the arms and head. Mobility of the leg joints is less important, but this control is still a factor in the maneuvering of the body’s center of gravity. The mobility problem with the upper limbs is that the spacesuit pressure provides resistance to movements of shoulders, elbows, and fingers. Overexertion of the arms can easily become a limitation in work performance in EVA. Even well before the onset of neuromuscular exhaustion, a reduction in the quality of performance is almost c d n to occur.Pehaps, the greatest fear in EVAshouldbethe loss of concentration and attention associated with the greater susceptibility to discomfort and pain which accompanies localized muscle fatigue. A single critically inaccurate movement resulting from these types of distractions could cause an accident. Human factors such as these will impact safety as well as productivity, if adequate accommodations are not made in the design of Space Station Freedom. At one stage in the planning, it was being assumed that there would be as many as 6-8 hours of EVA per day, several days per week during construction of the space station. Fortunately, this is no longer the case. However, the critical question remains: “What is an acceptable work schedule given the EVA equipment to be used?” The glove of the pressurized space suit presents one of the greatest limitations to work productivity in space!2 The fine control of the fingers is reduced markedly. There is the obvious loss of the usual touch sensations.In addition, the fingers must grasp objects by overcoming the restrictions in the basic design of the glove and the elevated atmospheric pressure within the glove which creates considerable resistance to grasping movements. Finger tips have become chaffed from the continuous abrasion between the skin and the internal surface of the glove during prolonged EVA tasks.82One way to minimize some of these limitations in hand control and other associated limitations in the absence of gravity, has been to devise special tools for EVA activities. Development of specialized tools for EVA often requires extensive practice in underwater simulations. An additional challenge in the design and use of tools specialized for EVA tasks is the limitation in visibility due to the helmet of the spacesuit. The curvature of the wrap-around visor of the helmet causes some visual distortion. This distortion actually may be more of a problem in the underwater practice sessions than in space because of the greater refraction due to water. On the other hand. the diffraction caused by the water results in an enlarged image, an advantage that is not availableduring repair tasks in space. In planning the construction of structures in space, considerations of human factors must be at a level of sophistication which transcends the point of view that an astronaut or cosmonaut can perform some physical task and survive. Safety and the optimization of productivity in human performance need more emphasis in efforts to expand human presence in space.87 D. Control of Movement upon Return to Earth

During landing of the spacecraft, adjustment of the neural control of the hand must occur within minutes during a continuous increase of the gravitational force

Neuromuscula r Adaptation to Weightlessness

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from 0 G to 1 G. Hand-eye coordination must be precise and timely. Improper perception and altered proprioceptive feedback as well as changes in the responsivenessof the muscles will increasethe magnitude of errors in movement control.87 Early in the Space Shufrle program, evidence of movement control errors was found. It was evident that special attention should be given to this problem to assure the precision needed for safely landing the shuttle. Once the spacecraft has landed safely, the next dificulty in the return to 1 G may consist of postural instability. This aberration in motor control may reflect the selective atrophy of those muscle fibers that normally execute the more precise postural control commands from the nervous system (see above) as well as the hypotension resulting from vascular deadaptation.IWA consistent observation by those who have experienced 0 G for prolonged periods has been a sensation of heaviness of the body, particularly of the head. The selectiveatrophy of the extensor musculature associated with weightlessness could contribute to this sensation of heaviness.87 Performing a task with atrophied muscles will require a sense of increased effort, since more motor units must be recruited at a higher frequency of activation. In turn, this elevated recruitment is likely to increase the activation of muscle proprioceptors. Apossibility of the need for rapid egress in case of an accident upon reentry has been reconsidered after the Challenger accident. While some improvements have been made in preparing for an accident upon landing of the shuttle, a clearer understanding of the performance capability of crew members in such a scenario is needed. For example, how rapidly will the crew members be able to escape from the craft in case of an emergency?Based on the experienceof both cosmonauts and astronauts, it is apparent that the ability to egress suddenly will be limited unless effective countermeasures for the loss of neuromuscularperformanceare identified and adhered to rigidly during prolonged spaceflights.

E. Readaptation to Earth's Gravity after Spaceflight Weightlessness can result in some pathological changes in the skeletal musculature of rats, at least in those muscles that are normally comprised predominantly of

slow fibers. For example, about one-half of the fibers in the soleus in rats flown on a 22day Cosms flight were reported to be swollen, necrotic or showed some sign ; ~ ~ of muscle regeneration appeared 5 days of degeneration 2 days p o ~ t f l i g h tsigns postflight. It is not clear, however, whether the changes resulted from the "functional overload" placed on the muscles within the first 48 hours after reentry to 1 Gorwhetherthese weredirect effects of spaceflight"' (seeref. 15 for adiscussion). In this light, Riley et al.'OZ have demonstrated that a much smallerpercentage; i.e.. only up to 1%, of the fibers in the soleus of rats flown on a 7day space shuttle mission were necrotic when processed 12-16 hours postflight. It was postulated that cell death of muscle fibers occurred, thus decreasing the total number of fibers, and that there would be a progressive increase in cell death with increasing length

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V. REGGlE EDGERTON and ROLAND R. ROY

of flights. Ultrastructurally, the myofibrils were smaller and less densely packed in the flight rats than in the ground-based control rats. Since the muscles showed only minimal lysosomal (protein digesting) activity and no changes in proteolytic activity, these data suggest that the mechanism of myofibril degradation during sprreflight could be due to focal physical disruption of myofilaments. It should be emphasized that musclescomprised of predominantly fast fibers did not show these effects and that a very high proportion of muscles in humans and other mammals am predominantly fast. Thus,it appears that the magnitude of this potential effect is rather small from a functional point of view. Further, no evidence of myofibrillar disruption has been seen in light microscopic studies of biopsies of eight astronauts taken 5 or 11 days po~tflight.'~ Some signs of muscle pathology in response to the ground-based model of hindlimb suspension of rats have been reported. Unlike after spaceflight, acid protease activitie~"~and cathepsins B and D'OQ in the rat soleus are elevated as early as 4-5 days after suspension. suggesting that the increasedproteindegradation rates are due, at least in part, to increased lysosomal activity. In addition, fibers demonstrating histological signs of denervation (pale centers and moth-eaten fibers) are observed up to 4 weeks post-suspension. In contrast, no incidence of degeneration-regeneration activity was found. The postulated decrease in the number of fibers in the soleus seen after spaceflight"' was not observed after 4 weeks of hindlimb suspen~ion.'~'

IV. PREVENTION OF SPACEFLIGHT EFFECTS To counter the muscle atrophy cccuning in spaceflight, one needs to know the means by which the space environment induces these effects. Two of the prevalent hypotheses are that muscle atrophy during flight is due to a reduction (1) in the activation of the muscles, or (2) in the muscle forces associated with the reduction in activation.For example, a common concept which has prevailed for many years is that muscles enlarge when they are active and atrophy when they are inactive. Further,a linear and direct relationship between muscle fiber size and neuromuscular activity or exercise level is often assumed. It is clear, however, that this assumption is incorrect or at least m i s l e a d i ~ ~ g . " *For ~ ~ example, *'~ within a given muscle those muscle fibers which are used (i.e., recruited)the least often are usually AM~YSCS of biopsies from endurance-trained swimmers and the largest fibe.r~.'*'~*~' weight-lifters also illustrate that the amount of activity is poorly correlated with fibersize?' Thus, it is apparent that the effectivenessof exercise as a countemeasure for muscle atrophy cannot be based solely on the quantity of exercise (total time, number of repetitions, etc.). To maintain muscle mass, it appears that a relatively small amount or duration of activity pcrday is needed and that the amount needed varies widely among fiber types and specific muscles. The more important factor appears to be the mechanical load on the muscle during activation (see refs.

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15 and 25 for discussions). This view certainly appears to be true in hindlimbsuspendedrats when theanimals areexercisedintermittently(seeref. 15forarecent review). These studies suggest that 6 minutes per day of climbing a grid with attached weights (i.e., a relatively high load exercise)" had a similar effect of ameliorating muscle atrophy as 90 minutes of daily treadmill exercise (i.e.. a relatively low load exercise).106-108 Whether a rat exercises for a few minutes or up to 2 hours per day, similar effects are observed on the muscle mass in hindlimbsuspended rats (see ref. 15 for discussion).Thus, some minimum amount of muscle activation and force may be required to maintain muscle mass. Neuromuscular activity may play a facilatory rather than a direct role in maintaining muscle mass. For example, it is becoming increasingly obvious that there can be important interactive effects between exercise and hormones. Glucocorticoids can induce marked and selective atrophy of fast muscles, and weightliftinglWor treadmill11oexercise during glucocorticoid administration can greatly reduce the severity of the atrophic response. Similarly, growth hormone can significantly decrease the seventy of atrophy induced by hindlimb suspension of rats.l'Oa This effect is greatly amplified when the growth hormone treated suspended rats are exercised (climbing a 1 meter grid inclined at 85' with weights attached as little as 15 timeshy). In humans, one model which has been used to study the effects of changing gravitational loads on the nwromuscular system involves wearing a weighted (13% of body weight) body vest throughout the waking hours. B o w and ~ u w o r k e r s ~ ~ ~ - ~ ~ ~ have shown that wearing this weighted vest for 3 weeks resulted in a shift to the right in the forcevelocity curve and an increase in the power generated during squat jumping in highly trained athletes. The authors suggested that the subjects had acclimated to a 1.1 G environment and when the load was removed for the final testing, the subjects were experiencing the relative sensation of a 0.9 G environment. Because of the relatively short experimental period (i.e., 3 weeks), the adaptive responses were thought to be more related to neurogenic factors (e.g.. greater effective activation of motor units) than myogenic factors (e.g., fiber type adaptations or hypertrophy). It is clear, however, that muscle atrophy occurs very rapidly in response to spaceflight. For example. the rat soleus can atrophy by 25% within 4 days of the initiation of flight.% Furthermore, it appears that significant atrophy can occur in humans after 5-1 1 days of flight.'* Kuznetsov and co-workers studied the effects of bed rest with headdown tilt for either 30114or 120 and 36O1l5days on the size of gastrocnemius fibers. Thirty days of bed rest resulted in about 15% atrophy in both slow and fast fibers. Treadmill exercise of a moderate intensity for 60midday for the first 24 days and 120 midday for the last 6 days did not ameliorate the atrophy. In fact, the fast fibers in the exercised group were 27% smaller than in the nonexercised group. The longer duration study involved two exercised groups. One group started exercising early in the experiment (at 21 days) and included relatively strenuous passive, strength building, and locomotor exercise. The second group started a relatively milder

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V. REGGIE EDGERTON and ROLAND R. ROY

exercise program on day 121. The duration of the exercise was either 60 or 120 minutes. Early onset of exercise resulted in the maintenance of fiber size nearer to control values at both 120 and 360 days. The overall mean fiber size was decreased by 40% in the second group and by only 15% in the first group. These data suggest that acclimatization to any exercise routine during the early phase of long-term flight, when the rate of atrophy is the highest. may have a significantresidual effect by maintaining acritical level of responsivenessto exercise training during the latter phases of a mission. Greenleaf et al.’16 studied the effects of 30 days of bed rest at a -6’ tilt in healthy men. ’Avo groups of subjects exercised in the supine position for two 30-min pericds/day, 5 times per week. One group performed short-term variable intensity isotonic exercise, while the other group followed an intermittent high-intensity isokinetic program. All subjects were tested weekly for muscle performance and peak oxygen uptake. Compared to control, peak torque for the knee extensors progressively decreased showing a 12% decline after 4 weeks. The peak knee extensor torques were not significantly different between the two exercisetrained groups and the control group. No consistent effect of bed rest or exercise was observed for the knee flexors. Cherephakin and c o - ~ o r k e r s ~studied ~ ~ * ~hcalthy ~ * males after 7 weeks of bed rest (4 to 6’ tilt). In threesubjects. the cross-sectionalarea of the “red” and “white” fibers of the soleus decreased by an average of 28 and 35%. respectively. Some lysis (separation of myofibrils) was evident in the fibers. Leg circumference was decreased by 13% and endurance time for a bicycle test was decreased by 10%after bed rest. The strength of the postural muscles was also significantly decreased. When a combination of exercise (intermittent periods of bicycling at a relatively high heart rate in the antiorthostatic position) and electrostimulation was used (25-30 midday, once or twicelday), the magnitude of all these adaptations was reduced. In a static endurance test, exercise before electrostimulation had a more positive effect (52% increase)than exercise after electrostimulation(36% increase). During a 30 day bed rest study,’‘9 three subjects had their knee and ankle extensors and flexors in the dominant leg stimulated twice daily for 20 minutes on a 3-day on and 1-day off schedule. The electrical stimulation program appeared to have a slight beneficial effect on maintaining the torque-velocity properties of the knee extensors, but not of the knee flexors, during the bed rest period. As stated by the authors, however. these data were preliminary and quite variable. Based on the evidence available to date from laboratory animals and humans, it seems difficult to maintain the mass of the extensor muscles of the legs, hip. uunk, and neck during bed rest. It also appears that these muscles will be affected the most by spaceflight. This might be expected, because the difference in the functional demands of these muscle groups at 1 G compared to 0 G will be greater than for those muscle groups which have less of an antigravity function. A key question is: “How much and what pattern of activation and resulting force is essential per day to maintain muscle mass?” For each physiological property of

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the muscle or each muscle protein, the same question must be asked. Further, it remains to be determined whether the altered activity and force patterns in spaceflight are the primary stimuli that account for the changes that occur in the muscles. For example, modulation of hormonal andor other tissue growth factors during spaceflight also may contribute to the etiology of spaceflight-induced muscle In defining exercise protocols and devices to counter the effects of spaceflight on skeletal muscle, the most efficacious exercise may be unique for each muscle type, e.g., extensors vs. flexors or muscles that are comprised predominantly of slow vs. fast fibers.Further. an exercise regimen that may prevent muscle atrophy may not be the most efficacious in preventing demineralization of bone. It seems likely that reasonable compromisesin exerciseprescriptions during spaceflightcan and must bc defined so that a crew member need not have to exercise several hours each day in order to maintain an acceptable functional state. From an operational point of view, some consensus needs to be reached on how much loss of function can be tolerated without a significant compromise in safety and possible long-term consequences.For example, one 1@minuteexercise period per day may be sufficient to maintain 90% of normal function of the extensors of the ankle, knee, hip, trunk, and neck, while it may require 90 midday to maintain 95% normal function. Does 90% of normal function provide an acceptable margin of safety? Similar operational issues are relevant for each physiological system. The individual differences among the flight candidates must also be taken into account, since the results from virtually every study of spaceflight and groundbased models of spaceflight demonstratemarked differences in the response of the neuromuscular system among individuals. These unique individual responses may hold the key to a better understanding of the etiology and magnitude of these specific effects. This approach necessitates an integrative physiological perspective and experimentalapproach in determining the adaptability of humans to prolonged periods in space and to the reduced gravitational fields of the moon and Mars.

V. CONCLUSIONS AND SUMMARY The chronic “unloading” of the neuromuscular system during spaceflight has detrimental functional and morphological effects. Changes in the metabolic and mechanical properties of the musculature can be attributed largely to the loss of muscle protein and the alteration in the relative proportion of the proteins in skeletal muscle, particularly in the muscles that have an antigravity function under normal loading conditions. These adaptations could result in decrements in the performanceof routine or specializedmotor tasks, both of which may be critical for survival in an altered gravitational field, i.e., during spaceflight and during return to 1 G. For example, the loss in extensor muscle mass requires a higher percentage of recruitment of the motor pools for any specific motor task. Thus, a faster rate of

V. REGGIE EDGERTON and ROLAND R. ROY

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fatigue will occur in the activated muscles. These consequences emphasize the importance of developing techniques for minimizing muscle loss during spaceflight, at least in preparation for the return to 1 G after spaceflight. New insights into the complexity and the interactive elements that contribute to the neuromuscular adaptations to space have been gained from studies of the role of exercise and/or growth factors as countermeasuresof atrophy.The present chapter illustrates the inevitable interactive effects of neural and muscular systems in adapting to space. It also describes the considerable progress that has been made toward the goal of minimizing the functional impact of the stimuli that induce the neuromuscular adaptations to space.

ACKNOWLEDGMENTS The authors wish to thank Drs. Richard Grindeland and Dave Pierotti for their helpful comments on the manuscript. This work was supported, in part, by NASA Grant NCA-IR 390-502 and NIH Grant NS16333.

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