Recent findings clearly suggest that one of the hallmarks of exposing humans and animals to the environment of spaceflight involves the process of muscle atrophy and associated deficits in one’s performance capability. This article describes the effects of spaceflight and/or states of muscle unloading on (1) the intrinsic structural and functional properties of skeletal muscle, (2) the performance of muscular activities associated with locomotion and other motor tasks both during and after exposure to spaceflight, and (3) theoretical concepts for enhancing our current understanding of the effectiveness of countermeasures routinely used either to maintain or prevent observed muscle loss and corresponding deficits in musculoskeletal function. Data from both human and animal models from in-flight and ground-based experiments are examined.

Concept of Muscle Homeostasis. The morphological and functional properties of skeletal muscle of adult mammalian species, including humans, normally are quite stable in the gravitational environment of Earth’s surface (1g). Although all of the proteins that make up a muscle undergo continuous synthesis and degradation, the kinetic properties of these pathways are such that muscle mass and protein phenotype, the key properties of strength, endurance, and locomotor/movement capacity, are readily maintained under normal circumstances. However, in the absence of a 1-g stimulus, these homeostatic properties are altered so that the ratio of protein synthesis to degradation is reduced and the ability to maintain protein pools and phenotypes is compromised, thereby contributing to reduced capacity of the muscle system to function at 1 g. Thus, the central objective of any countermeasure strategy during spaceflight is to maintain or closely preserve the neuromuscular properties that exist at 1 g. Concept of Motor Control of Muscular Activity. Under normal environmental conditions, the ability of the central nervous system (CNS) to control precisely a wide assortment of movement patterns is remarkable, given the variety of conditions under which this control must be managed. All physiological systems that play important roles in the control of movement are affected in one or more ways by the space environment; the chief of them involves a state of unloading on the organism. The supraspinal and spinal pathways of the CNS must accurately and rapidly coordinate a number of neurosensory and neuro-motor activities under constantly changing environmental conditions, that is, changing the orientation of the body relative to a 1-g vector on Earth or in a 1-g versus, 0-g environment. In considering any countermeasure to minimize dead-aptation to 1 g during spaceflight, it is important to recognize that spaceflight results in changes in the visual, vestibular, and proprioceptive functions; each of them probably contributes to changes in the coordination of activity of the flexor and extensor musculature of the arms and legs in controlling body orientation and locomotion. For example, in microgravity, the relative loadings of both the upper and lower extremities are markedly reduced, thereby affecting the velocity and extent of movement in performing flexion and extension at various joints. Further, the control of movement is shifted toward the upper extremities, hands, and fingers while relying on the lower extremities chiefly for adjusting the center of gravity (1,2). Changes will occur in the neural control of the percentage of the various motoneurons (defined as a nerve fiber arising from the spinal cord that innervates many fibers comprising a given muscle) that are recruited and the force generated by a given muscle or muscle group. This adjustment is accomplished by modulating the number of motoneurons needed for a specific task in accordance with the size principle (3), that is, smaller, high oxidative motor units recruited first and larger low oxidative motor units recruited last, and by frequency modulation.

Associated with the changes in motor activity during spaceflight, as noted above, is the occurrence of a range of detrimental effects on the functional and morphological properties of the skeletal musculature. Changes in the metabolic and mechanical properties of the musculature can be attributed largely to the loss of and alteration in the relative proportion of specific protein systems in the muscles, particularly in those muscles that have an antigravity function at 1 g. These adaptations can degrade performance of routine or specialized motor tasks, both of which may be critical for survival in an altered gravitational field, that is, during spaceflight and during the return to 1 g. For example, a loss in extensor muscle mass will require a higher percentage of recruitment of the motoneurons for any specific motor task involving extension. Thus, a faster rate of fatigue will occur in activated muscles because, for the same motor task, more motor units will be recruited, thus involving larger, less oxidative motor units that are more fatigable. For this fact alone, it would be advantageous to minimize muscle loss during spaceflight, at least in preparation for the return to 1 g after spaceflight. This section of the article illustrates the inevitable interactive effects of neural, muscular, and endocrine systems in adapting to spaceflight. Only modest progress has been made in understanding the physiological and biochemical stimuli that induce neuromuscular adaptations in a fully integrated system that considers both biological and environmental factors.

Effects of Microgravity and Simulated Models on Skeletal Muscle Properties

Observations on Animals. Numerous effects ofaltered loading states on the morphological, functional, and molecular properties of mammalian skeletal muscle have been observed. Both ground-based models (e.g., hindlimb unloading) and spaceflight missions (Cosmos Missions and Space Life Sciences 1 and 2) have been used to alter the amount of weight bearing chronically imposed on the muscle(s), thereby changing the amount and type of protein that is expressed in the targeted muscles. These data have been reviewed in detail recently (1-7). A number of adaptations occur as a result of changing the load-bearing function. Briefly, these include the following:

1. Atrophy of both slow-twitch and fast-twitch fibers comprising ankle and knee extensor muscles used for both weight bearing and locomotion (8,9).

2. A change in the type of contractile protein that is expressed in a select population of fibers reflecting a faster phenotype for controlling both cross-bridge and calcium cycling processes, the primary pathways for energy consumption in performing mechanical activity (10-14).

3. Corresponding changes in the functional properties of the muscle manifesting a faster rate of shortening and briefer periods for twitch contraction and relaxation (10,15,16).

4. A reduction in both the absolute and relative force and power generating properties of antigravity and locomotor muscles (10,16).

5. A shift in the force-frequency patterns of antigravity muscles, whereby a higher frequency of electrical stimulation (i.e., action potential frequency) is needed to generate a given submaximal level offorce output (10,16-18).

6. A shift in the intrinsic ability of the muscle to use different substrates for energy, whereby the ability to oxidize long chain fatty acids is reduced relative to that of carbohydrates (19).

7. An increase in enzymatic activities supporting the pathways of glycogen-olysis and glycolysis (9,12,13,20).

8. Corresponding decreases in the ability of muscle groups to sustain work (i.e., increased fatigability) most likely due to a reduction in the balance of energy supply to energy demand within a given motor unit and a demand for expanded recruitment of faster motor units with less resistance to fatigue (16).

9. A reduction in the oxidative properties of large dorsal root ganglia cells and small motoneurons that could impact the function of sensory neurons and motoneurons (21-23).

Observations on Humans. Based on more than 40 years of experiments in the Russian space program, as well as in the U.S. space program, including the Apollo and numerous Space Shuttle flights, a number of observations have been made that demonstrate a wide range of effects on the motor performance of humans (see Refs. 1 and 2 for recent reviews). Some of these effects include the following:

1. Loss of skeletal muscle mass, particularly in those muscles groups that function at 1 g to maintain extension against normal gravitational loads, often referred to as antigravity muscles (24,25).

2. Reduced ability to exert maximum torque at varying velocities of movement, but particularly at the lower velocities of movement (26,27).

3. Reduction in the size of slow and fast muscle fibers (28).

4. Increase in the proportion of fast myosin in some fibers within 2 weeks of exposure to spaceflight (28,29).

5. Diminished ability to maintain a stable standing posture (26,27).

6. An imbalance of the relative bias of activation of flexor and extensor muscle groups, with greater bias toward flexion in 0 g (30-32).

7. Reduced threshold of the stretch reflex combined with reduced sensitivity to stretch, that is, less gain in responsiveness at a given level of stretch (27).

8. Modified sensitivity to cutaneous vibrations to the sole of the foot (27).

9. Increased susceptibility to fatigue during a given motor task upon return from 0 g to 1 g (1,2).

10. Altered perception of postural position at 0 g and upon return to 1 g (30-32).

Functional Significance of Neuromuscular Adaptations to Spaceflight

Movement Patterns in a Microgravity Environment. 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 (30). The electrical activity (electromyography, EMG) of flexor and extensor muscles in the resting position of the neck, trunk, hip, knee, and ankle reflects a generalized flexor bias during flight compared to 1 g. This bias has been observed during spaceflight when astronauts have been asked to stand upright. This flexor bias effect is independent of whether or not their feet are anchored to a surface (30). Further, when the astronauts 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° versus 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 understood. Even after returning to 1g, this residual flexor bias provides a clear indicator of a general adaptation strategy for organizing movements in a 0-g environment.

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 days of continued exposure to the 0-g environment (30). This recovery of extensor activity and continued elevation of flexor activity has been clearly documented in ground-based models of weightlessness. For example, extensor EMG activity essentially disappears immediately upon unloading of the hindlimbs in rats (33). Within hours, however, some EMG activity reappears during continued hindlimb unloading, and by 7 days, the total daily amount of activation is near normal levels. This pattern has been observed in both predominantly slow (e.g., the soleus) and fast (e.g., the medial gastrocnemius) ankle extensors. In contrast, the EMG activity of the tibialis anterior, an ankle flexor, is significantly elevated throughout the unloading period (33). The “recovery” to normal or near normal levels of extensor EMG activity while remaining “unloaded” suggests that the CNS is “programmed” so that general extensor bias continues as it does at 1 g under normal gravitational loads (33). 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, that is, independent of any activity-dependent events associated with movement control in a 1-g environment. Movement Characteristics at 1 g After Exposure to 0g. The ability to perform movements, including posture and locomotion at 1 g, is adversely affected by exposure to as little as 1 week of spaceflight (26). All crew members tested to date have experienced some postural instability for 1-2 weeks following spaceflight, or even longer in some instance. This instability, which varies markedly from crew member to crew member, reflects alterations in perception, sensitivity, and responsiveness. In many cases, the altered motor functions may not be readily apparent due to use of compensatory mechanisms such as maintaining a wider stance, taking shorter steps, having a greater dependence on visual cues, and generally being more cautious.

Other physiological measures also reflect altered movement control following spaceflight, particularly that of altered postural responses to horizontal perturbations, for example, unusual magnitudes and durations of activation of extensor and flexor motor pools. Based on studies of the visiting crews in the Salyut-6 missions, ranging in duration from 4-14 days (most for 7 days), the EMG response of the soleus and tibialis anterior muscles to perturbations of the standing position was almost doubled, and the response time to the perturbation was three times longer after than before flight (27). Severe postural disruptions following 4-10 days of spaceflight on the Shuttle have also been reported (27). A rapid recovery rate was evident immediately after flight, and most of the recovery occurred within the first 10-12 hours postflight, followed by a slower recovery during the next 2-4 days. Further, it was estimated that 50% of the recovery occurred within 3 hours postflight. Adverse postural effects, however, persisted for as long as 42 days after a 175-day flight.

As was true for performance in a maximum torque-velocity test of the plantarflexors (e.g., the muscles that lift the heel off the ground), the duration of the spaceflight has not proven an important determinant in the severity of postural stability (2,34). For example, cosmonauts that had been on the Mir station for 326 days had a similar EMG amplitude response to postural perturbations immediately after flight as before flight. In contrast, the EMG response was doubled in cosmonauts from either a 160-day or a 175-day spaceflight (34). However, the similarities in the magnitude of the neural control adaptations may reflect improvements in the methods for countering the degradation in movement control, as the flights have become longer.

Another clear example of the modification of the input-output ratio of the motor system was demonstrated after 7 days of dry immersion. Before immersion, subjects were able to increase the force in relatively constant increments up to about 50% of maximal voluntary contraction in a succession of about 10 trials. After flight, the subjects overestimated the target force considerably even at the lower force levels, and the force differential became even more distorted at higher torques (27).

Although many adaptations are clearly manifested during the performance of motor tasks at 1 g after having adapted to spaceflight conditions for a specific duration, many details regarding the specific adaptations to spaceflight are not available because of the difficulty in conducting well-controlled experiments in very complex space mission flight plans and objectives. All studies of humans reflect some unknown combination of the effects of spaceflight conditions, the measures used to counter spaceflight effects, and individual differences in responsiveness to both spaceflight and the countermeasures used.

Changing the magnitude of the gravitational vector also alters body movement perception. There are immediate and longer term effects of these altered forces on perception. It is clear, for example, that there are disturbances in oculomotor control, vestibular function, pain sensitivity, muscle stretch sensitivity, joint position sense, and cutaneous sensitivity to vibration, all of which may play some role in modifying motion-position perception in response to spaceflight (2,27,35). Altered perceptions of speed of movement, the effort it takes to perform a movement, and movement of the body relative to its surroundings have been reported when alternating periods of 0 g and 2 g are imposed during parabolic flights (36). When subjects raised or lowered their bodies, from a squat position during the 2-g phase of parabolic flight, perceptual distortions of movement were evident. These findings were interpreted to indicate that the motor control of skeletal muscles had been calibrated to a 1-g reference level and that these illusions resulted from mismatches between the efferent control signals and the expected patterns of associated spindle activity.

Perception of upper limb position was also studied during parabolic flights, with and without vibration of the biceps or triceps brachii tendons. Because tendon vibration activates sensory Ia neurons of muscle spindles and to some extent the sensory type lib neurons (e.g., afferent nerve fibers) from the muscle tendon organs and because these receptors it is thought, contribute to the sensation of angular displacement, these studies provided some insight into their potential role of proprioception (i.e., how the body senses its position on the ground and in space) in the diminished accuracy of position sense observed after spaceflight (36-38). The perceived magnitude of displacement from the apparent limb position upon tendon vibration was 1.8g > 1g > 0 g. The subject’s perceptions of displacement were consistent with the actual displacements. The results of these experiments suggest that higher g forces on the body required greater postural tonus and an altered gain for the muscle spindles (38).

Many astronauts have reported that they are not aware of the positions of their limbs when they shut their eyes to sleep or relax while weightless; one crew member stated, ”It is almost as if the limbs are gone” (39). When they tense their muscles, the position sense returns. One explanation for this phenomenon is not that sensitivity of the receptors is blunted, but that the stimulus is reduced. Interestingly, this sensation is the antithesis of the phantom-limb phenomenon described by amputees, that is, sensing the presence and even the movement ofa limb, even though the limb has been amputated. A 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, upon return to 1 g. The selective atrophy of the extensor musculature associated with weightlessness could contribute to this sensation of heaviness. Muscle atrophy is not the only factor, given that this sensation of heaviness disappears in some crew members within a few hours. Performing a task with atrophied muscles will require a sense of greater effort than normal because 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, which are the sensor organs that detect mechanical stress on the muscle.

Contractile Properties of Skeletal Muscle Following Spaceflight. The ability to produce maximum force-producing ankle rotation, which is also called plantar flexor torque, at velocities ranging from 0 to 1807s is reduced in short-term (7-14 days) and long-term (75-237 days) spaceflight. After short-term spaceflight, maximum isometric torque decreased by 18% and at 607s by 38%. After long-term spaceflight, maximal torques were 25, 12, 10, and 18% lower than preflight values at 0, 60, 120 and 1807s, respectively. The changes in torque among the cosmonauts varied considerably, ranging from — 60 to + 15% of preflight values. Although muscle atrophy almost certainly contributes to the reduced torques commonly observed after short- and long-term spaceflights, neural activation of the motoneurons innervating the muscles must also be affected. The highly variable losses in torque, at high speeds in some cases and at low speeds in others, cannot be easily explained by changes in muscle properties alone (26,27).

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 instability of the astronauts and cosmonauts usually attributed to the neural control system upon return to 1 g. This possibility seems particularly feasible because the fibers innervated by the motoneurons that have the larger role in maintaining routine posture (i.e., the slow motor units) are those that often 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 exaggerated movement or sway during standing and may even result in the loss of balance, as described above.

In summary, during and after spaceflight, the effectiveness of the neuro-motor system is clearly compromised. There could be a degradation in the function 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.

Causative Factors for Muscle Alterations in Response to Weightlessness

What are (1) the potential stimuli that are likely to induce muscle adaptations to spaceflight and (2) the cellular/subcellular processes involved in the adaptive response? Adaptations at the cellular level that result in a change in the quantity and/or quality or the type of protein expression in response to reduced mechanical activity can be regulated theoretically at several levels of control involving transcriptional, pretranslational, translational, and posttranslational processes (40). In considering the types of adaptations reported above in the rodent model, available evidence suggests that all of these processes are likely to play pivotal role (2,41).

Neuromuscular Activity and Its Role in Plasticity

Hindlimb Unloading. Adaptation to chronic unloading of skeletal muscles is determined in part by the manner in which the muscles are activated. The activity patterns of the rat soleus, medial gastrocnemius, and tibialis anterior muscles have been monitored from the same chronically implanted intramuscular electrodes before and during 1 month of hindlimb unloading; this is a procedure whereby traction of the tail is applied to a rodent so that the hindlimbs can be lifted off of the floor of the cage (33). Total daily EMG activity (mV/s), measured in the soleus and medial gastrocnemius, was significantly reduced on the day of initial unloading, was similar to control levels by 7-10 days of ongoing unloading, and continued at nearly normal levels for the remainder of the experimental period. Daily EMG levels of the tibialis anterior were above normal during all postunloading days. In addition, the interrelationships of the EMG amplitude patterns, a reflection of recruitment patterns, between the soleus and medial gastrocnemius were altered on the day when initiating unloading, but recovered to a normal pattern by day 7 of unloading (42). These data indicate that the neural mechanisms controlling hindlimb muscles, at least for some extensor muscles, initially change in response to the unloaded environment but might return to normal within a short period of time after the unloading began.

However, based on 16min of continuous EMG activity per day from the soleus on 7 and 4 days before unloading, as well as after 4 and 7 days of unloading, Riley et al. (43) concluded that the average total time of soleus activity (normalized per hour) in suspended rats was about 12%, compared to preun-loading values. These authors also concluded that the activity developed a “phasic,” compared to a “tonic” pattern. The amplitude (root mean square) of the signals was smaller (25-50%) during, compared to before unloading. Blewett and Elder (44) recorded a total of 2.4 h/day (6 s/min) of activity from the soleus and plantaris muscles (both primary ankle extensors) during several days before and after unloading; both overall mean amplitude and frequency of motor unit action potentials (based on a ”turns analysis”) were significantly decreased during unloading, compared to normal cage activity. This experiment differed from that of Alford et al. (33) in the total duration of EMG recording and also in the experimental design. For example, rats were allowed to ambulate normally for a 2 h period each week throughout the experimental period, a procedure that may have impacted the results because short periods of load-bearing, it has been shown, have a significant effect on other muscle properties (2,5).

Combined, these data indicate a general decrease in activation duration and amplitude of extensor muscles during the first week of unloading. On the other hand, after longer periods of unloading, extensor EMG activity may return to normal. Although chronic tension levels in muscles of suspended rats have not been recorded, it is reasonable to assume that forces in the plantarflexors were small. In addition, it is likely that the plantarflexors were further unloaded when the limb is in the plantarflexed position, the usual position during unloading. In contrast, loads on the tibialis anterior muscle were most likely to be slightly elevated when the muscle is maintained in a ”stretched” position. It seems unlikely, however, that the greater activity (3-4 times) of the tibialis anterior was due to increased stretching of the muscle during unloading, compared to that during routine cage activity, because most muscle stretch receptors accommodate rapidly to sustained stretch. In any case, the effects of unloading on the actual loading properties of muscle need to be substantiated by recording muscle forces pre-, during, and postspaceflight.

Spaceflight. The effects of spaceflight on chronic neuromuscular activity in rats are less substantiated than for hindlimb unloading. Presumably, muscle forces during spaceflight would be minimal, although no force data are available. In humans during spaceflight, the tonic activity (EMG) of the soleus (a plan-tarflexor) is reduced, whereas the tonic activity of the tibialis anterior (a dorsi-flexor) is enhanced during postural adjustments (30). This activity reversal of extensors and flexors normally observed at 1g has also been reported during parabolic flights in humans (45) and in monkeys during and after short-term flights (46-48). No chronic EMG or muscular force data from either humans or animals during spaceflight have been published.

Reductions in Muscle Strength and Power. Studies of both humans and animals clearly show that the force generating capacity of extensor muscles of the hindlimb are reduced to varying degrees following either spaceflight or hindlimb unloading. This reduction has been attributed to (1) a decrease in muscle mass reflecting a reduction in the cross-sectional area of the muscle fibers, (2) a reduction in the capacity to activate the muscle via supraspinal pathways, and (3) a reduction in the specific force of the muscle (reduced force corrected for fiber cross-sectional area) (2,5,46). Though it is reasonable to conclude that the reduced force due to atrophy is due to a loss in contractile protein that contributes to the contraction process, the underlying mechanisms responsible for the inability to activate the various motoneurons that innervate the muscles are poorly understood. The same holds true for the factors involved in the reduction in specific tension. Clearly, more extensive research is needed on this important problem.

Mechanisms of Muscle Atrophy. During states of hindlimb unloading, the rate of total protein synthesis (a translational process) is significantly reduced within the first few hours of creating the unloaded state. This is coupled to a subsequent transient increase (during the next several days) in the net rate of protein degradation, thereby resulting in a ~ 50% smaller protein pool comprising the muscle, that is, the muscle becomes significantly atrophied (7,49). Though both the initiating events and the signal transducing process(es) associated with the atrophy response remain largely unknown (see above), the involvement of either growth factor(s) downregulation or the catabolic actions of other hormones appear to be involved. For example, mRNA signals for insulinlike growth factor-1 (IGF-1) expression in skeletal muscle is reduced in hindlimb muscle when the weight-bearing activity of the animal is reduced (50). In contrast, recent findings suggest an opposite response when a skeletal muscle is functionally overloaded, that is, IGF-1 expression is enhanced (51). Recent studies of cardiac muscle further suggest that IGF-1 expression is linked to the loading state imposed on the system (4). The potential roles of other hormonal factors in modulating the atrophy response are uncertain.

In this context, there appears to be a critical interplay between mechanical factors and growth-stimulation factors, such as growth hormone, in maintaining muscle mass when challenged by a state of unloading (52,53). Furthermore, it has been shown that the time course of the muscle atrophy response to un-weighting is altered when cellular glucocorticoid receptors are pharmacologically blocked (54). Under conditions involving muscle wasting in response to exogenous glucocorticoid treatment, a key enzyme, glutamine synthase, is also unregulated by elevations in the circulating level of this hormone (55). This enzyme it is thought, regulates both the formation and release ofthe amino acid, glutamine, that is, the primary amino acid to which most amino acids are converted during the protein degradation process, from the muscle during the wasting process. Experiments in which the level of glutamine is artificially elevated in both the plasma and muscle during glucocorticoid treatment, markedly reduces both the atrophy process and the decrease in total protein and myosin protein synthesis rates that occur under these conditions (55). On the other hand, agents that, it is thought, inhibit the proteosome axis component in the cascade of protein degradation processes appear to be partially effective in ameliorating the atrophy response to weightlessness (56). Clearly, a more basic understanding of the interactions of hormonal and activity factors in the regulation of protein synthetic and degradation processes, especially in the context of the atrophy response associated with muscle unloading, is needed. Alterations in Myosin Phenotype. Results from both cardiac and skeletal muscle suggest that transcriptional and pretranslational control of the slow type of myosin heavy chain (MHC) gene, a key gene encoding a regulatory contractile protein, is highly regulated by thyroid hormone (T3) (40,41). For example, T3, in conjunction with its nuclear receptor and other nuclear regulatory proteins, acts as a negative modulator of transcription of the beta (slow or type I) MHC gene while concomitantly exerting positive transcriptional control of the cardiac fast, alpha MHC gene (57). Thus, it is interesting that the downregulation of the slow myosin gene typically seen during states of unloading can be inhibited by making the animals hypothyroid (58). Collectively, these findings suggest that changes in the loading state may alter the muscle’s responsiveness or sensitivity to thyroid hormone. Furthermore, recent findings on cardiac muscle also suggest that transcription of the beta (slow, type I) MHC gene can be positively regulated by expression of a nuclear factor(s) that binds to a specific DNA sequence (designated as beta e2) upstream of the gene’s transcriptional initiation site (57). This factor can be upregulated in the rodent heart in response to pressure overload. Thus, there appears to be a complex interaction of mechanically (loading state) and hormonally induced transcriptional factors that are involved in regulating MHC plasticity in response to altered states of muscle loading (40). Understanding the regulatory factors associated with slow myosin gene expression is important because it is predominantly the slow myosin is oform that is sensitive to the gravity state. Furthermore, motor units expressing slow myosin are those predominantly recruited for posture control and low intensity movements (59,60).

Perspectives in Preventing Muscle Atrophy and Dysfunction

Basic Physiological Principles for Developing Exercise Countermeasures.

Any exercise-related countermeasure for preserving skeletal muscle function will be manifested via the spinal mechanisms that regulate the order and number of motor units recruited. In essence, all movements represent the net effect of the number of motor units recruited and the combination of motor units for each muscle that will be recruited, combined with the mechanical restraints placed on the muscles. The selection of which and how many motor units will be recruited is defined in some manner when kinematic features of the motor task are selected. Muscle activity also can be imposed by electrical stimulation of its nerve where, unless special technical considerations are instrumented, the most readily stimulated muscle fibers will be those innervated by the largest axons (and thus probably belong to the largest motor units). Such a recruitment order determined largely by axon diameter is opposite to that normally used by the central nervous system. Otherwise, the same general principles described below apply to electrical stimulation of muscle as a potential countermeasure.

In designing an exercise countermeasure, the major variables to modulate are the ”level of effort,” that is, the number (and frequency to some degree) of motor units recruited and the speed at which the muscle will shorten or lengthen. For any given level of recruitment, the changes in muscle length will be defined by the mechanical conditions under which the motor units are activated. The force produced will be a function primarily of the number of motor units (and thus muscle fibers) recruited and the mechanics that define the velocity and direction of movement. Because the force-velocity relationships are somewhat predictable, the ”types” of exercise (high resistance, high power, low resistance, etc.) largely reflect the number of motor units recruited and the temporal pattern for their recruitment. Whether that force is sufficient to shorten or lengthen the muscle and the speed at which the displacement will occur depend on the loading conditions. A high-resistance exercise is one in which a high proportion of the units within the appropriate motor pools is recruited and a high load is imposed, resulting in a relatively slow velocity of shortening. If the same recruitment pattern occurs and the load is reduced, then the velocity of movement will increase hyperbolically.

Although these basic physiological concepts derived from isolated (e.g., in situ) experiments are well recognized and generally accepted, they have not been translated into a rational and systematic approach to developing more effective countermeasures for the neuromotor deficits that develop during prolonged spaceflight. Further, a more integrative rather than reductive approach to motor performance is needed. A more integrative physiological perspective must also be maintained in assessing the metabolic consequences and the corresponding adaptations to spaceflight and exercise. Given the interdependence of the mot-oneuronal and muscle metabolic properties, however, recruitment and metabolic responses of recruitment are essentially inseparable.

Relevant questions for maintaining normal muscle tissue properties include the following:

1. What combinations of forces and velocities will most efficaciously maintain the normal physiological status for each type of motor unit and muscle fiber type?

2. What are the differences in the responsiveness of fiber types and muscle types to specific muscle force-velocity events? For example, does this responsiveness differ in the arm versus the leg, flexor versus extensor muscles, etc.?

3. What durations and intermittencies, that is, work-rest ratios of the mechanical stimuli, are necessary to maintain the normal properties of a muscle fiber?

An implied assumption in these questions is that there are some mechanical event(s) associated with exercise that produce the necessary stimuli for cell maintenance. However, these stimuli could be metabolic or some other event related to excitation-contraction coupling. In any case, the same considerations ofthe variables noted above would be appropriate for each potential physiological modulator.

The Quantity of Activity Needed for Muscle Homeostasis. To counter the atrophic effects of spaceflight, one needs to know the means by which the space environment induces flight effects. Two of the prevalent hypotheses are that muscles atrophy during flight because of a reduction in (1) activation of muscles, or (2) the muscle forces associated with the reduction in activation. For example, a common concept that 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 best, misleading. For example, within a given muscle, those muscle fibers that are used (i.e., recruited) least often are usually the largest fibers. Analyses of biopsies from endurance-trained swimmers and weight lifters also illustrate that the amount of activity is poorly correlated with fiber size (61).

Thus, it is apparent that the effectiveness of an exercise as a countermeasure to muscle atrophy cannot be based solely on the quantity (total time, number of repetitions, etc.) of exercise. To maintain muscle mass, it appears that a relatively small amount or duration of activity per day is needed and 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 (1,5,40). This view certainly appears to be true in hindlimb-suspended rats when the animals are exercised intermittently. These studies suggest that 6 minutes per day of climbing a grid with attached weights (i.e., a relatively high load exercise) had almost the same effect of ameliorating muscle atrophy as 90 minutes of daily treadmill exercise (i.e., a relatively low load exercise) (17). Thus, some minimum amount of muscle activation and force may be required to maintain muscle mass.

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 group, for example, extensors versus flexors and muscle type (i.e., 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. However, reasonable compromises in exercise prescriptions during spaceflight can and must be defined so that a crew member will not need to exercise several hours each day to maintain an acceptable functional state while spending prolonged periods in space and during periods of reduced gravitational forces while on the Moon or Mars. The Impact of Activity-Hormonal Interactions. Neuromuscular activity may play a facilitatory role, rather than a direct role, in maintaining muscle mass. For example, it is increasingly obvious that there can be important interactive effects between exercise and hormones. Glucocorticoids can induce marked and selective atrophy of fast muscles, and weightlifting or treadmill exercise during glucocorticoid administration can greatly reduce the severity of the atrophic response (62). Similarly, growth hormone alone can significantly decrease the severity of atrophy induced by hindlimb unloading of rats (52,53). Interestingly, 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 times/day) (52,53). Additional important aspects of neuromuscular activity and growth factors were discussed before in ”Mechanisms of Muscle Atrophy.”

Defining the Acceptable Limits of Muscle Dysfunction in Microgravity.

From an operational point of view, some consensus needs to be formulated regarding how much loss of function can be tolerated without a significant compromise in safety and possible long-term consequences. For example, one 10-min exercise period per day may be sufficient to maintain 90% of normal function of the extensors of the ankle, knee, hip, trunk, and neck, whereas it may require 90min/day to maintain 95% of normal function. Does 90% of normal function provide an acceptable margin of safety? Similar operational issues are relevant for each physiological system. Individual differences among flight candidates should also be taken into account, in particular, because the results from virtually every study of spaceflight and ground-based models of spaceflight have demonstrated marked individual differences in the response of the neuromuscular system. These unique individual responses may hold the key to better understanding of the etiology and magnitude of these specific effects. An integrative physiological perspective and experimental approach in determining the adaptability of humans to spaceflight is essential. Considerable insight into this problem of safety factors in biological systems can be gained by applying these concepts outlined by Diamond (63,64).

Concluding Perspectives. As we enter the new millennium, it is most apparent that mankind is set on expanding the human presence further into the universe. These visionary missions will require a tremendous commitment of resources plus the expanded knowledge base that will be necessary to maintain the health and safety of astronauts during missions that may take as long as 4-5 years to complete. This article has focused on only one system, skeletal muscle, but it is apparent that all systems of the body are compromised in the absence of gravity. Therefore, scientists must begin thinking about using an integrative biological approach in putting a strategic plan together to expand our understanding of how man can endure periods of time in a weightless environment that exceed by four- to fivefold the current duration of existence in such a unique environment. The question is, are we up to this challenge?

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