The goal of the paper is to review information concerning alterations in skeletal muscle morphology, functional capacity, and biochemical/metabolic properties in response to spaceflight exposure of varying duration. Where possible, attempts will be made to integrate information on humans and animal models (chiefly rodents) to discern the degree and type of muscle plasticity occurring in response to this unique environment. In some cases inferences will be made from ground-based models that attempt to simulate microgravity by eliminating weight bearing activity on the musculature. The topics to be covered include gross activity patterns of humans and rodents during and following spaceflight, functional properties of skeletal muscle following space flight, morphological, biochemical, and metabolic properties of skeletal muscle following spaceflight, possible mechanisms governing muscle plasticity in response to weightlessness, and countermeasures and future directions.
ACTIVITY PATTERNS DURING SPACEFLIGHT
Humans. When humans are exposed to the microgravity environment, both their movement patterns and muscular forces are dramatically altered(6). Their reliance on the leg musculature for movement and locomotion becomes practically nonexistent for both human and animal. These impressions are based largely on video recordings obtained during Space Shuttle missions. While quantitative information is scanty, it is apparent that very little muscular force is required to initiate movement and simulated locomotion during microgravity, and most movements are initiated by the upper extremities. In fact, individuals must be anchored to exercise devices to execute routine exercise paradigms such as running and cycling. In performing various movements in microgravity, eccentric contractile activity (i.e., lengthening muscle contractions opposing gravity) is largely absent. A comprehensive review of work physiology as performed in a microgravity environment has been published (6).
Rodents. While recorded observations are less extensive in rodents, the data suggest that they also rely less on the hindlimbs for executing movements. Their ankle appears to assume a plantarflexed position, which may reduce the passive tension imposed on the triceps surae muscle group. This posture could affect the residual tension placed on that muscle group in the absence of a normal weight bearing state. No doubt this non-weight bearing state provides a mechanical signal (or lack thereof) to trigger rapid atrophy that occurs in those rodent muscles used extensively for postural support and locomotor activity (2). As in humans, eccentric contractile activity is essentially absent due to lack of opposition to gravity in the execution of most movement patterns. Whether this alteration also serves as a signal to transform protein expression in muscle cells remains uncertain. In future experiments it will be important to record the electromyographic activity of skeletal muscles during weightlessness, as well as to monitor the forces generated by specific muscle groups. This particular information is important for establishing how a signal of altered neuromuscular activity is transformed into cellular adaptation of muscle function and structural properties.
OBSERVATIONS DURING EARLY RECOVERY FROM SPACEFLIGHT
When both humans and animals return from spaceflight of even short duration(days), there are alterations in their basic activity patterns. The center of gravity in rats is much lower than normal. They no longer support their body weight and initiate movement off the balls of their feet. Movement speed for most activities is much slower and deliberate, and the animals spend significantly less time in bipedal stances (D. Riley, personal communication). Furthermore, the rodents use their tails to a greater extent for basic support during both rest and movement, which is considerably different from their normal movement pattern (personal observation).
The overall muscular stability in humans, is also compromised as the extremities feel markedly heavier than normal(6,16,17). Normal standing postures are difficult to maintain for sustained periods, and the gaiting patterns are inconsistent and reflect instability(4-6,16,17). Neuromuscular reflex activity is altered, which is manifest in a higher sensitivity to evoked stimuli, and there appears to be greater electromyographic activity per generation of equivalent mechanical activity in the leg muscles(6,9,17). The conclusion from these observations on humans and rodents is that the neuromuscular system and its associated muscular functional integrity appear to be compromised. Also, there is some evidence that rodents exposed to spaceflight are more prone to muscle injury during the initial recovery period (20), which may be associated with the inability of certain antigravity muscles to withstand the stresses of eccentric contractile activity that are normally manifest in the 1g environment (20).
EFFECTS OF SPACEFLIGHT ON MUSCLE CONTRACTILE PROPERTIES
Humans. Data have shown that angle-specific strength (torque) is compromised by 23-50% following exposure to either spaceflight or simulated(i.e., bed rest; head-down tilt) muscle unloading of varying duration(5,6,17,24). This loss of force-generating capability is confined more to the leg musculature, and it appears to exceed the equivalent loss in limb girth associated with spaceflight (5,6,17,24). Accompanying the reduction in force generating capability there is also reduction in the angular velocity of shortening at a given level of force output(9,17). Whether these mechanical transformations also involve shifts in the maximal velocity of shortening of the muscle remains unknown. Information is also lacking as to how the loss of strength is related to the loss of muscle mass. Consequently, part of the mechanism of the loss in strength may be due to altered neuromuscular activity, i.e., the ability to recruit motor units rather than to an intrinsic reduction in the force-generating capacity of the muscle's contractile machinery. Accompanying the loss of strength is reduction in muscular stamina and overall contractile endurance (12,23). Thus, the reduction in both muscle strength and endurance could have a significant impact on sustained work performance during extravehicular activity during spaceflight(5,6), as well as hinder emergency egress capability during the landing of the spacecraft.
Rodents. Data from a recent study following 6 d of spaceflight involving young adult male rodents (2) confirmed similar changes, reported above on humans, concerning the force-velocity properties of soleus skeletal muscle using in situ techniques involving a computer-programmed ergometer. The P0 of the muscle was significantly reduced by 23%, which approximated the reduction in muscle weight(2). Although the Maximal velocity (˙Vmax) of muscle shortening was increased by 12-15%, the shortening velocity at any equivalent intermediate muscle force was actually reduced(2). This reduction in shortening velocity, in conjunction with the decrease in P0, produced an overall reduction in the peak power generating capability of the muscle following spaceflight(2). Thus, there is mounting evidence in both human and rodent that suggests that muscles involved in weight bearing activities undergo reduction in strength. These changes likely contribute to the reduced capacity for carrying out routine movements requiring increasing force production. Our results further indicate that both activation and relaxation times for performing isometric contractions become faster(2) suggesting that the calcium cycling processes are also altered in the affected fibers. As in humans, we observed reduction in capacity of rodent muscle to sustain repetitive isometric contractions as well as to maintain power generating capability after exposure to spaceflight for as little as 6 d (2). Thus, both humans and animals have compromised functional integrity of those lower extremity muscles heavily composed of slow-twitch fibers. Table 1
EFFECTS OF SPACEFLIGHT ON THE MORPHOLOGICAL, METABOLIC, AND BIOCHEMICAL PROPERTIES OF SKELETAL MUSCLE
Humans. Relatively little information is available concerning effects of spaceflight on the morphological, metabolic, and biochemical properties of human skeletal muscle. Recent analyses of biopsy samples of astronauts taken before and after Shuttle spaceflight missions lasting 5-11 d suggest atrophy occurred in both fast- and slow-twitch fibers(8). Data from bed rest studies provided similar observations concerning fiber size changes and suggested reductions in the activity level of marker enzymes of oxidative metabolism(14). Whether there are changes in the fiber type profile indicative of shifts in slow-twitch to fast-twitch properties accompanying this biochemical change remains uncertain. One handicap in pursuing cellular research in space physiology involving humans is lack of tissue availability for biochemical and molecular analyses which has resulted in greater reliance on animal models to study subcellular and molecular adaptations to weightlessness.
Rodents. Information has accumulated that suggests that both spaceflight and ground-based models induce decreases in fiber size involving both fast- and slow-twitch fibers(2,15,18,19). However, the slow fibers typically expressed in antigravity muscles, such as the soleus and vastus intermedius, as well as those slow fibers expressed in regions of fast muscle used extensively for locomotion, clearly are more sensitive than their fast-twitch counterparts. This observation is consistent with the findings that slow muscles atrophy to a greater extent than their faster synergists(2,11,15,18,19). Accompanying this atrophy response is the observation that many (but not all) of the slow fibers in antigravity muscles are induced to express fast myosin isoforms(2,15,19). This transformation is largely manifest as hybrid fibers in which both slow (type I) myosin heavy chain (MHC) and either fast IIx or possibly IIa MHC are coexpressed(2,11,15,19). Whether these fibers remain as hybrids is uncertain. These shifts in MHC profile are consistent with the intrinsic increase in the Vmax of soleus muscle shortening(2). Ground-based experiments using animal suspension show that unloading states also increase the expression of fast sarcoplasmic reticulum isoform proteins (21). Thus, spaceflight causes a selective number of slow fibers to take on a faster phenotype in terms of its contraction/relaxation properties. Because the steady-state level of mRNA, corresponding to these contractile proteins, is altered in parallel(11), there are likely alterations in the pretranslational regulatory process governing the expression of these proteins(11).
Studies on rodent skeletal muscle metabolic pathways have revealed a variety of responses with no clear-cut adaptive response in the oxidative system (3,15,19). We observed no reduction in the capacity of skeletal muscle mitochondria to carry out oxidation of pyruvate under state 3 metabolic conditions; i.e., under non-limiting amounts of substrate and cofactors (1). However, we found a reduction in the capacity of different muscle types to oxidize the long-chain fatty acid palmitate, even though there was no obvious factor accounting for this reduction in fatty acid oxidation capacity (1). This latter finding is in agreement with the fact that muscles exposed to spaceflight increase stored lipid (18). Also, the metabolic pathway for taking up glucose is increased in muscles undergoing unloading (13). Thus, while the enzyme data are equivocal, it appears that there may be some shift in substrate preference in response to states of unloading whereby carbohydrates are preferentially utilized. If this is indeed the case, it could result in a greater tendency for muscle fatigue should the carbohydrate stores become depleted.
MECHANISMS OF MUSCLE ADAPTATION IN RESPONSE TO SPACEFLIGHT
Most experiments have been largely descriptive due to the lack of spaceflight research opportunity and lack of laboratory resources during flight to test more mechanistic hypotheses. However, data from ground-based animal studies have begun to provide some insight concerning mechanisms governing the plasticity properties of unloaded muscles. Evidence suggests that both protein synthesis and protein degradation processes are altered, thereby accounting for the reduction in the quantity of protein maintained in the muscle (22). It appears that factors such as growth hormone, insulin like growth factor (IGF-1), glucocorticoids, and thyroid hormones may be linked in subtle ways to affect protein expression(7,10, R. Grindeland, personal communication). For example, exogenous treatment with growth hormone and IGF-1 in the context of physical activity, can partially abate the muscular atrophy in hindlimb-suspended rats (10). Also, we have shown that thyroid hormone depletion effectively blocks the up-regulation of fast MHC in the antigravity muscles of hindlimb-suspended animals (7). These findings suggest that by reducing the force output of the whole muscle, selective fibers may become either highly sensitive or unresponsive to a number of factors regulating both pretranslational, translational, and posttranslational processes involved in gene expression. These same factors could be pivotal in regulating protein turnover; i.e., protein synthesis and protein degradation. These changes in responsiveness to certain hormonal/growth factors could alter the size of the size of the muscle fiber as well as transform protein phenotype in those fibers shown to undergo changes in MHC and sarcoplasmic reticulum phenotype(11,21). Clearly, more research is needed to unravel the subcellular processes governing muscle atrophy and fiber-type transformations.
COUNTERMEASURES TO SPACEFLIGHT-INDUCED CHANGES IN MUSCLE PROPERTIES
Based on the findings summarized above, it is apparent that skeletal muscle is highly plastic and capable of adapting its structure and function in response to the environmental conditions imposed. Muscle atrophy is the most deleterious response to spaceflight and most likely caused by reduced protein mass in those specific muscle fibers routinely stressed by the 1 g environment. This down-regulation of protein expression would reduce the energy (ATP) turnover required to support the protein turnover normally occurring in each muscle fiber. However, this reduction in muscle mass creates a subsequent functional deficit upon return to 1 g. With reduction in both muscle strength and stamina (resistance to fatigue), the locomotor and work capacities of the individual are compromised(5,6). However, several countermeasures for this atrophying response can maintain both muscle fiber mass and protein phenotype; these include resistance training paradigms, GH and IGF hormonal therapy, and pharmacological intervention using catecholamine derivatives(6,10,25). Each treatment has shown some degree of effectiveness in ameliorating the atrophy, but no single countermeasure in and of itself has been successful in the long term. In all likelihood, some combination of the above interventions will be necessary. It is apparent that a combination of aerobic and heavy resistance activity will be necessary for supporting different protein fractions in the muscle cell. Thus, careful consideration needs to be given to both the type and quantity of exercise (5), as this intervention may be the only one to maintain integrity of key neurological (sensory and motor) pathways needed for coordination of the complex movement patterns necessary for supporting activities of different intensity upon return to a 1 g environment.
Based on the state of muscle plasticity in response to unloading, future research should 1) explore the mechanisms of muscle plasticity associated with this unique environment, and 2) ascertain the countermeasures necessary to maintain the normal integrity of this system. There needs to be both basic and applied research utilizing animal and human models in conjunction with modern molecular probes coupled with novel physical activity, hormonal, and pharmacological experimental treatments. This work is important because the transformations having an impact on muscle during weightlessness are often similar to those transformations occurring with chronic inactivity and aging on Earth. A major challenge facing society will be to maintain the functional integrity of an ever aging population with an inherent proneness to injury and incapacitation.
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