contraction-relaxation processes. since calcium cycling and crossbridge cycling are the two major systems that account for the vast majority of the energy expended during muscle contraction to support movement, when this property of the muscle is switched to a faster system the muscle can function more effectively in the unloaded environment. however, when the muscle encounters environments with a high gravitational stimulus, the faster properties are inherently less economical in opposing gravity and thus the muscle fibers become more fatigable when contracting against a load for long durations. metabolic processes in contrast to the contractile apparatus, studies on various rodent skeletal muscle metabolic enzymes have revealed a variety of responses with no clear-cut adaptive changes in oxidative enzyme expression. these observations are consistent with the results of studies focusing on mitochondrial function after 9 days of spaceflight in which no reduction in the capacity of skeletal muscle mitochondria to metabolize pyruvate (a carbohydrate derivative) was observed. these analyses were carried out under state 3 metabolic conditions, that is, non-limiting amounts of substrate and cofactors to simulate an energy turnover demand similar to that of high-intensity exercise. however, when a fatty acid substrate was tested, a reduction in the capacity of different muscle types to oxidize the long-chain fatty acid, palmitate, was observed. this latter finding is in agreement with the observation that muscles exposed to spaceflight increase the level of stored lipid within their myofibers. additionally, use of the metabolic pathway for glucose uptake is increased in muscles undergoing hs. thus, while the enzyme data are equivocal, it appears that in response to states of unloading, some shift in substrate preference may occur whereby carbohydrates are preferentially utilized based on utilization capability. if this is indeed the case, it could result in a greater tendency for muscle fatigue, should the carbohydrate stores become limited during prolonged bouts of eva activity. functional correlates to the alterations in muscle mass and contractile phenotype in response to spaceflight stevens and associates reported that in isolated single-fiber analyses, deficits in force generation capacity were found along with a reduced sensitivity to calcium stimulation. similar observations occurred for both slow and fast ankle extensor fibers after 14 days of spaceflight. this study focused on the force-generating aspects of muscle fibers. it appears that only two additional studies have been conducted to examine the effects of spaceflight on rodent skeletal muscle functional properties using a more comprehensive set of analyses. one project was carried out for 6 days while the other involved a 2-week flight (sls-2). in both studies, the measurements focused on the force-velocity properties, which define the limits of functional capacity of the muscle. these studies were conducted on the soleus skeletal muscle, in which slow-twitch myofibers predominate, because of the dynamic changes in fiber morphology and phenotype that were observed in the other studies summarized above. analyses on the animals were initiated within 6 hours of return from spaceflight. the findings showed that the maximal strength of the muscle, as studied in situ using a computer-programmed ergometer system, was reduced by 24% after the 6-day flight and 37% after the 14-day flight. these changes were consistent with the degree of atrophy observed at both the gross and single-myofiber level. also, shifts occurred in the force-frequency response of the soleus in the flight animals, suggesting a switch to a faster contractile phenotype. maximal shortening velocities were increased by 14% and 24% in the 6-day and 14-day spaceflight groups, respectively. these intrinsic increases in shortening speed were attributed, in part, to the de novo expression of the fast type iix mhc in many of the slow muscle fibers. on the other hand, both work- and power-generating capacities of the flight-induced atrophied muscles were significantly decreased. additionally, the resistance to fatigue was significantly decreased as well as the ability to sustain work and power output in response to a paradigm involving repetitive contraction output. similar findings have been observed using comparable analytical approaches involving the hs model. taken together, the findings clearly indicate that when skeletal muscles, especially those having a large proportion of slow myofibers, undergo both atrophy and remodeling of the contractile phenotype, the functional capacity of the muscle is reduced along with its ability to sustain work output. if a sufficient mass of muscle tissue across several key muscle groups were similarly affected, this would most likely impair the fitness of the individual when challenged with moderate-intensity exercise scenarios. are atrophied muscles vulnerable to injury riley and associates have provided an excellent synopsis of the structural integrity of mammalian muscle during the early stages after return from spaceflight. their findings suggest that in atrophied slow types of skeletal muscle, there is no evidence of fiber damage when the muscles are taken from animals euthanized and processed during spaceflight. however, observations suggest that during the first 5–6 hours after spaceflight (the earliest time point at which the animals can be accessed), edema occurs in the target anti-gravity muscles such as the soleus and the adductor longus (al). this is thought to occur by increased blood flow to the muscles when they become initially reloaded in opposition to gravity. in addition, in certain regions of the al, there is some indication of fiber damage based on histological analyses of the myofibril integrity and protein alignment in the sarcomere. while these observations were noted in ~2.5% of the fibers of the al, they were not present in the soleus. riley has proposed that the reason for the differential response between the two muscle groups is that weakened animals have altered their posture and gait so that eccentric stress is placed on the al, resulting in some fiber damage. edema and fiber damage were not noted in another cohort of animals studied 9 days after landing. however, in additional studies performed on both spaceflight and hs rodents in which 12 to 48 hours were allowed to pass before the muscles were analyzed, observations indicated that the normal cage activity induced significant lesions in the muscles after sufficient reambulation was allowed. these included eccentric-like lesioned sarcomeres, myofibrillar disruptions, edema, and evidence of macrophage activation and monocyte infiltration (known markers of injury-repair processes in the muscle) within target myofibers. the inference of these findings is that there is indeed a propensity for muscle injury secondary to the atrophic process that weakens the muscle, and given the instability of the animal after spaceflight as described above, there is most likely a potential for injury if stressful stimuli are imposed on the muscle system before it can regain its proper structural and functional capability. cellular and molecular mechanisms of muscle atrophy in response to unloading stimuli as presented above, skeletal muscle atrophy involves an imbalance between the processes that control protein synthesis (also known as protein translation) and those that control protein breakdown. when the two processes are in synchrony, muscle mass is stable. however, if there is an imbalance such that the protein synthetic pathway is decreased relative to that of the rate of degradation, muscle atrophy will occur. in the case of skeletal muscle atrophy in response to spaceflight or hs, a decrease in the capacity for synthesis as well as an increase in the processes that regulate degradation seem to occur, creating a rapid net degradation response to the unloading stimulus. on the basis of the available information, such a scenario is thought to involve the following chain of events. at the onset of unloading involving a wide range of models including spaceflight, a decrease in transcriptional and/or pre-translational activity occurs in skeletal muscle that affects the type i and iia mhc genes as well as the actin gene. this results in a reduced level of both pre-mrna and mrna pools (the latter being a substrate for protein translation) for these three proteins. together, mhc and actin provide the bulk of the myofibril fraction that accounts for most of the protein in the muscle cell. concomitantly, a decrease occurs in the activity of key protein kinase enzyme systems (constituting the pi3kinase/akt/mtor pathway), which regulates the protein synthetic apparatus controlling protein translation. this alteration, in combination with a smaller amount of mrna substrate, collectively contributes to a reduction in the net capacity for protein synthesis. occurring simultaneously with this process is the up-regulation of a set of genes that encode proteins that play a regulatory role in augmenting protein degradation. these include the myostatin gene, the atrogin 1 gene, and a gene called muscle ring finger protein (murf). myostatin is an antigrowth transcription factor, which is thought to negatively modulate the genes that promote growth. atrogin and murf are e3 ligases that are responsible for ubiquinating target proteins to mark them for degradation in a system designated as the proteasome. this murf protein has been reported to be a key regulator for specifically targeting breakdown of the type i and type iia mhc proteins. as a result of the reduction in net capacity for protein synthesis and the augmentation of protein degradation, a net loss of muscle protein in the muscle fiber occurs along with a change in the relative proportion of the mhc protein content, since available findings show that the faster mhc genes are up-regulated during muscle atrophy. hence, this results in a smaller, faster muscle phenotype, which is apparently more suitable for muscle performance in states of unloading. the chain of events described above must be blunted or reversed if the muscle is to perform optimally when faced with an increased gravitational stimulus in returning to earth or transitioning from low gravity (microgravity) to higher gravitational environments such as landing on the moon or mars. it is apparent that the best strategy to accomplish this task is via a vigorous countermeasure program that provides a high level of mechanical stress to prevent the imbalance in protein expression that occurs when the muscle is insufficiently loaded for significant periods without an intervening anabolic stimulus. effects of spaceflight on non-human primates to our knowledge the only other species besides the rat that has been involved in spaceflight studies on skeletal muscle is the rhesus monkey. two monkeys were flown in space for 14 days on the bion 11 satellite. they were compared to ground-based vivarium control animals as well as a chair- restricted group that involved immobilization of the upper arm and shoulder. the results from these studies provided the following insights. individual fibers (slow and fast) of the monkey displayed functional properties that were more closely aligned to those of human fibers than to those of rodents, in that the fibers were larger but less powerful per unit cross-sectional area than rodent fibers. however, in pre- versus postflight analyses of single fibers, slow fibers in both the slow-twitch soleus and triceps muscles underwent greater atrophy and reductions in force and power production than fast-twitch fibers. also, transformations in the myosin heavy chain profile indicated that there was a greater level of hybrid slow/fast fibers in the two different muscle groups. immobilization of the triceps muscle group produced similar responses, but the magnitude of change was much less than that in the spaceflight animals. additional experiments performed on these same animals, involving locomotor activity before and after spaceflight via muscle electromagnetic and tendon force recordings, respectively, demonstrated that postural and locomotor control was compromised by spaceflight as has been observed in humans. these alterations were chiefly manifested in modified load-related cues as reflected in the altered relative recruitment bias of flexor muscles versus extensors and fast versus slow motor unit pools. in an additional flight study (cosmos flight 2229) involving two rhesus monkeys, emg recordings were obtained before, during, and after spaceflight. these experiments were unique in that recordings obtained during spaceflight revealed a preferential shift in recruitment patterns favoring the fast medial gastrocnemius versus its synergistic slow soleus muscle, that is, the normal recruitment pattern was reversed; and this alteration was maintained well into the recovery stage after spaceflight, further suggesting a reorganization of the neuromotor system during and immediately after exposure to microgravity. thus, it is apparent that skeletal muscle fibers of humans, monkeys, and rodents share similar patterns of myofiber alterations that, in the case of monkeys and humans, are also linked to altered motor performance in response to different states of unloading, reduced usage, and return to an earth gravitational environment. computer-based