constraints and limitations of up mass, crew time, and on-board logistics, cannot be overstated. figure 6-10. exercise equipment failures and other constraints have limited the access of iss crewmembers to the full complement of aerobic and resistance exercise protocols. full capability for all 3 devices was present only for 2 short windows during expeditions 3 and 4 (tall white rectangles). another problem was exercise hardware that was built and launched but failed to meet science requirements. (the resistive exercise device science requirement was to provide a load of up to an equivalent of 600 lbs., but the interim resistive exercise device (ired) provides only half of that amount. ground-based studies have shown that it does produce a positive training effect similar to equivalent free weights when used in a high-intensity program, but it will likely not provide sufficient load in a zero-gravity environment to prevent loss of muscle and bone tissue, as determined from parabolic flight studies.) other problems were failure at one time or another of each piece of onboard exercise hardware with reduced utilization at other times, and other limitations imposed because transmission of forces to the space frame have confounded inflight exercise sessions. in fact, during the first eleven iss expeditions, only for 2 short periods during expeditions 3 and 4 were all three u.s. onboard exercise devices (cycle egometer with vibration isolation system , treadmill with vibration isolation system, and ired) capable of being used under nominal conditions (figure 6-10). the almost continuously suboptimal availability of exercise equipment likely has reduced maintenance of crew physical fitness. figure 6-11. lean tissue mass losses in percent change from preflight for nasa-mir, iss, and three bed rest studies from 120 to 170 days in duration. despite these shortcomings, lean tissue mass data collected by means of dual-energy x-ray absorptiometry (dexa) before and after flight compares favorably with data from nasamir, and the total body and leg losses are in fact less than seen during nasa-mir or during three separate bed rest studies of similar durations in the range of 20–170 d (figure 6-11). however, the news is not entirely good since knee extensor and knee flexor strength losses in long-duration crewmembers after flights aboard mir and iss were ~23% and ~25%, respectively (figure 6-12), indicating that strength losses in the quadriceps and hamstring muscle groups were significant and similar for nasa-mir and early iss missions, despite apparent slightly increased preservation of muscle mass (lean tissue) in the legs of iss crewmembers compared to crewmembers on nasa-mir missions (also figure 6-11). these near equivalent losses occurred in spite of ired being present on the iss. unfortunately, mri data collected by fitts and colleagues to assess skeletal muscle volumes in iss crewmembers are not yet available to allow comparison with those from nasa-mir. with respect to endurance, the following comparison (figure 6-13) shows a trend for improved maintenance of muscle endurance on iss with respect to nasa-mir although the loss of endurance on iss was greater than that documented during short-duration space shuttle missions (for iss, n = 2). figure 6-12. comparison of postflight percent change in knee extensor and flexor strength from preflight in shuttle (sts), the three skylab missions (sl2-4), nasa-mir (mir), and iss. iss crewmembers, under the supervision of their crew surgeons, participate in a postflight exercise program implemented by certified trainers who comprise the astronaut strength, conditioning and rehabilitation (ascr) group at johnson space center. a portion of this program includes physical fitness testing on an individual basis. the results of these “functional” tests, which consist of six exercises, reveal that crewmembers return with less physical capability than when they launch but that most of the decrements are reversed by postflight day 30 secondary to the ground-based exercises the crewmembers complete in the days after their return to earth (figures 14 and 15). figure 6-13. postflight (r+0) percent change from preflight measures in muscle endurance at the knee expressed as total work for space shuttle (sts), nasa-mir (mir) and iss (for iss, n = 2). in this section, only the historical highlights of some highly relevant skeletal muscle investigations have been included and discussed. a complete treatment of all data would cover several volumes. however, from this brief historical overview it is possible to see how initial indications of losses in skeletal muscle function led to attempts to provide exercise countermeasures. such countermeasures were utilized during spaceflight, crewmembers were tested upon return, and exercise regimens and equipment were modified for use in future missions. in the subsequent sections, human spaceflight and ground-based analog studies and experimental animal studies are reviewed that contribute to the evidence base on the alterations in skeletal muscle form and function that occur with the muscle unloading associated with the microgravity environment. it is this knowledge base on which future operational countermeasures and investigations into the fundamental changes in muscle physiology will be based. figure 6-14. results of functional fitness testing in crewmembers from iss expeditions 1–11. percent change from before flight at postflight days 5/7 and 30. figure 6-15. results of functional fitness testing in crewmembers from iss expeditions 1–11. percent change from before flight at postflight days 5/7 and 30. other human spaceflight the responses of the human body to microgravity exposure during spaceflight involve adaptations at numerous levels. it is believed that skeletal muscle adaptations to microgravity, which affect both muscle mass and function, involve structural alterations in the neural as well as the myofibrillar components of skeletal muscle. it is well accepted that the muscles involved in the maintenance of an upright position in terrestrial gravity (the antigravity muscles) are the most susceptible to spaceflight-induced adaptations. this susceptibility may reflect the almost continuous levels of self-generated (active) and environmentally generated (reactive) mechanical loading to which these muscles are exposed under normal earth gravity. thus, effects related to the decrease in the level of mechanical loading that occurs during microgravity exposure logically would be reflected most acutely in these muscles. changes at the structural level within skeletal muscle after spaceflight are paralleled by spaceflight-induced changes at the functional level such as decreased muscle strength and increased muscle fatigability. this summary addresses nearly exclusively those investigations in which the effects of mechanical unloading on antigravity muscles were examined, and the consequent tissue remodeling at the structural and biochemical levels. additionally, the relative success of various countermeasures is examined. decreases in skeletal muscle size and function have been reported since humans first began to explore space. spaceflight results in the loss of lean body mass as determined by body composition measurements. urinary amino acid and nitrogen excretion, both indirect measures of catabolism of lean body mass, are elevated during both brief and long spaceflights. direct measurement of protein synthesis during spaceflight using 15n-glycine incorporation as a marker revealed an increase in whole-body protein synthesis rates. these results indicated that the significant decrease in lean body mass observed after spaceflight must be associated with a significant increase in protein degradation rates rather than an inhibition of protein synthesis. decreases in lower-limb muscle circumference and calculated muscle volumes were detected in apollo and spacelab astronauts. decreases in muscle strength, circumference, and tone have also been reported in cosmonauts. more recently, these findings have been confirmed by direct volume measurements (by magnetic resonance imaging of astronauts on the space shuttle and of russian cosmonauts and u.s. astronauts after tours of duty on the mir space station. changes in lean body mass and muscle volume are paralleled by a concomitant decrease in myofiber cross-sectional area (csa). to date, preflight and postflight muscle biopsy samples have been obtained from only a few crewmembers. in u.s. studies, muscle biopsies were obtained before and after flight from the m. vastus lateralis of 8 astronauts after 5- and 11-day missions. notably, postflight muscle sampling was carried out within 2–3 hours of landing, which minimized the effects of reambulation on the muscle. analysis of the muscle biopsy samples with a variety of morphologic, histochemical, and biochemical techniques indicated that the myofiber csa was significantly decreased after spaceflight; that atrophy was greatest in type iib myofibers, followed by type iia and then type i myofibers; that expression of type ii myosin heavy chain (mhc) protein was significantly increased, with an apparent decrease in the amount of type i mhc protein expressed; and that the number of myonuclei per mm of myofiber length was significantly decreased in type ii myofibers after 11 days of spaceflight. in contrast to these findings, analysis of needle biopsy samples from cosmonauts, conducted by the institute for biomedical problems after 76- and 180-day flights, indicated a large degree of individual variation in the extent of myofiber atrophy, with the decrease in myofiber csa ranging from about 4% to 20%. this variation was attributed to variations in compliance with exercise countermeasures by individual cosmonauts during the flights. more recent muscle biopsy studies have indicated that despite consistent decreases in myofiber csa in the m. soleus and m. gastrocnemius after spaceflight, mhc expression does not seem to shift, as was previously described by zhou et al. this discrepancy may reflect the effects of exercise countermeasure protocols carried out by the astronauts during the later flight and the examination of muscles different from those studied in the earlier flight (gastrocnemius and soleus vs. vastus lateralis). decrements in the aerobic capacity of crewmembers after spaceflight, coupled with a reduction in muscle oxidative capacity, indicate that the vascular supply to skeletal muscle may also be affected by spaceflight. however, at present no consistent relationship is apparent between the degree of muscle atrophy (measured by mri or myofiber csa determination after muscle biopsy) and the reported changes in muscle strength and function, although typically loss in muscle strength exceeds the loss in muscle volume. the reasons for these counter-intuitive results are unclear and will probably remain so until resources become available for long-term, on-orbit study of the skeletal muscle atrophic response to spaceflight. in addition to the effects of spaceflight on the myofibrillar component of skeletal muscle, the role of the neural components of skeletal muscle atrophy must not be understated. a functional disruption of neuronal control at the neuromuscular level, which seems to be paralleled by a reduction in the overall electrical activity of the muscle after spaceflight, raises the possibility that neuron-derived factors that play a role in the growth or maintenance of skeletal muscle may be disrupted. the hypothesis that microgravity causes a fundamental alteration in motor control has also been suggested. studies conducted at jsc by the exercise physiology laboratory showed that two-legged muscle power declines considerably more than can be explained by the loss in muscle mass alone. additionally, the loss of explosive leg power was associated with a substantial reduction in the electromyography (emg) activity of the m. rectus femoris, m. vastus lateralis, and m. vastus medialis. these investigators concluded that microgravity induced a basic change in motor control and coordination such that motor activation of extensor muscles was reduced. similar observations have been made after long-duration spaceflight on mir and iss. evidence exists that exercise strategies are effective in attenuating muscle strength loss in bed rest. bamman et al. preserved pre-bed rest muscle strength of the thigh and calf in subjects who performed resistive exercise with loads equivalent to 80–85% of their pre-bed rest strength (repetition maximum test). protection of muscle volume occurred through the maintenance of protein synthesis, which also likely influenced muscle strength. similarly, akima et al. were able to maintain isometric peak torque in subjects who performed daily maximal isometric contractions of the knee extensors during 20 days of bed rest. using an aggressive resistive exercise training protocol, shackelford et al. preserved isokinetic muscle strength and observed substantial increases in isotonic muscle strength over the course of 89 days of bed rest in exercising subjects. using a flywheel resistive exercise device, alkner and tesch prevented the loss of muscle mass and strength in the thigh and attenuated the losses in the calf. the similarity in skeletal muscle responses during spaceflight and bed rest were elegantly demonstrated by trappe and colleagues in a combined 17-day spaceflight study of 4 crewmembers and a 17-day bed rest study of 8 test subjects. in all of these subjects, assessment of muscle fiber size, composition, and in vivo contractile characteristics of the calf muscle were completed. protocols