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6 Animal and Human Biology Over millions of years, the structure and function of organisms have evolved under the influence of a constant gravity stimulus, which consists of the natural force of attraction exerted by celestial bodies such as Earth. To fully understand this influence of gravity, living systems must be studied by essentially eliminating the gravity variable. This task can be daunting because organisms must live for a sufficient time outside the effects of Earth’s gravity, in a state of free-fall. In the United States, the agency designated by Congress to develop a space research program involving the life and physical sciences is the National Aeronautics and Space Administration (NASA). During its 50 years of existence, NASA has continued to evolve such a program, which, at the present time, is centered primarily on operational medicine objectives being pursued on the National Space Laboratory, a key component of the International Space Station (ISS). It is now recognized that habitation of the microgravity environment poses potential deleterious consequences for essentially all the organ systems of the body, even though it is routine for human astronauts and cosmonauts to spend 180 days or longer living and performing a number of challenging tasks on the ISS. Given the typical lifespan of humans, 180 days in space may seem trivial. However, in the case of rodents, the animal model most scientists have used to study fundamental biological processes in space, such a time frame represents approxi - mately one-fourth to one-third of the species’ adult life. Thus, studies on these rodents in space have the potential to extrapolate important implications for humans living in space well beyond 6 months. As part of the decadal survey process, the Committee for the Decadal Survey on Biological and Physical Sci - ences in Space formed the advisory Animal and Human Biology (AHB) Panel and tasked it to address the research needed to (1) enable humans to carry out long-term space exploration and (2) ascertain opportunities provided by the space environment that enable a greater understanding of how gravity shapes fundamental biological processes of various organisms. To meet its objectives, the AHB Panel focused on the following topics: (1) what is known about the risk and deleterious effects of spaceflight (and ground-based analogs) on the structure and function of the musculoskeletal (bone and muscle), sensory-motor, cardiovascular, pulmonary, endocrine, and immune systems, as well as how animals develop in the absence of gravity; (2) the effectiveness of the countermeasures currently used to maintain organ system homeostasis in the face of microgravity; (3) the knowledge gaps in understanding of the above topics that need to be addressed; (4) the research platforms needed to undertake new research initiatives in the next decade; (5) the overarching issues that have to be addressed in fostering cutting-edge, integrative research in humans and animals, and spanning multiple physiological systems, to generate future countermeasure strategies; and (6) the 99
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100 RECAPTURING A FUTURE FOR SPACE EXPLORATION specific high-priority research initiatives that are needed to sharpen and advance the science knowledge necessary for progress in the next decade. (It is important to note that certain topics that have a major impact across mul - tiple physiological systems, such as nutrition, are in most cases not covered in this chapter, but rather in Chapter 7, which focuses on crosscutting issues.) Finally, in examining programmatic activities relevant to this chapter, and as discussed in the committee’s interim report to NASA,1 the AHB Panel was deeply concerned that NASA had severely reduced research initiatives in the life and physical sciences in the latter half of the past decade. In the panel’s view, this action has effectively paralyzed research initiatives previously recommended by National Research Council (NRC) study committees (as reflected by the relative paucity of publications since 2005 in recommended subject areas such as bone) and poses a daunting challenge to future administrations attempting to reverse the neglect and to accomplish the life and physical sciences research initiatives recommended in this report. RESEARCH ISSUES Risks for Bone Loss During Long-Duration Space Missions The skeletal (bone) system provides the solid framework for humans and mammals to oppose gravity, and its fidelity in accomplishing this fundamental process has evolved over millions of years. Given this evolutionary role, it is not surprising that bone loss occurs in astronauts at a rate that is both substantial and progressive with time spent in microgravity.2-5 Accordingly, without appropriate countermeasures, spaceflight of 2 years or longer will present serious risks due to progressive bone fragility. Therefore, there is a need to adopt effective countermeasures that have been appropriately tested in relevant human and animal models. The 1998 NRC report A Strategy for Research in Space Biology and Medicine in the New Century6 recommended several experiments to address the problem of bone loss during spaceflight. At present, several key issues raised in the 1998 NRC report have not been addressed. For instance, the report recommended that genetically altered mice be used in flight experiments to investigate the molecular mechanisms of bone loss, yet these experiments have not been completed. The report also recommended that in-flight animal facilities should house 30 adult rats or mice, but the ISS can currently house only 6 mice (in the Mice Drawer System on the Italian Space Agency investigation). These recommendations should be implemented, and additional steps should be taken to advance research into bone loss in microgravity for the development of effective countermeasures. Effects of Spaceflight Environment on the Structure and Function of Bone Bone loss during spaceflight appears to be due primarily to increased resorption in load-bearing regions of the skeleton.7,8,9 There is also some evidence of a decrease in bone formation. The rate of bone loss in microgravity is roughly 10 times greater than the bone mineral density (BMD) loss per month that occurs in postmenopausal women on Earth who are not on estrogen therapy.10-13 Results from Skylab,14 Mir,15,16 the space shuttle,17 and the ISS18,19,20 missions have shown substantial areal and volumetric bone loss in critical regions such as the proximal femur and spine. The most accurate data, derived from quantitative computed tomography, have shown that spinal volumetric BMD was lost at a rate of 0.9 percent per month and total hip volumetric BMD was lost at rate of 1.4 percent per month; there was, however, considerable variability between individuals. 21 Changes in bone strength (expressed as percentage loss) were much greater than changes in BMD. 22 BMD lost in 6-month missions appears to be mostly reversible by 1,000 days after return to normal gravity (1 g).23,24 However, changes in bone structure are not reversible and seem to mimic changes in the elderly. 25 An important question that remains unanswered is whether any loading that is performed by simply living and working in partial gravity—such as the 1/6 g of the Moon or the 1/3 g of Mars—will provide any protection from the bone loss that occurs in microgravity. Expert opinion as presented in a recent symposia is that it will not,26 although data from a partial-gravity mouse model is just becoming available. 27 Animal Studies Rodents have been flown on the Cosmos biosatellite28-33 and on space shuttle missions34-46 to measure bone loss. The most consistent finding was the striking decrease in bone formation with spaceflight, which stopped
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101 ANIIMAL AND HUMAN BIOLOGY completely at some skeletal sites.47 In contrast to what occurs in humans, bone resorption in rats was not substan - tially changed in one flight experiment.48 whereas it was increased in another.49 Most rodents flown in space have been immature and undergoing rapid bone growth.50 In these studies, bone formation dominates during growth, and so it is not surprising that greater changes were observed in bone formation than in bone mineral resorption. It is difficult to extrapolate from these data to the expected changes in the mature skeleton during long-term space - flight. A few studies have used adult animals, and in these studies bone formation was suppressed at the periosteal surface.51,52,53 In contrast, longitudinal growth was minimally affected by either spaceflight or hindlimb unloading (HU).54 One study has shown bone loss in spaceflight to be greater than that in ground-based models, such as HU,55 although it is important to distinguish between bone loss, the removal of existing bone, and failure to gain bone in growing animals. In this model, traction applied to the tail of rodents elevates the lower extremities and eliminates generation of ground reaction forces. In Vitro Studies Bone cell culture experiments have been performed on space shuttle missions, 56,57 on Skylab,58 and on the free-flyer Foton-M.59 These studies demonstrated differences in gene expression and growth factor production by osteoblasts.60 Osteoclasts were also affected by spaceflight.61 Interpretation of these experiments is a challenge, because cells in culture behave much differently than cells embedded in bone. Furthermore, the vibration during launch can confound cell culture experiments, particularly for short-term (1 to 2 weeks) experiments. 62 The experi- mental complications during spaceflight and the difficulty with interpretation make bone cell experiments of lower priority compared with animal or human spaceflight studies. There is, however, a potential use of cultured bone cells in biotechnology applications. Status of Countermeasures Exercise Countermeasures To date, NASA and the Russian space program have relied primarily on exercise countermeasures to attenuate bone loss,63,64,65 but no exercise has yet proven to be uniformly effective for maintaining bone mass66,67 during flight or bed rest. Similarly, low-magnitude, low-frequency mechanical signals were not effective in prolonged best rest.68 There is evidence that the external loading on previous exercise devices used in space has been insufficient to provide the required stimulus to bone.69,70 Recent (fall 2009) additions to the exercise devices on the ISS now offer the possibility for greater loading and for definitive research to examine the efficacy of exercise countermeasures. The capacity to measure loads was also added to these new devices, but interaction with NASA personnel indicates that further refinements are required to produce accurate load estimates. The ISS provides an excellent research platform for studies that are relevant to missions outside low Earth orbit because the microgravity environment on the ISS presents a greater challenge to the musculoskeletal system than does a partial-gravity environment. 71 Ground-based research using bed rest (head-down for microgravity or head-up for lunar simulation) provides another important research platform for exercise countermeasures. 72-81 For example, bed rest studies suggest that bone may be somewhat protected with sufficient loads and exercise time. Results from Vernikos et al. 82 showed that intermittent upright posture and exercise reduce the increased blood calcium levels observed in bed rest, and data from Smith et al.,83,84 and Zwart et al.85 showed positive benefits of supine treadmill running within lower- body negative pressure during 30 and 60 days of bed rest. There are no studies indicating positive effects on bone in passive intermittent rotational artificial gravity.86 It is possible that lower-body negative pressure or centrifuga- tion coupled with exercise may be more effective than exercise alone, perhaps through modulation of some other necessary physiological factor (e.g., improved blood flow, fluid shifts, or circulating hormones). Pharmaceutical and Nutritional Countermeasures Vitamin D supplementation has been used by NASA during spaceflight, 87,88,89 but one report90 showed that serum 25-hydroxycholecalciferol was decreased after flight despite supplementation with vitamin D. Short-term calcium supplementation has not been effective in reducing bone loss during spaceflight or head- down bed rest.91,92 Over the past 15 years, several drugs have been developed to prevent bone loss associated with osteoporosis
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102 RECAPTURING A FUTURE FOR SPACE EXPLORATION (e.g., bisphosphonates, selective estrogen receptor modulators, parathyroid hormone). Some of these drugs may be useful for preventing bone loss in astronauts during long-term spaceflight. As with exercise countermeasures, the ISS is ideal for testing the effectiveness of drugs. However, at the time of the writing of this report only one experiment involving oral bisphosphonates had been flown on the ISS, and only two astronauts had participated. Bisphosphonates substantially reduce bone resorption in Earth-bound patients and can be given by mouth daily or weekly, or yearly by infusion. A new potent antiresorptive bisphosphonate, zolendronic acid, effectively preserves bone mass in osteoporotic patients when given by infusion once per year. 93 Bisphosphonates have shown promise in ground-based studies. As an example, a single injection of pamidronate maintained a slightly increased BMD in the spine and hip in a 90-day bed rest study. 94 These drugs have been shown to attenuate bone loss in hindlimb unloaded rodents.95 In addition, excess urinary calcium excretion was reversed by pamidronate. This dual action, blocking bone loss and reducing urinary calcium excess, suggests there is potential utility for bisphosphonates in space. A theoretical concern with use of bisphosphonates is that suppressing of resorption will also suppress bone formation, but data from spaceflight are lacking to address this issue. Should a fracture occur in space, use of bisphosphonates might slow healing. Consequently, it will be important to study fracture healing in space with antiresorptives to provide assurance that fractures will heal. Further, the long-acting nature of some bisphosphonates means that the suppression of bone turnover could persist upon return to normal gravity. The suppression of bone turnover in people who maintain vigorous levels of activity could have deleterious effects on bone quality. Other potential issues with the use of bisphosphonates include osteonecrosis of the jaw 96 and atypical sub-trochanteric fractures after prolonged bisphosphonate use.97 Another drug recently approved for use in postmenopausal women with osteoporosis, Denosumab, blocks an important orthoclase-stimulating peptide called RANKL and stops bone loss in osteoporotic patients when given by injection every 6 months.98 A bone anabolic drug, teriparatide, is approved by the Food and Drug Administration for the treatment of patients at high risk for fracture,99 but there are ethical concerns in the treatment of a person with a normal skeleton with this drug because of the possibility of undesirable side effects. Challenges for the use of drugs in space include storage and packaging that prevent degradation in the space environment. Additionally, it is not known whether drugs will have the same bioactivity when taken in a weight - less environment.100,101 Bone-acting drugs have not yet been tested to determine the length of time they remain active in space, where, for example, they are exposed to higher radiation levels than on the ground. If bioactivity is compromised, long-acting drugs might be given pre-flight to avoid the need for in-flight dosing, although cur- rently the longest interval between dosing of any appropriate drug is 12 months. Treatment of astronauts upon return to Earth with therapeutic drugs also needs to be explored. An animal experiment using a myostatin inhibitor was tested on the space shuttle (STS-118). Myostatin is an antigrowth factor protein that blocks muscle growth, and so researchers expected the use of myostatin inhibitors to prevent muscle loss. In addition to preventing muscle loss during the 13-day mission, there are initial indications that the drug also preserved bone mass and strength.102,103 In another important recent study, sclerostin knockout mice did not lose bone during ground-based disuse.104,105 In addition, a sclerostin antibody improved bone mass in an animal model of colitis-induced bone loss.106 Gaps in Knowledge Mechanism of Bone Loss An animal research program offers many vitally needed tools to better understand bone loss during weightless- ness—both to better define risks to the skeletal health of humans in prolonged spaceflight and to provide models to rigorously test recently developed pharmacologic strategies to control bone loss. However, past animal studies in spaceflight have been confusing. As discussed previously, many studies of rodents found that bone loss was due primarily to cessation of bone formation. Studies of astronauts using biomarkers have identified increased bone breakdown by resorption as the predominant mechanism, although the role of suppressed bone formation should be further investigated. These findings are complicated by the fact that most rodents studied in space were immature and growing, whereas all astronauts are mature and have stopped growing. Further experiments with
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103 ANIIMAL AND HUMAN BIOLOGY mature animals will help determine the relative contributions of decreased bone formation and increased bone mineral resorption in bone loss in microgravity. This will be critical in identifying effective pharmacologic coun - termeasures, which target either bone mineral resorption or bone formation. Molecular and Cellular Mechanisms There are many unanswered questions about bone loss during spaceflight. For instance, the molecular mecha - nisms by which bone senses gravitational forces remain unknown. Currently, it is thought that osteocytes within the bone sense mechanical perturbations and signal to osteoblasts and osteoclasts, but the biochemical nature of these signals among cells is poorly understood. Bone cell factors that have been identified as therapeutic targets include sclerostin (an inhibitor of bone formation), RANKL (a stimulator of bone resorption), and osteoprotegerin (an inhibitor of bone resorption); others will likely emerge in the coming decade. 107 These targets are ideal for continued studies using animal models. Fracture Repair Without an effective countermeasure during spaceflight, bone loss occurs at an alarming rate and fracture risk is increased. Any fracture sustained by an astronaut during a long-duration mission must heal in a microgravity or partial-gravity environment. Fracture healing was studied on shuttle flight STS-29, and deficiencies in angiogenesis were noted.108 However, the shuttle flight was too short in duration (5 days) to fully evaluate fracture healing. A subsequent 5-week ground-based study showed that fracture healing was impaired in rats subjected to HU. 109 Effects of Radiation A major obstacle to long-term spaceflight is the effects of space radiation on astronauts. The effects of radia - tion on bone during spaceflight are currently unknown. However, ground-based studies demonstrate that space-like radiation causes bone loss.110 Further studies of the combined effects of radiation and unloading on bone structure are urgently needed. Hormonal Issues Endocrine hormones, such as parathyroid hormone, calcitonin, glucocorticoids, and insulin-like growth factor, influence bone homeostasis on Earth. Estrogen deficiency plays a major role in the pathogenesis of bone loss and fracture in both women and men on Earth.111 It has also recently been shown that the leptin receptor plays a key role in mechano-signal transduction.112 There is no direct evidence that these endocrine hormones play a major role in bone loss in space, as evidenced by the site-specific, rather than systemic, nature of bone loss in the skeleton due to microgravity. However, experiments with the rodent model have shown that estrogen status alters the skeletal response to spaceflight and HU.113,114 Recent evidence suggests that local (autocrine or paracrine) effects are more important in regulating bone lost as a result of disuse,115,116 and local expression of autocrine and paracrine factors have been investigated in the rat.117,118,119 However, traditional systemic endocrine factors (e.g., estrogen, cortisol) can also act in a paracrine manner because bone cells contain the enzymatic machinery to produce these factors locally. Fluid Shifts Bone loss in human volunteers subjected to bed rest is greatest in the lower extremities, particularly the calcaneus. In contrast, the upper extremities do not lose bone, and there is a net gain in bone mass in the cranial bones.120 This pattern of bone loss matches the expected changes in fluid pressures caused by change in body position during bed rest, relative to the gravitational vector. A similar pattern in bone loss occurs in rats subjected to HU.121 Because fluid shifts are an important physiological adaptation to spaceflight, further studies of animals and humans during spaceflight are warranted to allow a better understanding of the mechanisms of bone loss and their possible associations with fluid shifts. McCarthy122 postulated that the shear forces created by interstitial fluid flow influence bone loss in micro - gravity. He has created a pneumatic venous tourniquet that can modulate fluid flow within tissues when placed around the ankle of an astronaut or a rat. More recently Yokota and colleagues 123 have shown that lateral loading
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104 RECAPTURING A FUTURE FOR SPACE EXPLORATION of joints increases both fluid flow within bone and bone formation. These findings demonstrate the link between bone fluid flow and the maintenance of bone mass. Further research using tourniquets or other means will help to determine to what extent fluid shifts are responsible for bone loss. Calcium Metabolism and Kidney Stones Risk factors for renal stone formation (high urinary calcium excretion, low urinary volume) are exaggerated in spaceflight.124,125 Urinary calcium excretion was highly variable both before and during flight, but impressively elevated calcium excretions were noted in several individuals,126,127 and the source was likely increased bone resorption.128 Calcium oxalate and calcium phosphate concentrations during flight increased to levels that favored crystallization.129 Countermeasures should include increased fluid intake to increase urine volumes, but such efforts are complicated by fluid shifts in microgravity, reduced plasma volume, fluid retention from hormonal adjustments, and practical constraints encountered in spaceflight. Studies on agents to prevent reductions in urinary pH and citrate in flight130 and during bed rest131 have been explored, but their effectiveness is uncertain. The key logical countermeasure would be to reduce bone breakdown and thereby achieve a dual benefit. For example, pamidronate both blocked bone resorption and reduced excessive urinary calcium excretion in a bed rest study.132 Nutrition plays a role in calcium metabolism and bone health during long-duration spaceflight that needs further investigation. Astronauts have been reported to consume only 80 percent of the recommended energy intake during long-duration spaceflight, and food restriction has been shown to exaggerate the effects on bone of unloading in animals and humans.133,134,135 Nutrition, a crosscutting issue affecting multiple systems, is discussed in detail in Chapter 7. Research Models and Platforms Animal Experiments An active animal research program is critical both to better understand the adaptive response of bone to weightlessness and to better define risks to the skeletal health of humans in prolonged spaceflight. In addition, animal experiments are necessary to rigorously test pharmacological strategies to control bone loss. Studies of genetically modified mice, such as the sclerostin knockout mouse, provide a means of isolating the importance of specific signaling factors in bone.136,137 Further studies of genetically altered mice subjected to weightlessness, both as ground-based models and on the ISS, are urgently needed. The sclerostin knockout mouse is an example of the wide variety of highly informative and newly available 138 genetically modified animals. In fact, there are several hundred genetically modified mouse strains that selectively delete (gene knockout or replacement) or overexpress (transgenic animals) specific genes and gene products that are important in bone biology.139-144 The rapid pace of advances in molecular biology pertinent to bone metabolism provides the basis for breakthroughs in space biology, thus emphasizing the importance of reinvigorating basic research on bone biology in altered gravity. In ground-based studies, rodent HU is a proven model for disuse and fluid shift caused by spaceflight,145 and this model should continue to be exploited and supported. The ISS would be an excellent platform for spaceflight studies of rodents, if adequate rodent housing facilities were added. Given the breadth of this field, a rigorous selection process will be needed to prioritize the use of particular genetically modified mice, including conditional knockouts, which are best suited to answer the research questions. The limitations in comparing effects in the mouse to those in humans should be carefully considered, and the recent breakthroughs in gene technology in rats may provide alternatives to mice for genetic studies. 146,147 Human Experiments The six-degree head-down bed rest model has been successfully exploited in a number of U.S. and European studies.148,149,150 In human bed rest studies, the rate of bone resorption increased two-fold and bone formation was significantly reduced.151 However, changes in bone formation markers did not reflect the histologic evidence of reduced bone formation.152 This finding calls attention to the relative insensitivity of bone formation markers to detect reduced bone formation. More research on bone cell turnover is needed.
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105 ANIIMAL AND HUMAN BIOLOGY Research Recommendations Need for More Basic Research The severe drop in NASA funding between 2005 and 2009 has had a chilling effect on basic research to explain the changes seen in physiological systems during spaceflight. In the ISS era (2000 to the present), the emphasis of NASA research has been on exercise countermeasures to bone loss in humans (see relevant NASA Research Announcements).153 Basic research into the mechanisms of bone adaptation in altered gravity using animal and human models needs to be reinvigorated. The agreement between, and the joint solicitations from, the National Institutes of Health and NASA could be exploited to expand the research focus from primarily operational issues to include fundamental science that will inform future missions. Maximizing the possibilities offered by the ISS National Laboratory over the next decade will also be critical to the future success and safety of long-duration missions. Recommended Experiments Human Studies. All experiments listed below can be completed within the next decade. 1. Ongoing human research on the efficacy of exercise to preserve bone during ISS missions should continue. There is a need for studies with adequate statistical power of all the available ISS exercise devices (including the latest devices: the advanced resistive exercise device and T2 treadmill), with accurate quantification of external loads and compliance with prescribed exercise in order to determine whether exercise is an effective countermea - sure for bone loss. 2. The efficacy of bisphosphonates and other anti-osteoporosis drugs should be tested on the ISS during approximately 6-month missions in an adequate population of astronauts. The interaction of pharmacological and exercise countermeasures also needs to be studied, since prior use on Earth has invariably involved weight bear- ing, and only a single study has examined the use of bisphosphonates in the bed rest analog, and the subjects in this study did not exercise.154 3. Use of any drug as a countermeasure during long-term spaceflight will require that the drug can be stored in space without losing its effectiveness. Whether bone-active drugs can be stored in space is currently not known, and this question should be studied further using the ISS. 4. The possibility exists that neither exercise nor currently available pharmaceutical countermeasures will stop bone loss completely during spaceflight. In this case, studies that include exercise and existing or new pharmaco - logical therapies should be undertaken to test the synergy between these countermeasures. These studies should include the evaluation of changes in bone structure and strength. 155,156,157 5. The bone health of women during long-duration spaceflight requires further study. The practice of inhibit - ing menstrual periods during flights of up to 6 months is likely to contribute to marked, and possibly irreversible, bone loss in longer missions. These issues are further addressed in the section of Chapter 7 titled “Biological Sex/ Gender Considerations.” 6. Interventions to accelerate skeletal recovery following long-duration spaceflight should be conducted. 7. More studies are required on the lifetime bone health of astronauts who have flown on long-duration missions. In particular, the risks of fracture and renal stones need to be examined and, if found to be elevated, addressed. 8. Future studies should address issues of bone quality and not just bone mineral density, because the former is more relevant to performance and fracture resistance. Animal Studies. All ground-based studies listed below can be completed within the next decade, but flight studies will be limited by the inadequate animal housing on the ISS. 1. Animal experiments should be conducted on rodents that are skeletally mature for relevance to adult organisms.
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106 RECAPTURING A FUTURE FOR SPACE EXPLORATION 2. Studies of genetically altered mice exposed to weightlessness in space and to the newly developed partial- gravity analogs on Earth are strongly recommended. 3. The efficacy of existing and new osteoporosis drugs under clinical development should be tested in animal models of weightlessness (both ground-based and in spaceflight). 4. Fracture healing, methods to improve fracture healing, and effects of antiresorptive drugs on fracture heal - ing should be further evaluated in animal models of weightlessness (both ground-based and in spaceflight). 5. The combined effects on bone of space radiation and altered-gravity should be evaluated in ground-based animal models. 6. The precise cellular signaling mechanisms responsible for initiating increased bone resorption and reduced bone formation in weightlessness should be studied further in animal models of weightlessness. Consideration should be given to using the rat model because of its successful track record in predicting the actions of pharmacological interventions on human bone and because of new technology to genetically manipulate rats. Obstacles to Progress Progress in identifying countermeasures to bone loss during long-duration spaceflight has been hindered by a number of factors that need to be addressed in the next decade. Historically, the exercise devices that have been flown on the ISS (with the exception of the advanced resistive exercise device158) have undergone limited pre-flight testing to establish their efficacy. This is evidenced by the lack of published studies in the literature. In addition, conversations and direct interaction with NASA personnel indicate that the devices have not had the longevity required to survive programmed use by crew members without large investments of crew time in maintenance. For example, large maintenance and redesign costs are known to have been incurred for repairs of the interim resistive exercise device (iRED) and TVIS. A further issue is whether or not the stimuli provided by the exercise devices are sufficient to generate the required responses to preserve musculoskeletal homeostasis. This has not been the case in the past. 159,160 NASA should develop a larger bed rest facility that will allow more rapid evaluation of ground-based simula - tions of countermeasures with adequate statistical power. As indicated a number of times elsewhere in this chapter, having appropriate facilities on the ISS for conducting animal studies is also an important need. Pharmaceutical countermeasures include bisphosphonates, but two rare potential problems with this class of drugs have received much negative public attention and may have prevented their more widespread use. Atypical subtrochanteric femoral fractures have been reported after long-term use. 161 Osteonecrosis of the jaw has also been observed, but the frequency from bisphosphonate use is generally agreed to be quite low, estimated to be 0.7 per 100,000 person-years of exposure.162,163 The American Dental Association has published guidelines that propose careful examination of patients for underlying dental conditions. Despite this recommendation, community dental care has been denied to individuals (including astronauts) who have used bisphosphonates. Thus the negative perception of some of the rare side effects of bisphosphonate use has prevented more widespread use of this class of drugs among astronauts. NASA should help allay concerns by assisting with careful selection of dentists who do needed dental work for astronauts in advance of bisphosphonate dosing and agree to take on dental care later if required. Further exploration of the effects of artificial gravity on bone is also warranted. A specific discussion of the use of artificial gravity as an integrated countermeasure for a wide range of systems can be found in Chapter 7. Risks for Skeletal Muscle During Long-Duration Spaceflight While the skeletal (bone) system evolved to provide a solid foundation in animals and humans in opposing the force of gravity during weight bearing, the skeletal muscle system, which is the largest organ system of the body, also evolved in response to gravity. The skeletal system developed the capacity for generating high-force contraction processes not only to synergize with bone in opposing gravity but also to enable individuals to perform a wide range of activity patterns under normal gravity loading conditions such as running, jumping, lifting, and moving heavy objects. Hence, over millions of years mammalian skeletal muscle fibers evolved into two general
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107 ANIIMAL AND HUMAN BIOLOGY functional types, referred to as motor units. A motor unit consists of a group of fibers of relatively similar structural and functional properties that is innervated by a common neuron. Motor units can be classified as either slow con - tracting (type I) or fast contracting (type II).164 These contrasting fibers types, under the influence of the nervous system, account for the great diversity in activity pattern that humans and animals can achieve in transitioning from the physiological state of inactivity to activity of varying intensity. Similar to the bone system, both the slow and fast muscle fiber types are negatively affected by reduced gravitational loading, which occurs during spaceflight, as well as along the long axis of the skeleton in ground- based analogs such as prolonged bed rest. Therefore, the goal of this section is to summarize what is known and not known about the risks of spaceflight for the skeletal muscle system. 165 The concern is that when human and animal subjects are exposed to microgravity, their lower limb and core trunk muscles atrophy and lose strength and stamina, thereby reducing the fidelity of movement spanning a wide range of activities. 166,167,168 This, in turn, can negatively affect the overall fitness of the astronaut when functioning in gravity environments, whether on Earth or other celestial bodies.169 These alterations in muscle structure and function were clearly identified by the 1998 NRC report A Strategy for Research in Space Biology and Medicine in the New Century170 and are elaborated further in this section. Effects of the Spaceflight Environment on the Structure and Function of the Skeletal Muscle System Muscle Mass Rodent Studies. Exposure to microgravity during the Russian Cosmos Program and NASA Space Lab missions showed that skeletal muscle fibers rapidly atrophy. This alteration occurs principally in the soleus (ankle plantar flexor), the vastus intermedius (deep quadriceps knee extensor), and the adductor longus (femur adductor) muscles, all of which predominantly express slow type I fibers.171,172 The muscle atrophy of these slow muscles is greater than that of their fast type synergists such as the gastrocnemius and vastus lateralis muscles. 173,174 As much as a 40 to 45 percent loss in muscle fiber mass/size can occur in the soleus muscle, depending on the duration of the unloading state.175 As a result, both slow and fast muscle fibers shrink in size.176 The ground-based analog for spaceflight involving rodents is the HU model.177-180 This analog is described in the previous section. Interest- ingly, this model mimics the muscle loss seen in response to spaceflight, suggesting that HU is a good model to undertake studies on the rodent skeletal muscle system, given the current lack of opportunities to study animal subjects in space. Human Studies. A similar response of muscle wasting has been reported in humans for muscles such as the soleus and the vastus, thereby resulting in loss of muscle volume and muscle fiber size.181-184 However, in humans the reduction in fast fiber cross-sectional area can equal or even exceed the loss in slow fiber size. 185 Since the fast fibers are larger than the slow fibers in humans, it appears that the larger fibers may be more susceptible to the unloading stimulus. In bed rest studies, which are the primary analog to mimic spaceflight microgravity conditions in humans, losses in muscle mass (volume) and reductions in the size of the individual fibers closely resemble the responses seen in both short-duration spaceflight on the space shuttle and long-duration missions on the ISS. 186 These losses in muscle fiber mass are the signature alteration affecting muscle fiber homeostasis. Alterations in Protein Balance, Expression, and Contractile Phenotype Rodent Studies. The Cosmos and shuttle spaceflight animal studies have provided insight on alterations in the subcellular muscle protein milieu.187-190 The myofibril fraction, which accounts for more than 50 percent of a muscle’s total protein pool, is the primary target for degradation, especially of the key proteins such as myosin heavy chain (referred to as MHC) and actin,191 which govern force development and hence the strength of the contraction.192,193,194 Also, there are shifts in MHC isoform gene expression,195-198 showing that the slow MHCs become repressed while the fast type II MHCs are turned on, which indicates a significant shift from a slow anti - gravity to a faster contractile phenotype. Moreover, such studies in spaceflight conditions were corroborated by
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108 RECAPTURING A FUTURE FOR SPACE EXPLORATION studies using the rodent HU model.199 Taken together, it is apparent that the HU model is an important analog to the spaceflight environment in terms of altering muscle mass, strength, and contractile phenotype. 200-203 Unfor- tunately after the completion of the NASA flight program in 1998 involving animals, there has been little further progress in ascertaining the effects of long-duration spaceflight on the homeostasis not only of the skeletal muscle system but also of other important systems such as bone, cardiovascular, pulmonary, sensory-motor, and immune systems. This has left a tremendous void in understanding the biological processes governing muscle atrophy and phenotype plasticity in response to long-duration spaceflight missions. Human Studies. In the early 1990s, Edgerton and colleagues were the first to obtain biopsy samples from astro - nauts before and after short-duration shuttle spaceflight missions (5 and 11 days). 204 Their findings suggest that shifts in slow to fast MHC gene expression also occur in humans. Additional studies obtained from missions of longer duration revealed that individual fibers demonstrated lower force per cross-sectional area as well as shifts to fast type IIa and IIx MHC expression.205,206 Such losses in muscle mass and shifts in contractile phenotype have important functional consequences as presented below. Functional Alterations in Skeletal Muscle Rodent Studies. While only a few studies have been performed to examine the functional properties of rodent muscle immediately following spaceflight, these studies clearly show that there are alterations in the contractile processes as delineated by force-velocity tests involving the antigravity soleus muscle. 207,208 These alterations involve (1) a reduction in force output for any given velocity of contraction, (2) a reduction in power output, and (3) a decrease in the resistance to fatigue in response to repetitive contraction output. These observations of reduced function are consistent with the atrophy process and the transformation from a slow to faster contractile phenotype as discussed above. In additional studies, there is strong evidence that the slow muscle fibers show evidence of susceptibility to injury as a result of initially readapting to the normal gravity environment. 209,210 Collectively, these observations suggest that the performance of individuals undertaking physical activity in a gravity environ - ment could be compromised and that the muscle could be prone to further injury in performing tasks demanding high functional output. Such deficits are illustrated by marked changes in rodent posture (low center of gravity), as well as the extensive use of the tail for support. Also, there is an inability to move quickly while pushing off from the balls of the feet for locomotion.211 Thus, these observations point to deficits in the sensory-motor system of rodents following spaceflight that warrant further investigation, especially in response to long-term spaceflight. Human Studies. Studies on humans following both spaceflight and ground-based bed rest exposure demonstrate alterations similar to those reported in rodents. The signature response involves a reduction in absolute strength of the target muscle group and decrements in the torque-velocity relationship. 212-215 These functional alterations appear to be greater than the deficits in muscle mass, especially early on in the time course of spaceflight. 216 The differential responses in muscle strength could be due, in part, to sensory-motor alterations, which impair the ner- vous system’s ability to recruit motor units in response to high loading stimuli. Individual-fiber analyses further suggest that the loss in force capability could also be due to deficits in the intrinsic properties of the myofibers. 217,218 Also, there appears to be a wide range of response in such muscle function deficits among human subjects. 219,220 Whether such diversity is due to the responsiveness of astronaut subjects to the unloading state or to differences in countermeasure strategies that are being employed among the astronaut subjects remains to be determined. (Note: astronauts do not perform a prescribed exercise routine.) In humans, little information is available as to whether skeletal muscle is prone to injury during early recovery from spaceflight. However, significant soreness has been reported anecdotally by astronauts; such soreness could impact high-intensity emergency egress capability during the early recovery period.221 In a previous report on astronauts and cosmonauts following spaceflight of varying duration, evidence based on magnetic resonance T2 analyses suggested that muscle injury was probably occurring in some of the subjects during the early stages (days) of recovery. 222
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109 ANIIMAL AND HUMAN BIOLOGY Key Synergies with Other Systems Bone. It is well recognized that both skeletal muscle and bone homeostasis are negatively affected by prolonged exposure to spaceflight as well as to ground-based simulations of spaceflight. 223,224 As noted in the bone section, pre- and post-flight quantitative computed tomography analysis has shown that long-duration spaceflight missions induced average volumetric BMD losses of about 0.9 percent per month and 1.4 percent per month in the spine and hip, respectively.225,226 Findings on skeletal muscles similarly suggest a range of atrophy averaging about 6 percent to 8 percent per month, also with greater losses in the lower extremities compared with the upper extremities. 227 These respective deficit profiles for bone and muscle actually exceed what is observed during the aging-induced disorders of osteoporosis of bone and muscle sarcopenia. Hence, the question arises as to whether the structural and functional integrity of the two systems are physiologically linked. Recent bed rest study findings provide evidence that the mechanical stress strategically imposed on skeletal muscles by physical exercise during spaceflight or ground-based analogs can have a positive impact on the homeo - stasis of bone. However, pharmacological strategies specifically targeting bone homeostasis do not synergistically affect skeletal muscle.228 These findings suggest that while both resistance exercise (RE) and bisphosphonate treatment (an inhibitor of bone resorption) have a positive effect on bone homeostasis, only the RE treatment has a positive impact on both skeletal muscle and bone, particularly in those regions where the mechanical stress on the muscle system is enhanced. Similar findings were provided by Shackelford et al.,229 who compared bed rest plus RE with bed rest alone. The RE consisted of a vigorous loading program targeting multiple muscle groups for a period of 17 weeks. Voli - tional strength increased significantly compared to pretraining values in the RE group, whereas it declined in the bed rest control group. Losses in muscle mass across the muscle groups were significantly less than that which occurred for the control group, indicating that muscle atrophy was markedly retarded by the RE program. Interest - ingly, losses in BMD were significantly less in the RE group than in the controls. In fact, in the calcaneal region the BMD was actually increased somewhat over the pre-exposure values, indicating that RE can have a powerful impact on bone even under unloading states. These studies point to the potential positive value of RE programs, when carried out under appropriate training conditions, in reducing the deleterious effects of chronic unloading on muscle strength and muscle and bone mass. Sensory-Motor. As noted above, during the early stages of unloading (as seen in microgravity and bed rest), muscle group strength is compromised before significant muscle atrophy occurs, providing evidence that the ability to recruit motor units likely is compromised during the early stages of unloading states. In animal studies, locomo - tor patterns are compromised, as reported above. These observations indicate that the combined skeletal muscle and sensory-motor systems are highly integrated; dysfunction in either system has deleterious consequences when the systems are challenged following spaceflight. In the future, the two systems should be studied as a functional entity. Such research not only should examine muscle structure and performance but also should examine func - tion originating from different areas of the cortex, the activation of muscle motor units, and the properties of the neuromuscular junction, in order to dissect the complete pathways in the control of movement. Status of Countermeasures Animal Studies. Studies on animals have used a variety of manipulations to counteract atrophy responses induced by HU. The most physiologically relevant to the human resistance exercise program involves two different resis - tance loading paradigms: one employed a paradigm of repetitive isometric contractions; 230 the second used a sequenced combination of isometric, concentric, and eccentric muscular actions during each contraction cycle. 231 Both studies used an experimental strategy of studying the effectiveness of the training paradigm during the rapid state of atrophy, which occurs during the first 7 to 10 days of HU, during which the rodent gastrocnemius muscles atrophy by approximately 25 percent. The isometric-only paradigm was not fully successful in maintain - ing muscle mass. This result was attributed to imposing an insufficient amount of loading stimuli on the muscle. This interpretation was supported by the inability of the muscle to maintain sufficient signaling pathway stimuli to optimize protein synthesis capability.232 However, in the second study involving the integrated contraction mode
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