4
Muscle Physiology

INTRODUCTION

Human spaceflight results in loss of skeletal muscle mass, diminished strength and endurance, degraded motor performance, and increased susceptibility to reloading injury. The in-flight changes begin within a few days and increase in severity with time in space. Exercise countermeasures are marginally effective. Muscle deterioration remains a significant crew health and safety issue with a high potential to adversely affect missions, especially those involving extravehicular activities (EVAs) and transitions into a gravity environment such as Mars, as well as emergency egress. For example, the committee was informed by NASA that assisted egress was often required after long-duration missions. For emergency egress, astronauts need to be as fit as possible, and this includes both strength and aerobic capacity. Although prolonged intensive use of leg muscles may not be necessary in flight, it will be required on reentry and for future planetary exploration.

Maintaining muscle health requires elucidating underlying mechanisms and developing effective countermeasures through well-controlled, scientific flight investigations. Extensive attempts to obtain such data over the past decade through supplemental mission objectives rather than as primary investigations have not yielded definitive results (NASA, 1987, 1991, 1994, 1999). The absence of a formal process for countermeasure evaluation open to extramural input and the paucity of flight opportunities hamper in-flight validation of potential countermeasures cultivated in ground-based experiments. The in-flight exercise employed to date has afforded little protection against muscle wasting. Consensus is lacking on the specific exercise protocols required to maintain fitness, and the absence of a definition of fitness further compounds the problem.

The Strategy report (NRC, 1998) recommended that priority be given to research focusing on cellular and molecular mechanisms underlying muscle deterioration. Human and animal ground-based simulations should be exploited to investigate spaceflight effects on muscle mass, protein composition, myogenesis, fiber-type differentiation, and neuromuscular development. It is important to determine how muscle cells sense working length and the mechanical stress of gravity. The recommended approaches include analysis of signal transduction pathways for growth factors, stretch-activated ion



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Review of NASA’s Biomedical Research Program 4 Muscle Physiology INTRODUCTION Human spaceflight results in loss of skeletal muscle mass, diminished strength and endurance, degraded motor performance, and increased susceptibility to reloading injury. The in-flight changes begin within a few days and increase in severity with time in space. Exercise countermeasures are marginally effective. Muscle deterioration remains a significant crew health and safety issue with a high potential to adversely affect missions, especially those involving extravehicular activities (EVAs) and transitions into a gravity environment such as Mars, as well as emergency egress. For example, the committee was informed by NASA that assisted egress was often required after long-duration missions. For emergency egress, astronauts need to be as fit as possible, and this includes both strength and aerobic capacity. Although prolonged intensive use of leg muscles may not be necessary in flight, it will be required on reentry and for future planetary exploration. Maintaining muscle health requires elucidating underlying mechanisms and developing effective countermeasures through well-controlled, scientific flight investigations. Extensive attempts to obtain such data over the past decade through supplemental mission objectives rather than as primary investigations have not yielded definitive results (NASA, 1987, 1991, 1994, 1999). The absence of a formal process for countermeasure evaluation open to extramural input and the paucity of flight opportunities hamper in-flight validation of potential countermeasures cultivated in ground-based experiments. The in-flight exercise employed to date has afforded little protection against muscle wasting. Consensus is lacking on the specific exercise protocols required to maintain fitness, and the absence of a definition of fitness further compounds the problem. The Strategy report (NRC, 1998) recommended that priority be given to research focusing on cellular and molecular mechanisms underlying muscle deterioration. Human and animal ground-based simulations should be exploited to investigate spaceflight effects on muscle mass, protein composition, myogenesis, fiber-type differentiation, and neuromuscular development. It is important to determine how muscle cells sense working length and the mechanical stress of gravity. The recommended approaches include analysis of signal transduction pathways for growth factors, stretch-activated ion

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Review of NASA’s Biomedical Research Program channels, regulators of protein synthesis, and interactions of extracellular matrix and membrane proteins with the cytoskeleton. NASA’S CURRENT RESEARCH PROGRAM IN MUSCLE PHYSIOLOGY The total expenditure for the Biomedical Research and Countermeasure (BR&C) program in FY 1999 was about $2.805 million distributed among approximately 18 projects in the NASA Research Announcement (NRA) and National Space Biomedical Research Institute (NSBRI) programs (see Table 4.1). Current funding is distributed as approximately 60 percent for human studies and 40 percent for animal studies. About nine investigations with at least a partial emphasis on muscle physiology are supported by the NRA process ($1.801 million), and there are six main projects in the NSBRI program ($1.087 million). The human studies focus primarily on countermeasures, including the utility of lower-body negative pressure (LBNP) and resistance exercise. Three human flight protocols funded in FY 1999 involved a pre-post muscle biopsy study, a test of foot function during spaceflight, and an examination of protein turnover during spaceflight. Investigators in NASA centers, NSBRI, and NRA extramural programs collaborate on exercise testing during bed rest, rodent hindlimb unloading (exercise, pharmacological and hormonal countermeasures), calcium signaling in human skeletal muscle cultures, and gravity effects on sarcolemmal structure and function. Parabolic flights producing brief periods of reduced gravity are used to probe rapid changes in muscle cell membranes. The First Biennial Space Biomedical Investigators’ Workshop in 1999 demonstrated that excellent mechanistic research is being conducted on skeletal muscle that is in line with the 1998 Strategy report recommendations (NASA and USRA, 1999; NRC, 1998). The presentations included fundamental studies on fiber-type differentiation, multiple signaling pathways, hormonal regulation, and control of fiber-type gene expression. Investigators pursued novel genetic and biochemical strategies for combating muscle atrophy during rodent hindlimb unloading, such as growth hormone (GH)/insulin-like growth factor-I (IGF-I) gene therapy in genetically engineered mice and pharmacologic blockage of the ubiquitin degradation pathway. The inclusion of genetically modified organisms in the muscle research program is consistent with the Strategy report recommendation to exploit these animal models. The Fundamental Biology Research Program (FBRP) also supports through the NRA process muscle physiology studies that explore fundamental mechanisms. Five of these investigations probe the signaling of muscle atrophy, skeletal muscle artery adaptation, muscle growth and repair, insulin signal TABLE 4.1 Summary of Funding in FY 1999 for Muscle Physiology Subdisciplines   NRA   NSBRI   Subdiscipline Total ($ thousands) No. of Projects Total ($ thousands) No. of Projects Organism Ground 758 4 40 1 Flight 750 2 — — Countermeasure 293 3 — — Cell and molecular — — 1,047 8 Total 1,801 9 1,087 9

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Review of NASA’s Biomedical Research Program transduction in muscle, and mechanical signal transduction in countermeasures to muscle atrophy in rats subjected to hindlimb suspension unloading. Two of the studies involve muscle cultures to explore growth factors and tension-induced skeletal muscle growth and the effects of space travel on skeletal myofibers. In summary, research to date has been descriptive, and the next generation of experiments promises to elucidate mechanisms and identify effective countermeasures. The objectives of the muscle physiology investigations supported by NASA’s BR&C and FBRP are consistent with the Strategy report recommendation to determine how muscle cells sense the mechanical stress of gravity. In agreement with the Strategy report, continuing ground and flight studies of human and animals are necessary to advance the understanding of debilitation and maladaptation of muscle to spaceflight. PROGRAMMATIC BALANCE Balance of Subdiscipline Areas NASA muscle research ranges from basic studies of cells to studies of the whole organism. A portion of the funding is directed at countermeasure testing in human ground-based models. The collection of investigations represents an appropriate balance of cellular, molecular, and whole-animal mechanistic studies and human countermeasure evaluation. Balance of Ground and Flight Investigations There have been many excellent flight investigations, most recently on Spacelabs SLS-2 and Neurolab and on earlier Spacelab missions and rodent experiments carried in the Shuttle middeck. However, with closure of the Spacelab era, Mir-Shuttle missions, and the Bion program, flight opportunities have largely disappeared. Investigations will continue on Spacehab and Shuttle missions, but they will be much reduced in number and scope because the prime objective of these missions is currently International Space Station (ISS) construction rather than experimentation. Ground-based research will, therefore, necessarily predominate until ISS completion. Unfortunately, this hiatus in flight investigations further delays testing, validation, and implementation of countermeasures to ameliorate muscle wasting. Emphasis Given to Fundamental Mechanisms High priority is appropriately assigned to research on cellular and molecular mechanisms, utilizing ground-based models for human and animal studies. Most of the NSBRI-funded animal work pursues basic mechanisms. This emphasis agrees with the Strategy report recommendation to employ such models for testing and refining hypotheses seeking to understand the fundamental mechanisms of how workload is transduced into molecular signals regulating muscle properties. The muscle research program focuses on (a) elucidating the cellular and molecular mechanisms underlying muscle atrophy, weakness, faulty coordination, and delayed muscle soreness, (b) the use of appropriate ground-based models to investigate these problems, and (c) the process by which muscle senses working length and the mechanical stress of gravity. This emphasis is compatible with the Strategy report recommendations.

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Review of NASA’s Biomedical Research Program Utilization and Validation of Ground and Animal Models Continued research on muscle changes during human bed rest and rodent hindlimb unloading is justified for investigating basic mechanisms. These models simulate spaceflight changes very well for skeletal muscle. During bed rest, muscle responds positively to resistance training by partial amelioration of atrophy (Bamman et al., 1998). Given the limited access to spaceflight and low numbers of flight subjects, selection of muscle wasting countermeasures for flight will rely increasingly on results of well-controlled studies in ground-based models. The rodent model of hindlimb unloading, traditionally used for rats, also works well with normal and genetically altered mice. This provides valuable breadth to the investigations of mechanism, a point emphasized in the Strategy report. For humans, a buoyancy-equipped treadmill at the Ames Research Center (ARC) simulates the effects on locomotion at a reduced loading (0.38 g) environment of Mars. The centrifuge research facilities at ARC are serving the renewed interest in hypergravity investigations generated by the projected use of acceleration to simulate gravity on ISS and the potential use of artificial gravity as a countermeasure. Congruent with the Strategy report, the optimal balance of studies necessitates greater reliance on ground-based models, mostly involving animal studies, to elucidate basic mechanisms, refine hypotheses, and assess the efficacy of countermeasures because of the paucity of flight experiment opportunities. DEVELOPMENT AND VALIDATION OF COUNTERMEASURES The Extended Duration Orbiter Medical Project (EDOMP) succeeded the Detailed Supplemental Objective (DSO) Program when Shuttle flights became 16 days or longer (NASA, 1999). EDOMP continued the testing of countermeasures as secondary mission objectives with the goal of optimizing crew ability to maintain performance. As part of the EDOMP, in-flight aerobic exercise was proposed for evaluation. Appropriate data were sought, but the amounts and quality obtained were insufficient to reach unambiguous conclusions. In-flight cycle ergometry exercise ameliorated cardiovascular aerobic deconditioning but not skeletal muscle deterioration. Maximal exercise testing on the treadmill on landing day (DSO 476) was abandoned in 1988 because the test produced delayed-onset muscle soreness, whereas cycle ergometers did not have this effect (NASA, 1999). Currently, postflight testing is limited to minimizing risk of muscle injury. This avoidance philosophy leaves the muscle reloading injury problem unresolved. Countermeasures utilizing resistive lengthening muscle contractions hold promise, but their efficacy must be assessed during postflight transition to gravity loading. By and large, the supplemental objectives have not provided definitive answers to the muscle debilitation and countermeasure problem. The DSOs were specifically designed not to interfere with primary mission objectives, and unlike scientific investigations with fixed aims, the objectives of DSOs were changed frequently in response to the needs of the flight program. Exercise protocols are tailored to individuals. The lack of standard protocols across subjects greatly hampers distinguishing individual response from protocol variation. Following the Challenger accident, the exercise protocols emphasized the new requirement for unaided emergency egress. The uncontrolled nature of these studies and the small number of subjects contributed to the failed consensus on defining an optimal exercise regimen for maintaining muscle health. Medical Operations at the Johnson Space Center (JSC) directs muscle countermeasure studies for humans and regulates the repertoire of measures tested. Valuable input from extramural labs is lacking. This constrains the breadth of countermeasure development. A formal process is necessary to capitalize on the novel countermeasures expected to emerge from basic cellular and molecular research, a major

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Review of NASA’s Biomedical Research Program focus of the NSBRI Muscle Atrophy Team (NSBRI, 1998). Hypo- and hyperloading on treadmills, under investigation at ARC, represent promising countermeasures (NASA, 1997a). Although JSC is developing elaborate plans for executing countermeasure studies, the countermeasure program suffers from the lack of a formal mechanism for transitioning potential countermeasures from ground-based investigations to flight testing (NASA, 1998a). The current database is inadequate to define a strategy for meeting the goal of maintaining muscle health during and after long-term spaceflight. Maintenance of muscle health requires a multipronged approach. The Task Force Report on Countermeasures (NASA, 1997b) concluded that existing cycling, rowing, and treadmill exercise protocols did not maintain muscle mass and a positive nitrogen balance. However, the benefits of muscle stretching during these exercises cannot be overlooked. A side benefit of aerobic conditioning exercise is that leg muscles are stretched nearly through their full range. Ground-based studies have shown that muscle length regulation depends on the working range of movement. In these exercises, loading forces were insufficient to conserve muscle mass and prevent conversion from slow to fast isomyosin. The report recommends high priority for resistance exercise training and the use of existing exercise hardware in the short term. Appropriate countermeasures should maintain the mass of both skeletal and cardiac muscle and preserve motor skills and posture. Fitness standards, skill levels, and performance criteria should be defined. Countermeasure program design should foster compliance and ensure adequate nutrition. The Exercise Physiology Laboratory and Muscle Research Laboratories at JSC study mechanical loading and growth factor release as potential countermeasures for preserving muscle mass. There are pending ground studies of Russian exercise countermeasures and new resistance exercise countermeasures. As concluded in the Strategy report, LBNP coupled with resistance exercise should be tested for maintaining the microcirculation and strength of the muscle. NASA funded an LNBP investigation in 1999 as an advanced technology development countermeasure. A current NASA flight rule requires that some exercise take place on all missions of 11 days or longer duration. Current exercise regimens do not preserve sufficient muscle strength and are unlikely to prevent susceptibility to reloading injury. Countermeasure testing and validation targeting operationally relevant activities must be primary objectives on future spaceflight missions. Without this change or a formal process to translate potential countermeasures from both intra- and extramural laboratories, progress in solving muscle-related problems will fall further behind that required to support the continuous presence of humans in space. EPIDEMIOLOGY AND MONITORING Plans for Monitoring Crew Health and Fitness on the International Space Station A program of operational monitoring and validation of in-flight countermeasures will be implemented on the ISS (NASA, 1998a). Additional countermeasures may be added based on perceived need and scientific verification. Currently, mission length determines countermeasure requirements. The battery of proposed in-flight countermeasures includes exercise (treadmill, required cycle ergometer and resistive exercise, LBNP, and electromyostimulation). Although these interventions may have merit, the rationale for their inclusion is not solidly based on proven effectiveness for maintaining muscle health. The Environmental Physiology and Biophysics Laboratory will examine exercise intensity during extravehicular activity and monitor its effect on decompression sickness and muscle deconditioning. The Nutritional Biochemistry Laboratory tracks nutritional intake on selected flights and cooperates with operational medicine in deciding on individualized menus for flight.

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Review of NASA’s Biomedical Research Program International collaboration is evident in the Russian Motomir project to develop resistance exercise devices, and interactions utilizing the European Space Agency (ESA) Muscle Atrophy Research and Exercise System (MARES) in bed rest experiments. This hardware is slated for use on ISS. The International Space Life Sciences Working Group should coordinate these efforts. In the era of ISS, progress on preventing muscle debilitation will depend greatly on close coordination of medical operations monitoring of crew health and fitness with basic research flight investigations on humans. Assessment of the health of human skeletal muscle is proceeding on a variety of fronts, such as measuring fatigue and high-energy phosphates by magnetic resonance imaging (MRI) and spectroscopy. Increased attention to noninvasive monitoring of muscle function and health is in accord with the Strategy report recommendation to document more thoroughly the history of muscle use for astronauts. SUPPORT OF ADVANCED TECHNOLOGIES In the 1998 NRA, the BR&C program called for advanced technology development of implantable sensors, electronics, and software to monitor and analyze long-term nerve and muscle activities in unrestrained subjects as well as exercise apparatuses, which provide a means of quantifying the amount and pattern of work performed while controlling the levels and patterns of loading imposed on muscles, bones, and joints (NASA, 1998b). Documenting individual activity in flight by automated recording unburdens crew members from manual logging tasks. Moving in this direction is consistent with the Strategy report recommendation for improved documentation of individual activity before, during, and after flight that would greatly facilitate interpretation of results in muscle investigations. The Advanced Technology Development Division at ARC is perfecting quantitative computed tomography and simulated altered gravity locomotion under terrestrial conditions, using LBNP, upper-body positive pressure, and lower-body positive pressure. The Sensors 2000 program at ARC interacts with the NSBRI Technology Program to advance telemetric-based sensor systems for measuring muscle properties such as muscle activity, interstitial pressure, and blood flow. The goal is noninvasive or mildly invasive physiological monitoring of astronauts, utilizing instruments to display health status in flight. Additional advanced technologies are being pursued by NSBRI, NASA centers, and NRA extramural technology development programs. These include development of rapid freeze equipment to preserve muscle cell constituents for biochemical and molecular analyses, more ergonomic space suits to reduce muscle fatigue, and imaging instruments for documenting muscle deterioration and real-time assessment of countermeasure efficacy. Closer interaction between muscle researchers and engineers designing space suits is desirable. Coordination of the efforts of these programs promises to increase advances in muscle physiology. In agreement with the Strategy report, the development of new technologies for noninvasive monitoring of astronaut muscle physiology is being pursued with the goal of improved definition of the history of muscle use for clearer interpretation of the effects of spaceflight and the efficacy of countermeasures. SUMMARY Skeletal muscle deterioration remains a significant crew health, performance, and safety issue for spaceflight. Research to date has identified exercise as affording minimal protection. However, the Strategy report and the Countermeasures Task Force report point out that the lack of well-controlled,

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Review of NASA’s Biomedical Research Program scientific flight investigations prevents consensus on specific protocols for maintaining fitness. The Strategy report emphasizes that the paucity of flight experiment opportunities necessitates greater reliance on ground-based models for refining hypotheses and assessing countermeasure efficacy and implementation. In the era of ISS, progress on preventing muscle debilitation will depend greatly on the close coordination of medical operations monitoring of crew health and fitness with basic research flight investigations on humans. New technologies for noninvasive monitoring of muscle health during spaceflight are being developed. This should achieve the Strategy report goal of improved documentation of individual astronaut’s history of muscle use to control for intersubject variation and reduce uncontrolled variables. In the past, countermeasure testing and validation were not the primary objectives of spaceflight missions. Without manifesting them as high-priority goals, as recommended in the Strategy report, and instituting a formal process to incorporate potential countermeasures from both intra- and extramural laboratories, progress in solving muscle-related problems will fall further behind that required to support the continuous presence of humans in space. Congruent with the Strategy report, the muscle research program is putting great effort into understanding the basic cellular and molecular mechanisms for atrophy, weakness, and susceptibility to injury. Progress is being to be made in defining how muscle cells sense working length and load imposed by gravity through unloading and hypergravity ground-based studies of normal and genetically altered rodents, as recommended by the Strategy report. These studies are exploring hormones, growth factors, second messengers, and drugs that potentially translate into novel countermeasure applications. Additional studies called out in the Strategy report are needed to examine nerve and muscle repair, failed microcirculation, and fundamental aspects of myogenesis and regeneration because muscle damage and repair during spaceflight are inevitable in spite of rigorous safety practices and countermeasures. REFERENCES Bamman, M.M., M.S. Clarke, D.L. Feeback, R.J. Talmadge, B.R. Stevens, S.A. Lieberman, and M.C.J. Greenisen. 1998. Impact of resistance exercise during bed rest on skeletal muscle sarcopenia and myosin isoform distribution. Appl. Physiol. 84(1):157-163. National Aeronautics and Space Administration (NASA). 1987. Results of the Life Sciences DSOs Conducted Aboard the Space Shuttle 1981-1986. M.W. Bungo, T.M. Bagian, M.A. Bowman, and B.M. Levitan, eds. Houston, Tex.: NASA. NASA. 1991. Results of Life Sciences DSOs conducted Aboard the Space Shuttle 1988-1990. Houston, Tex.: NASA. NASA. 1994. Results of Life Sciences DSOs Conducted Aboard the Shuttle 1991-1993. Houston, Tex.: NASA. NASA. 1997a. Life Sciences Division Report. NASA Ames Research Center. Moffett Field, Calif.: NASA. NASA. 1997b. Task Force Report on Countermeasures: Final Report. Washington, D.C.: NASA. NASA. 1998a. International Space Station Medical Operations Requirements Document (ISS MORD), Baseline SSP 50260. Houston, Tex.: NASA. NASA. 1998b. NASA Research Announcement: Space Life Science—Research Opportunities in the Advanced Support Technology (AHST) Programs. NRA-98-HEDS-01. Washington, D.C.: NASA. NASA. 1999. Extended Duration Orbiter Medical Project Final Report 1989-1995. C.F. Sawin, G.R. Taylor, and W.L Smith, eds. NASA SP-534. Houston, Tex.: NASA. NASA and Universities Space Research Association (USRA). 1999. Proceedings of the First Biennial Biomedical Investigators’ Workshop, January 11-13, 1999, League City, Texas. Houston, Tex.: NASA and USRA. National Research Council (NRC), Space Studies Board. 1998. A Strategy for Research in Space Biology and Medicine in the New Century. Washington, D.C.: National Academy Press. National Space Biomedical Research Institute (NSBRI). 1998. Annual Report: October 1, 1997-September 30, 1998. Houston Tex. : NSBRI.