Weight, muscle and bone loss during space flight: another perspective

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1 DOI /s INVITED REVIEW Weight, muscle and bone loss during space flight: another perspective T. P. Stein Received: 11 July 2012 / Accepted: 5 November 2012 Ó Springer-Verlag Berlin Heidelberg 2012 Abstract Space flight is a new experience for humans. Humans adapt if not perfectly, rather well to life without gravity. There is a reductive remodeling of the musculoskeletal system. Protein is lost from muscles and calcium from bones with anti-gravity functions. The observed biochemical and physiological changes reflect this accommodative process. The two major direct effects of the muscle loss are weakness post-flight and the increased incidence of low back ache pre- and post-flight. The muscle protein losses are compromised by the inability to maintain energy balance inflight. Voluntary dietary intake is reduced during space flight by *20 %. These adaptations to weightlessness leave astronauts ill-equipped for life with gravity. Exercise, the obvious counter-measure has been repeatedly tried and since the muscle and bone losses persist it is not unreasonable to assume that success has been limited at best. Nevertheless, more than 500 people have now flown in space for up to 1 year and have done remarkably well. This review addresses the question of whether enough is now known about these three problems (negative energy balance, muscle loss and bone loss) for to the risks to be considered either acceptable or correctible enough to meet the requirements for a Mars mission. Keywords Space flight Weight loss Exercise Muscle loss Bone loss Energy balance Communicated by Nigel A.S. Taylor. T. P. Stein (&) Department of Surgery, University of Medicine and Dentistry of New Jersey, SOM, 2 Medical Center Drive, Stratford, NJ 08084, USA tpstein@umdnj.edu Background Space flight is a new experience for humans. Lack of gravity removes the force that causes water to gravitate toward the lower body; hence there are fluid shifts from the lower body to the upper body and accompanying cardiovascular changes. Tension on the weight bearing components of the musculo-skeletal system is greatly reduced, as is the work required for movement. The body responds by a reductive remodeling of the musculo-skeletal system. This has been a constant finding with space flight and groundbased models (bed rest and rodent hind limb unloading). The human space flight response is more complex than that found with ground-based models. Observations from space flight missions not only reflect the response to microgravity; there are other contributing factors to the overall response, specifically the constraints imposed by the complex environment needed to support life. Environmental factors are multiple and varied. They include cabin temperature, air composition, lighting, noise, food supply and the work goals of the mission. With increasing flight duration, other factors such as radiation exposure, social factors such as isolation effects and inter-personal dynamics are likely to become progressively more important. Many of these factors are difficult or impossible to control during space missions. Some are likely to vary from person to person, others are mission-dependent. An example of mission dependence is dietary intake. Figure 1 compares energy intake during the first 2 weeks of space flight for the three Skylab missions, and three shuttle missions. For the three Skylab missions the astronauts ate a required diet, for the three shuttle missions diet was ad-lib (Leach and Rambaut 1977; Stein 2000, 2001; Whedon et al. 1977). The Spacelab Life Sciences 2 (SLS2) shuttle mission was a repeat of the Spacelab Life Sciences 1

2 ENERGY INTAKE (kcal. kg -1.d -1 ) (SLS1) mission so as to provide enough subjects for statistical analyses. The Life and Microgravity Sciences (LMS) shuttle mission had a very high inflight exercise requirement; much less exercise was done on the SLS1/2 missions. Figure 1 shows that astronauts on the same mission appear to eat about the same amount of food. The observation suggests that mission specifics rather than subject-related factors affect dietary intake (Stein 2000, 2001). Objectives of this review DAYS SKYLAB 4 SKYLAB 3 SKYLAB 2 SLS1/2 LMS Fig. 1 Comparison of energy intake during the first 2 weeks of space flight for the three Skylab missions (Whedon et al. 1977), SLS1/2 (Stein et al. 1996) and the LMS shuttle mission (Stein et al. 1999b) There have been many reviews over the last 30 years of the human metabolic response to space flight. For the most part, the reviews focused on the biochemical/physiological aspects of the muscle and bone losses, assessing their potential for adverse effects on crew health and performance and the limited success of various proposed counter-measures for the muscle and bone losses. Some of the reviews have been commissioned by government agencies to assist in program development. There is a potential conflict of interest in these reviews because often the reviewers are content experts, tend to emphasize the importance of their areas of interest and sometimes are the beneficiary of future grants. (The same might be said of this review). That said, this review will argue that there is a lack of balance in the literature; the published reviews are unduly pessimistic. They focus almost exclusively on the numerous biochemical changes and physiological decrements found with the musculo-skeletal system found during space flight and its ground-based analogs. Even though the problems have been known for many years, progress over the last 40 years is questionable. Are some of the problems manageable with current protocols? Which problems require further work before humans can safely venture into space long-term? Reviewing a problem from a different perspective might provide new insights. In an era of limited resources, prioritization is necessary. Identifying a problem provides the rationale for further research. But to get a funding agency to pay for the research requires making a convincing case that there is a serious risk to the astronauts if the problem is not better understood and a counter-measure developed. There is a natural tendency by investigators to over-exaggerate the importance of their particular area of research. Thus, the literature is replete with warnings about the dire consequences of allowing problems to continue unresolved. These concerns might have been justified 40 years ago, but are they today? An unintended consequence has been to delay further human exploration of space beyond the Space Station era. Planning for new manned missions have moved ever further into the future for both financial and physiological reasons. Are the physiological concerns really valid? The basic fact is that more than 500 people have now flown in space for up to 1 year and have done remarkably well. Humans adapt if not perfectly, rather well to life without gravity. The observed biochemical and physiological changes reflect this accommodative process. There have been no life-threatening events. (In contrast there have been catastrophic engineering failures with both the US and Russian programs resulting in the death of 14 US and 4 Russian astronauts). Traditionally, there have been two ways of studying the human response to space flight. (i) From actual measurements, preferably inflight but for relatively invariant parameters such as body composition, immediately postflight data are acceptable. (ii) By the use of ground-based models, principally bed rest for humans and hind limb unloading for rats. There is now a third. The use of NASA s longitudinal study of astronaut health (LSAH) data base. The LSAH includes data from the earliest space missions (Apollo, Skylab) through the latest ISS missions. It is likely that use of the LSAH will assume increasing prominence as the data base increases and interest focuses on long-duration missions. The longitudinal study of astronaut health (LSAH) data base Nearly all reported studies on the human response to space flight, especially those pertaining to the muscle loss

3 % BODY WT LOSS DAYS IN ORBIT Fig. 2 Variability of weight loss on the ISS (Matsumoto et al. 2011; Smith et al. 2005) problem have been based on measurements made on a few astronauts on one mission. Because no two missions are alike, extrapolating the results of one mission to space flight in general is problematic. The ever-expanding LSAH data base makes comprehensive meta-analyses feasible and a better assessment of long-term risks as more data are accumulated on the ISS. Few measurements of changes in lean body mass or body protein content with space flight are available, so body weight is often used as a proxy for lean body mass. A number of investigators have used this data base and important findings have resulted. Three analyses are relevant to the topic of this review. (1) Factors associated with weight loss. Weight loss is highly variable. Figure 2 shows recent data from the ISS (Matsumoto et al. 2011; Smith et al. 2004). Does analysis of the LSAH contribute new information? (2) The type, incidence and severity of injuries to the musculoskeletal system incurred during space flight and (3) Are there long-term health-related problems post-flight? Risk from the weight/muscles loss The two major direct effects of the muscle loss that have been observed are weakness post-flight and the increased incidence of low back pain during and after flight. Most of the muscle loss occurs early in flight but continues at a lower rate, once the initial response is over (Matsumoto et al. 2011; Smith et al. 2004, 2005). After several months in space, the loss of muscle (and bone) can be substantial. The rate of body weight loss has been estimated as 2.4 %/ 100 days in space (Matsumoto et al. 2011). Details of how much of this weight loss is body fat and how much lean body mass are not known. Inflight, the most serious problem reported with the musculo-skeletal system is an increased risk of minor injuries secondary to muscle strain, usually manifesting as low back pain early in flight (Wing et al. 1991). A recent analysis of the available data in the LSAH data base by Scheuring gave quantitative data on the frequency, severity and possible causes of muscle injury during and after spaceflight (Scheuring et al. 2009). 219 injuries were attributed to the musculo-skeletal system (Table 1). Figures 3 and 4 show the location of the injuries and type of injury. None of the injuries can be considered to be serious for the inflight phase of mission. Hand injuries, abrasions and small lacerations were the most common injuries. Crew activity in the space-craft, such as moving between modules, exercise and EVA suit injuries were the most common causes. The rate of exercise-related muscle injuries was estimated to be per flight day (Scheuring et al. 2009). The rate did not increase with increased flight duration. For a 1-year mission with six astronauts, this translates into a probability of *7 injuries (Scheuring et al. 2009). The adaptation to weightlessness leaves astronauts illequipped for life with gravity when they return to earth. Astronauts returning from even short duration space flights of 1 2 weeks often experience muscle fatigue, weakness, a lack of coordination in movement and muscle soreness (Edgerton and Roy 1994; Riley et al. 1995; Stauber et al. 1990). Isometric, concentric and eccentric force development declines by as much as 30 %. The loss of muscle mass is responsible at least in part for the decrease in muscle strength and increased fatigability observed after space flight (Fitts et al. 2000; Grigorev et al. 1996; Leonard et al. 1983; Nicogossian 1994; Vorobyov et al. 1981). The post-flight muscle weakness has been a major focus of counter-measure programs. The available flight data show Table 1 The frequency of inflight injury has declined with space vehicle development (Scheuring et al. 2009) Program Total flight hours Incidence Mercury Gemini 1, Apollo 7, Skylab 12, Shuttle 1299, Apollo/Soyuz NASA/MIR 22, ISS 56,

4 Number of Injuries Crew Activity EVASuit Exercise that these problems do not seem to impair inflight performance or post-flight health status for missions lasting up to 1 year (Smith et al. 2005; Zwart et al. 2009). Three factors have been identified as contributing to the inflight muscle loss. Firstly, the reductive remodeling, secondly the level of pre-flight physical fitness and thirdly an inability to maintain energy balance inflight. The reductive remodeling Unknown LES/ACES Experiment Fig. 3 Injury sites during space flight (Scheuring et al. 2009) Number of Injuries Hand Foot Shoulder Arm Fig. 4 Injury frequency during space flight (Scheuring et al. 2009) The reductive remodeling of the musculo-skeletal system is an inevitable consequence of space flight. It has been found on all missions with humans and rodents and all groundbased models. Bed rest studies on subjects in energy balance have shown that the reduction in muscle size and strength is due to the decreased work load on the muscle. Wrist Leg Back EVA Neck Egress Trunk The major sites of the losses are the muscles and bones with anti-gravity functions that are located in the trunk and legs (Grigoriev and Egorov 1992; LeBlanc et al. 1995, 1996; Thornton and Rummel 1977; Whedon et al. 1977). These losses have occurred on both US and Russian missions despite attempts to ensure an adequate diet and a vigorous exercise regimen (Fitts et al. 2010; Kozlovskaya et al. 1990; LeBlanc et al. 1996; Leonard et al. 1983). In addition to a net loss of protein, there is a shift in myosin isoforms from slow to fast isoforms (Fitts et al. 2000, 2010; Trappe et al. 2009). Fast twitch fibers are primarily glycolytic and prone to fatigue with endurance. This metabolic shift toward increased reliance on glycolysis is found with space flight (Baldwin and Haddad 2001; Fitts et al. 2001), the rat hind limb suspension model (Fitts et al. 2000; Henriksen and Tischler 1988; Langfort et al. 1997) and bed rest (Acheson et al. 1995). Glycolysis is very effective for high intensity short duration acute activities, but if sustained output is needed, an energy profile where fat use is favored is desirable. And, as stated above, this adaptive response leaves the astronauts ill-suited for the return to earth. How serious a problem is this reduced capacity for work? A recent Soyuz landing illustrates the worst case scenario observed to date. After a 5 -month flight, the Soyuz re-entry vehicle landed somewhere in Kazakhstan. It took more than 5 h to recover the crew. For safety reasons, the crew had to get out of the landing capsule unassisted. It took them 5 h to accomplish what should have been a halfhour task. The misadventure provides strong evidence for impaired muscle functionality after Mars-like transit, demonstrating serious weaknesses in crew performance. All three crew members exhibited reduced capability, up to voluntary immobility. Nevertheless, the inconvenience was only temporary; the crew were rescued and transported to a state-of-the-art rehabilitation facility. Counter-measures for the reductive remodeling Exercise If a resistive exercise program is incorporated into the bed rest protocol, the muscle loss can be prevented (Bamman et al. 1998; Ferrando et al. 1997; Loehr et al. 2011). This does not appear to be the case with space flight. Exercise, the obvious counter-measure has been repeatedly tried and since the problem persists it is not unreasonable to assume that success has been limited at best (Fitts 1996; Trappe et al. 2009). Current counter-measures have focused on exercise. Defining success depends on what the designated endpoint is. What should the end-point be? The question is important. Much money, valuable crew time and resources have been spent on trying to develop effective counter-

5 measures. Is the target set unrealistically high for the overcompensated astronaut? Pre-flight astronauts are at peak physical fitness, many engage in strenuous exercise regimens preflight and so may have more to lose during a period favoring deconditioning. Data from the LSAH show that this does in fact occur. Matsumoto et al. used the LSAH data base to investigate which covariates predicted weight loss during spaceflight (Matsumoto et al. 2011). The data base used involved 246 astronauts from Skylab to Shuttle to ISS with a total of 514 missions (some astronauts flew more than one mission). The mean rate of weight loss was -2.4 % per 100 days in space (Matsumoto et al. 2011). As previously mentioned, the weight loss is highly variable (Fig. 3). Type and amount of pre-flight exercise were predictors of inflight weight loss. Astronauts who reported walking, the least stressful exercise as part of their pre-flight exercise program lost less body weight than those who engaged in more aggressive exercise regimens (body weight change: ± 0.19 %/100 days for exercise walkers, (n = 132) vs ± 0.14 %/100 days for other exercise modalities (n = 265, p = 0.05). Furthermore, pre-flight exercise sessions of greater than 1 h predicted greater weight loss during spaceflight (body weight change: ± 0.30 %/ 100 days for C1 h, n = 82 vs ± 0.12 %/100 days for \1 h, n = 315, p = 0.02) (Matsumoto et al. 2011). These findings are consistent with most astronauts being in an over-compensated state pre-flight; the nearer they are to a normal baseline, the less the weight loss. If an astronaut has more to lose to start with, should it be of concern if he or she lose more protein inflight and shows a degree of deconditioning? The human species is very adaptable. While the combination of adaptation and accommodation may not be perfect, modern humans thrive in just about every ecological niche available, including space flight. Adaptive mechanisms are numerous ranging from darker skin color in the tropics to increased oxygen carrying capacity at high altitude. Two adaptations are particularly relevant to space flight. The first is a decreased reliance on muscle power. The second pertains to energy balance. Acute minor defects in the adaptation/accommodation process can have serious chronic consequences. Does this also apply to space flight? Adaptation to decreased work requirement from the musculo-skeletal system is not a totally novel experience for humans. Over the last *200 years, humans have adopted from the lifestyle of our ancestral hunter-gatherers relying on muscle power to one where the work is done by machines and there has been a profound shift to a much more sedentary lifestyle. Space flight is further along this continuum than modern humans who drive to work at a desk job to be followed by an evening of watching television. How much is an open question. Humans seem to have adapted rather well to a decreased need for skeletal muscle by the millions on the ground and by the hundreds in space. The only major adverse performance-related consequences are an increased incidence of low back pain and a decreased capacity to perform physical work. Low back pain affects one in every three adults over the age of 50 (Manek and MacGregor 2005). For the general population, a sedentary lifestyle is also strongly associated with a pre-disposition toward developing obesity and hence metabolic syndrome. In turn metabolic syndrome is a major contributing factor to the chronic metabolic diseases such as type II diabetes, cardiovascular disease and some cancers. Nevertheless, metabolic syndrome is not likely to be a serious health risk factor for astronauts because once a mission is over, astronauts resume their normally active lives. For ground-based humans, decreased work capacity need not be a problem. Not so for astronauts where there is a requirement to maintain a certain level of physical fitness. An unanswered question here is, what is the level of fitness required to support the mission? For sure it should be sufficient to enable astronauts to complete extra-vehicular activities (EVA) and emergency egress with a margin of safety. Should it go beyond the need to minimize the inflight losses to facilitate recovery post-flight? Or should post-flight problems be treated after return to earth as part of the rehabilitation program? The answer to these questions should define the objectives and type of the inflight exercise program. Targeted dietary interventions Exercise is anabolic leading to an increase in protein mass. There is ample ground-based data showing that protein accretion with exercise can benefit from additional amino acids being available. During the past few years, there has been much interest in the use of dietary amino acids supplements to exercise to decrease the losses in muscle mass and strength observed after space flight. The published bed rest study results do not make a convincing case for amino acid/protein supplementation as countermeasure for lessening loss in protein mass during space flight (Blanc and Stein 2011). A single amino acid supplementation study with women showed no benefit from leucine supplementation (Trappe et al. 2007). Of the six published bed rest protein supplementation studies, three showed benefit, three did not. A recent development in evaluating protein requirements in humans may explain the discrepancy in the results. The current official RDA/ DRI (0.8 g/kg/d) could under-estimate requirements by as much as 40 % (Elango et al. 2008; Humayun et al. 2007). Interestingly, the three supplementation studies that showed benefits fed their test subjects a baseline protein

6 levels around the old RDA/DRI for protein i.e g/ kg/d. The three that did not show benefit gave the subjects a baseline protein intake of 1.0 or more g/kg/d of protein. Thus, the positive effects from protein supplementation observed in some of the studies might just reflect the benefits of supplementing a marginally adequate baseline protein intake during bed rest because of under-estimation of the actual RDA/RDI rather than a protective effect against bed rest-induced disuse (Blanc and Stein 2011). Although the precise protein requirements for long-duration space flight are not known, it is not likely to be substantially different from ground-based needs (Lane et al. 2007). The available dietary protein intake of astronauts is usually well above the current RDA/DRI (Table 2). Minor adjustments in amino acid/protein intakes are unlikely to significantly affect crew health. Endocrine interventions Endocrine factors are obviously involved in the regulation of muscle mass and power. Three of the major hormones known to regulate muscle mass are testosterone, cortisone and insulin. Insulin and testosterone are anabolic; cortisol is catabolic and usually associated with a stress response. Short term shuttle data suggest that testosterone is decreased, cortisol either increased or unchanged and insulin resistance increased. In the case of cortisol, if there is an increase, it does not seem to apply to all astronauts and in the case of insulin, the measurements are indirect being based on urinary C-peptide excretion (Ferrando et al. 1999, 2002; Stein 2001). However, data from short term missions are likely to be complicated by the acute adaptive changes that occur as the body adjusts to fluid shifts, disturbed circadian rhythms, loss of tension on the weight bearing muscles, the novel diet and the emotional response to an exhilarating experience. Data from long-duration missions are more informative about adaptation/accommodation to space flight. The primary questions here are: (i) what are the changes with long-duration space flight (ii) what would the interventions be to reduce the rate of muscle deconditioning? A recent study by Smith and colleagues reviewed all the data for testosterone and cortisol from the early long-duration Skylab flights through the shuttle missions to the more recent ISS missions resolves the question for testosterone and cortisol. Essentially, they found no change with either testosterone or cortisol with long-duration space flight (Smith et al. 2012). No matter what form of testosterone (total, free, or bioavailable) was measured, or with which method, there was clearly no change during long-duration space flight (Smith et al. 2012). Although there was much scatter in the serum cortisol data, it too did not change with long-duration space flight. The phrase no change implies that there were no detectable change within the limits of measurement. There is noise in the measurement because of limiting sampling (maximum of only five inflight data points) and inadequate dietary intake inflight which could complicate data interpretation. The implication is that failure to detect any change precludes developing an endocrine-based intervention to attenuate the muscle loss because the experimental data indicate no change. In fact there might be change, either too small to detect, or the changes occurring at different times during the day from when the samples were collected. Much more data would be required to test for this and there is no guarantee that anything useful would be found. The default position is that the body has adapted very well to life without gravity. Either way, the Smith data strongly suggest that when compared to other approaches for maintaining health during long-duration space flight, endocrine studies are not likely to be as productive as investigating exercise modalities, nutrition etc. An interesting point from the Smith study was the discrepancy with bed rest and animal models. Long-duration space flight showed no change in cortisol, whereas there was an increase with bed rest (Smith Table 2 Energy and protein intake during space flight Mission Protein intake Adequate? Energy intake Adequate? Reference G protein kg -1 d -1 Kcal kg -1 d -1 Apollo 1.09 ± 0.05 Adequate 24.9 ± 1.0 Inadequate Lane and Rambaut (1994) Skylab ± 0.02 Adequate 39.2 ± 0.7 Adequate Leach and Rambaut (1977) Skylab ± 0.12 Adequate 43.3 ± 4.8 Adequate Leach and Rambaut (1977) Skylab ± 0.02 Adequate 43.5 ± 0.7 Adequate Leach and Rambaut (1977) Shuttle, early 1.01 ± 0.10 Marginal 27.0 ± 1.9 Inadequate Lane and Rambaut (1994) SLS1/ ± 0.06 Adequate 34.4 ± 3.1 Adequate Stein (2001) LMS 0.81 ± 0.08 Inadequate 24.4 ± 2.4 Inadequate Stein et al. (1999b) MIR 1.13 ± 0.19 Adequate 26.1 ± 2.4 Inadequate Stein et al. (1999a) ISS 1.37 ± 0.12 Adequate 30.7 ± 2.5 Inadequate Smith et al. (2005)

7 et al. 2012). Apparently, space flight is a more comfortable situation than lying in bed with a downward tilt for weeks at a time. Results from ground-based models are data from model systems that have to be verified by flight experiments. Low back pain The other major effect on skeletal muscle is an increased susceptibility to transient low back pain (Scheuring et al. 2009). At the worst, low back pain will compromise mobility and at best subject the individual to discomfort. Three approaches are actively being pursued for the inflight situation. Counter measures low back pain 1. Engineering modification to the design of the space vehicle. There has been success here. Analysis of the LSAH data base shows a progressive reduction in the incidence of low back pain from Skylab to the ISS. Scheuring attributed this trend to improvements in cabin design (Scheuring et al. 2009). 2. Exercise paradigms based on the results of bed rest studies. Aerobic or low load exercise is not as effective in maintaining muscle size during bed rest as high load exercise (Suzuki et al. 1994; Zange et al. 2009). Low load exercise (1 9 body weight) does not prevent the atrophy of the spinal extensors during long-term bed rest but higher loads (1.5 9 body weight) do. Complicating result interpretation is variability with type of exercise (Akima et al. 2003; Alkner and Tesch 2004; Armbrecht et al. 2010; Belavy et al. 2009; Shackelford et al. 2004). 3. Supplementing exercise with vibration. Whole body vibration increases muscle activation (Cochrane et al. 2009; Roelants et al. 2006), so it is possible that this might be additive to exercise. Indeed, structural studies have shown that high load resistive exercise with whole body vibration reduces the changes in the cross sectional areas of extensor and psoas muscles (Belavy et al. 2008). A recent bed rest study addressed the question whether high load resistive exercise plus vibration was better than resistive exercise alone in reducing the lumbar muscle CSA changes and the incidence of lower back pain after 60 days of bed rest (Armbrecht et al. 2010; Belavy et al. 2010). The exercise counter-measure was successful in reducing the muscle cross sectional area losses, but there was no extra benefit from vibration. Rather disconcertingly, exercise subjects reported an increased incidence of low back pain during the first week of bed rest (Belavy et al. 2010). 4. A caveat. The number of subjects was small, the instrumentation for testing vibration (and exercise) cumbersome and these might have contributed to the null result. The other point to be aware of is that the lower back pain is transitory, and only seems to be a minor inconvenience. Is development of a countermeasure for something that is transitory, manageable and not as health threatening as some of the other adverse effects of long-duration flight might be (e.g. radiation, social factors) cost effective? On the ground, non-prescription drugs are often helpful! The energy deficit The energy requirements for space flight are *1.7 9 RMR (Lane 1992; Smith et al. 2005; Stein et al. 1999b; Zwart et al. 2009). A consistent finding with space flight has been that astronauts fall short of this goal. Smith reported that the average intake on the ISS was *80 % of recommended (Smith et al. 2005; Zwart et al. 2009). For small (\*10 %) energy intake deficits the body adapts by reducing protein turnover, substrate cycling, involuntary physical activity etc. (Stein 2001). For larger energy deficits such as those found with the ISS, adaptation is not possible. The weight loss is chronic, in the long-term incompatible with health and eventually life-threatening. From a meta-analysis of data in the LSAH data base, Matsumoto et al. concluded that if weight loss continued at the rate currently observed on the ISS, clinically significant weight loss (10 % or more) would occur in the second year of a future long-term missions (Matsumoto et al. 2011). A loss of *30 % is life-threatening. The inflight energy deficit is enough to negatively impact protein metabolism, both from the ability to maintain protein turnover and to minimize the protein losses from the reductive remodeling. With bed rest, a % decrease in the whole body protein turnover rate is found and is due to a *50 % decrease in muscle protein synthesis (Ferrando et al. 1996; Gibson et al. 1987). A much greater decrease *50 % was found with long-duration space flight on the Russian Space Station, MIR. The reason was that energy intake was 25 % lower inflight (Stein et al. 1999a). Increasing inflight exercise without a corresponding increase in intake appears to exacerbate the negative protein balance. Figure 5 compares energy intake, expenditure, balance and nitrogen balance for the two very similar shuttle missions, SLS1/2 and LMS. The periods of comparison are the first 9/12 days on SLS1/2 (Stein et al. 1996) and the first 12 days for LMS (Stein 2001; Stein et al. 1999b). The same

8 Energy deficits counter measures Fig. 5 Comparison of energy intake, expenditure and balance and nitrogen balance during space flight on the SLS1/2 and LMS shuttle missions (Stein et al. 1996, 1999b). Data are mean ± SEM orbiter (Columbia) in the same configuration (with the Space Lab module) was used for both missions. Both missions were very busy missions with science as the primary mission objective. Crew members were very active moving about the cabin throughout the day doing investigator originated experiments. The principal difference was that LMS had extensive exercise requirements as part of the scientific program. Dietary intake was not regulated on either mission. The SLS1/2 astronauts did not exercise, ate more and were in approximate energy balance. On LMS, energy intake failed to meet extra energy needs of the exercise program and the protein loss was much greater (Fig. 5) (Stein 2000). A high rate of aerobic exercising is extremely costly in energy needs (Convertino 1990). Interestingly, a recent 60-day bed rest study on two groups of women replicated the flight observations (Bergouignan et al. 2010). One group followed a rigorous exercise regimen during bed rest; the other (control) group did not. The control group was in slight negative energy balance, the exercised group was in marked negative energy balance during bed rest. They concluded that humans can adjust energy intake to meet needs in the absence of exercise but not with exercise. Testing exercise modalities and equipment is a very high priority on the ISS. But testing an exercise program when energy balance is negative does not provide a valid assessment of the effectiveness of the exercise program in preventing muscle loss and weakness because of complex interactions between the anabolic effects of exercise and the limited availability of energy to support it. This cannot be done unless the negative energy balance problem is corrected. Thus, we really do not know how successful the inflight exercise programs are. They might be very effective if the astronauts were in energy balance. Is it reasonable to expect human physiology to fully adapt? Based on ground-based population observations, it seems highly improbable that the inability to maintain energy balance will self-correct. The food supply has changed dramatically over the last 50 years and there have been clinically significant effects. Recent epidemics of a number of otherwise unrelated diseases are now attributed to a consequence of a mismatch between the world we live in today and the Paleolithic bodies we have inherited. With the combination of lifestyle and diet changes, for many people there is an inability to regulate energy balance. The hypothesis provides a rational explanation for such well-known diseases as cardiovascular disease, diabetes and obesity. The central problem is obesity. Obesity is the end result of an inability to maintain energy balance. The prevalence of obesity in the US, as defined by proportion of adults with BMI s greater than 30 has increased from less than 20 % in 1980 to more than 30 % by This time period is far too short for genotypic changes; the changes are phenotypic. Normally dietary intake fluctuates around energy requirements; long-term balance is effected by a complex and incompletely understood combination of effects on the intake side, (appetite regulation) and the energy expenditure side (substrate cycling, brown adipose tissue thermogenesis, non-exercise-induced thermogenesis, physical activity etc.). In contrast to the elegant reductive remodeling of the anti-gravity muscles, metabolism has not accommodated as well. Energy intake during space flight fails to balance expenditure. To this author, this does not seem like an insurmountable problem even though the underlying mechanisms are poorly understood (Bergouignan et al. 2010; Westerterp 2010). The energy costs of spaceflight are reasonably well known, RMR (Lane 1992; Smith et al. 2005; Stein et al. 1999b; Zwart et al. 2009) as are the overall nutritional requirements (Lane et al. 2007). Some adjustment on an individual basis might be required for astronauts involved in extensive extra-vehicular activities (EVA). On the ISS daily dietary intake is routinely monitored so it should not be too difficult to estimate an astronauts energy balance on a weekly basis and require supplementary energy intake on an as needed basis. Bone: counter-measures Like muscle, the inflight losses of bone occur in spite of aggressive exercise regimens with a variety of very expensive devices (Cavanagh et al. 2005; Keyak et al. 2009; Lang et al. 2004). There are two conclusions that can be drawn. (1) Further development of exercise regimens

9 and equipment is not likely to be very productive and cost effective. (2) As discussed above for the muscle problem and below for the bone problem, they are manageable. For bone, there are options other than more or different exercise. On the ground, much success with millions of women has been obtained by giving a bisphosphonate to reduce the post-menopausal resorption of bone. Bisphosphonates have also been successful with bed rest (LeBlanc et al. 2007). There is currently a bisphosphonate treatment study on the ISS. This is a crucial experiment. If even partial success is achieved, the already low inflight risks from the bone loss would be further reduced. The level of risk from the reductive remodeling of the musculo-skeletal system could be managed by a combination of bisphosphonates, some exercise, an adequate diet and care to avoid heavy lifting. Bone loss will be a problem after return to 1 g from very long missions. Recovery is a very slow process; it takes much longer than the actual duration of the mission (Sibonga et al.; Loehr et al.; Sibonga et al. 2007). But, however slow the recovery of lost bone is in a rehabilitation center after a mission it will not impact the actual mission. After return to earth, extensive rehabilitation facilities are available. So, it might be a much more practical option to focus on limiting the inflight bone loss enough to minimize any inflight risk rather than try to prevent the inflight bone loss (Payne et al. 2007). Osteoporosis is a formidable problem affecting millions of women (and some men). It is the objective of major research efforts by government health agencies. The relatively small amounts of money spent looking at disuse bone loss in a very small number of subjects (astronauts) should not be sold to the public as a promise by the space program to advance the treatment of osteoporosis. Targeting counter-measures to the mission Counter-measures are designed to keep the astronauts as close as possible to their pre-flight status. How would the inflight weight loss look if it were expressed as percentage of body weight 6 or 12 months post-flight? As previously discussed, analysis of data in the LSAH suggests it would be smaller (Matsumoto et al. 2011). Rather than aim for maintaining pre-flight status, inflight counter-measures should be targeted at maintaining a level of fitness to: (i) support EVA activity and (ii) meet the requirements of the post-flight phase. The former does not appear to be a problem. An important factor here has been progressively decreasing the work load required for EVA activity by improvements in suit design. While some exercise should be done throughout the mission, limiting an aggressive exercise program to the last couple of months of a long-duration mission might lessen the impact of exercise on energy balance inflight and strengthen the muscles before landing. For the post-flight period, there are four scenarios depending on the mission involved. (1) Return to earth, (2) a Mars landing (1/3 g), (3) a return to the Moon and (4) an asteroid landing. (1) Return to earth is not a problem; there are already excellent and well-tested facilities in place for astronaut rehabilitation. (2) Current Space Agency plans propose a Mars landing far into the future 2040 or even later. Who knows how far science will have progressed in the intervening years? There is no urgency to continue to evaluate late 20th technology for an event that is not likely to occur until the mid 21st century. (3) For a moon landing with an extended stay, there is effectively no gravity. Humans have already have had experience with the problems encountered on the moon nearly half a century ago. The space suits were very cumbersome and restricted mobility and flexibility. Much improvement has been made with EVA space suits in the intervening half century so this should improve both comfort and the ability to work (Scheuring et al. 2009). (4), Likewise for an asteroid landing at the time of writing, NASA s preferred immediate short term (* ) objective because there is no gravity. Conclusions 1. A case can be made for down-grading the inflight exercise program relative to the other problems for long-duration space flight. Some exercise is needed, but maybe not so much as currently planned? How much is the question? Counter-measures are designed to keep the astronauts as close as possible to their preflight status. Are we over-estimating the inflight muscle losses? If the inflight weight loss was expressed as percentage of the body weight 6 or 12 months pre- or post-flight it would probably be smaller than when it is compared to the immediate pre-flight period (Matsumoto et al. 2011). 2. An increase in the incidence of low back pain occurs. Given that ground treatments are not very successful, the problem is not disabling, is transient and selfresolving the problem is manageable. Attempts to develop a counter-measure are not likely to be cheap or productive, but success could have considerable benefits to society! 3. Because of the underlying energy deficits, inflight exercise regimens have not been properly tested. 4. As missions become longer, the inability to maintain energy balance will become progressively more important. Solving it is not a sophisticated technical

10 problem; a combination of dietary record keeping and monitoring body weight procedures already available and commercially available energy bars should suffice. 5. Exaggerating the potential negative consequences of space flight-induced changes in the skeletal muscle has been counter-productive. It has raised concerns with legislators that may be unnecessary about the safety of the human space program and has led governments to delay into the far future the mission that is of real interest to the public, a Mars landing. If the mission is not going to be for another years, why spend money now? The net result has been a loss interest in the human space program. References Acheson KJ, Decombaz J, Piguet-Welsch C, Montigon F, Decarli B, Bartholdi I, Fern EB (1995) Energy, protein, and substrate metabolism in simulated microgravity. Am J Physiol (Regul Integ) 269:R252 R260 Akima H, Ushiyama J, Kubo J, Tonosaki S, Itoh M, Kawakami Y, Fukuoka H, Kanehisa H, Fukunaga T (2003) Resistance training during unweighting maintains muscle size and function in human calf. Med Sci Sports Exerc 35: Alkner BA, Tesch PA (2004) Knee extensor and plantar flexor muscle size and function following 90 days of bed rest with or without resistance exercise. Eur J Appl Physiol 93: Armbrecht G, Belavy DL, Gast U, Bongrazio M, Touby F, Beller G, Roth HJ, Perschel FH, Rittweger J, Felsenberg D (2010) Resistive vibration exercise attenuates bone and muscle atrophy in 56 days of bed rest: biochemical markers of bone metabolism. Osteoporos Int 21: Baldwin KM, Haddad F (2001) Effects of different activity and inactivity paradigms on myosin heavy chain gene expression in striated muscle. J Appl Physiol 90: Bamman MM, Clarke MS, Feeback DL, Talmadge RJ, Stevens BR, Lieberman SA, Greenisen MC (1998) Impact of resistance exercise during bed rest on skeletal muscle sarcopenia and myosin isoform distribution. J Appl Physiol 84: Belavy DL, Hides JA, Wilson SJ, Stanton W, Dimeo FC, Rittweger J, Felsenberg D, Richardson CA (2008) Resistive simulated weightbearing exercise with whole body vibration reduces lumbar spine deconditioning in bed-rest. Spine 33:E121 E131 Belavy DL, Miokovic T, Armbrecht G, Rittweger J, Felsenberg D (2009) Resistive vibration exercise reduces lower limb muscle atrophy during 56-day bed-rest. J Musculoskelet Neuronal Interact 9: Belavy DL, Armbrecht G, Gast U, Richardson CA, Hides JA, Felsenberg D (2010) Countermeasures against lumbar spine deconditioning in prolonged bed rest: resistive exercise with and without whole body vibration. J Appl Physiol 109: Bergouignan A, Momken I, Schoeller DA, Normand S, Zahariev A, Lescure B, Simon C, Blanc S (2010) Regulation of energy balance during long-term physical inactivity induced by bed rest with and without exercise training. J Clin Endocrinol Metab 95: Blanc S, Stein TP (2011) Does protein supplementation prevent muscle disuse atrophy and loss of strength? Crit Rev Food Sci 11: Cavanagh PR, Licata AA, Rice AJ (2005) Exercise and pharmacological countermeasures for bone loss during long-duration space flight. Gravit Space Biol Bull 18:39 58 Cochrane DJ, Loram ID, Stannard SR, Rittweger J (2009) Changes in joint angle, muscle-tendon complex length, muscle contractile tissue displacement, and modulation of EMG activity during acute whole-body vibration. Muscle Nerve 40: Convertino VA (1990) Physiological adaptations to weightlessness: effects on exercise and work performance. Exerc Sport Sci Rev 18: Edgerton VR, Roy RR (eds) (1994) Neuromuscular adaptation to actual and simulated spaceflight. American Physiological Society, Bethesda Elango R, Ball RO, Pencharz PB (2008) Individual amino acid requirements in humans: an update. Curr Opinion Clin Nutr Metab Care 11:34 39 Ferrando AA, Lane HW, Stuart CA, Davis-Street J, Wolfe RR (1996) Prolonged bed rest decreases skeletal muscle and whole body protein synthesis. Am J Physiol (Endo Metab) 270:E627 E633 Ferrando AA, Tipton KD, Bamman MM, Wolfe RR (1997) Resistance exercise maintains skeletal muscle protein synthesis during bed rest. J Appl Physiol 82: Ferrando AA, Stuart CA, Sheffield-Moore M, Wolfe RR (1999) Inactivity amplifies the catabolic response of skeletal muscle to cortisol. J Clin Endocrinol Metab 84: Ferrando AA, Paddon-Jones D, Wolfe RR (2002) Alterations in protein metabolism during space flight and inactivity. Nutrition 18: Fitts RH (1996) Muscle fatigue: the cellular aspects. Am J Sports Med 24:S9 S13 Fitts RH, Riley DR, Widrick JJ (2000) Physiology of a microgravity environment invited review: microgravity and skeletal muscle. J Appl Physiol 89: Fitts RH, Riley DR, Widrick JJ (2001) Functional and structural adaptations of skeletal muscle to microgravity. J Exp Biol 204: Fitts RH, Trappe SW, Costill DL, Gallagher PM, Creer AC, Colloton PA, Peters JR, Romatowski JG, Bain JL, Riley DA (2010) Prolonged space flight-induced alterations in the structure and function of human skeletal muscle fibres. J Physiol 588: Gibson JN, Halliday D, Morrison WL, Stoward PJ, Hornsby GA, Watt PW, Murdoch G, Rennie AJ (1987) Decrease in human quadriceps muscle protein turnover consequent upon leg immobilization. Clin Sci 72: Grigorev AI, Larina IM, Noskov VB, Menshtkin VV, Natochkin IV (1996) Effect of short- and long-time space flights on some biochemical and physical-chemical parameters of cosmonauts blood. Aviakosm Ekolog Med 30:4 10 Grigoriev AI, Egorov AD (1992) Physiological aspects of adaptation of main human body systems during and after spaceflights. Adv Space Biol Med 2:43 82 Henriksen EJ, Tischler ME (1988) Glucose uptake in rat soleus: effect of acute unloading and subsequent reloading. J Appl Physiol 64: Humayun MA, Elango R, Ball RO, Pencharz PB (2007) Reevaluation of the protein requirement in young men with the indicator amino acid oxidation technique. Am J Clin Nutr 86: Keyak JH, Koyama AK, LeBlanc A, Lu Y, Lang TF (2009) Reduction in proximal femoral strength due to long-duration spaceflight. Bone 44: Kozlovskaya IB, Barmin VA, Stepantsov VI, Kharitonov NM (1990) Results of studies of motor functions in long-term space flights. Physiologist 33:S1 S3 Lane HW (1992) Energy requirements for space flight. J Nutr 122:13 18

11 Lane HW, Rambaut PC (1994) Nutrition. In: Nicogossian AE, Huntoon C, Pool SL (eds) Space physiology and medicine, chap 15. Lea and Febiger, Philadelphia, pp Lane HW, Kloeris V, Perchonok M, Szwart S, Smith SM (2007) Food and nutrition for the moon base. Nutr Today 42: Lang T, LeBlanc A, Evans H, Lu Y, Genant H, Yu A (2004) Cortical and trabecular bone mineral loss from the spine and hip in longduration spaceflight. J Bone Miner Res 19: Langfort J, Zernicka E, Mayet-Sornay MH, Dubaniewicz A, Desplanches D (1997) Effects of acute and chronic hindlimb suspension on sensitivity and responsiveness to insulin in the rat soleus muscle. Biochem Cell Biol 75:41 44 Leach CS, Rambaut PC (1977) Biomedical responses of the Skylab crewmen: an overview. In: Dietlein LF (ed) Biomedical results from Skylab (NASA SP-377). US Govt Printing Office, Washington, pp LeBlanc A, Rowe R, Schneider V, Evans H, Hedrick T (1995) Regional muscle loss after short duration spaceflight. Aviat Space Environ Med 66: LeBlanc AD, Schneider VS, Shakelford L, West V, Oganov A, Bakulin L, Voronin L (1996) Bone mineral and lean tissue loss after long duration space flight. J Bone Miner Res 11:S323 LeBlanc AD, Spector ER, Evans HJ, Sibonga JD (2007) Skeletal responses to space flight and the bed rest analog: a review. J Musculoskelet Neuronal Interact 7:33 47 Leonard JI, Leach CS, Rambaut PC (1983) Quantitation of tissue loss during prolonged space flight. Am J Clin Nutr 38: Loehr JA, Lee SM, English KL, Sibonga J, Smith SM, Spiering BA, Hagan RD (2011) Musculoskeletal adaptations to training with the advanced resistive exercise device. Med Sci Sports Exerc 43: Manek NJ, MacGregor AJ (2005) Epidemiology of back disorders: prevalence, risk factors, and prognosis. epidemiology of back disorders: prevalence, risk factors, and prognosis. Curr Opin Rheumatol 17: Matsumoto AK, Storch KJ, Stolfi A, Mohler S, Frey MA, Stein TP (2011) Weight loss in humans in space. Aviat Space Environ Med 82: Nicogossian AE (1994) Microgravity simulations and analogues. In: Nicogossian AE, Huntoon CL, Pool SL (eds) Space physiology and medicine, Chap 20. Lea and Febiger, Philadelphia, pp Payne MW, Williams DR, Trudel G (2007) Space flight rehabilitation. Am J Phys Med Rehabil 86: Riley DA, Thompson JL, Prippendorf B, Slocum GR (1995) Review of spaceflight and hindlimb suspension unloading induced sarcomere damage and repair. Bas Appl Myol 5: Roelants M, Verschueren SM, Delecluse C, Levin O, Stijnen V (2006) Whole-body-vibration-induced increase in leg muscle activity during different squat exercises. J Strength Cond Res 20: Scheuring RA, Mathers CH, Jones JA, Wear ML (2009) Musculoskeletal injuries and minor trauma in space: incidence and injury mechanisms in U.S. astronauts. Aviat Space Environ Med 80: Shackelford LC, LeBlanc AD, Driscoll TB, Evans HJ, Rianon NJ, Smith SM, Spector E, Feeback DL, Lai D (2004) Resistance exercise as a countermeasure to disuse-induced bone loss. J Appl Physiol 97: Sibonga JD, Evans HJ, Sung HG, Spector ER, Lang TF, Oganov VS, Bakulin AV, Shackelford LC, LeBlanc AD (2007) Recovery of spaceflight-induced bone loss: bone mineral density after longduration missions as fitted with an exponential function. Bone 41: Smith SM, Davis-Street JE, Fesperman JV, Smith MD, Rice BL, Zwart SR (2004) Nutritional status changes in humans during a 14-day saturation dive: the NASA extreme environment mission operations V project. J Nutr 134: Smith SM, Zwart SR, Block G, Rice BL, Davis-Street JE (2005) The nutritional status of astronauts is altered after long-term space flight aboard the International Space Station. J Nutr 135: Smith SM, Heer M, Wang Z, Huntoon CL, Zwart SR (2012) Longduration space flight and bed rest effects on testosterone and other steroids. J Clin Endo Metab 97: Stauber WT, Clarkson PM, Fritz VK, Evans WJ (1990) Extracellular matrix disruption and pain after eccentric muscle action. J Appl Physiol 69: Stein TP (2000) The relationship between dietary intake, exercise, energy balance and the space craft environment. Pflugers Arch 441:R21 R31 Stein TP (2001) Nutrition in the space station era. Nutr Res Rev 14: Stein TP, Leskiw MJ, Schluter MD (1996) Diet and nitrogen metabolism during spaceflight on the shuttle. J Appl Physiol 81:82 97 Stein TP, Leskiw MJ, Schluter MD, Donaldson MR, Larina I (1999a) Protein kinetics during and after long term space flight on MIR. Am J Physiol (Endo and Metab) 276:E1014 E1021 Stein TP, Leskiw MJ, Schluter MD, Hoyt RW, Lane HW, Gretebeck RE, LeBlanc AD (1999b) Energy expenditure and balance during space flight on the shuttle: The LMS mission. Am J Physiol (Endo and Metab) 276:R1739 R1748 Suzuki Y, Kashihara H, Takenaka K, Kawakubo K, Makita Y, Goto S, Ikawa S, Gunji A (1994) Effects of daily mild supine exercise on physical performance after 20 days bed rest in young persons. Acta Astronaut 33: Thornton W, Rummel J (1977) Muscular deconditioning and its prevention in space flight (NASA SP-377). Biomedical results from Skylab. US Government Printing Office, Washington, DC, pp Trappe S, Creer A, Slivka D, Minchev K, Trappe T (2007) Single muscle fiber function with concurrent exercise or nutrition countermeasures during 60 days of bed rest in women. J Appl Physiol 103: Trappe S, Costill D, Gallagher P, Creer A, Peters JR, Evans H, Riley DA, Fitts RH (2009) Exercise in space: human skeletal muscle after 6 months aboard the International Space Station. J Appl Physiol 106: Vorobyov EI, Gazenko OG, Genin AM, Egorov AD (1981) Medical results of Salyut-6 manned space flights. Biol Aviakosm Med 15:18 22 Westerterp KR (2010) Physical activity, food intake, and body weight regulation: insights from doubly labeled water studies. Nutr Rev 68: Whedon G, Lutwak L, Rambaut P, Whittle M, Smith M, Read J, Leach C, Staedler CR, Sanford DD (1977) Mineral and nitrogen metabolic studies, Experiment M071. In: Johnson RS, Dietlein LF (eds) Biomedical results from Skylab (NASA SP-377), Section 3. NASA, Washington, pp Wing PC, Tsang IK, Susak L, Gagnon F, Gagnon R, Potts JE (1991) Back pain and spinal changes in microgravity. Orthop Clin N Am 22: Zange J, Mester J, Heer M, Kluge G, Liphardt AM (2009) 20-Hz whole body vibration training fails to counteract the decrease in leg muscle volume caused by 14 days of 6 degrees head down tilt bed rest. Eur J Appl Physiol 105: Zwart SR, Oliver SA, Fesperman JV, Kala G, Krauhs J, Ericson K, Smith SM (2009) Nutritional status assessment before, during, and after long-duration head-down bed rest. Aviat Space Environ Med 80:A15 A22