Encyclopedia of Bioastronautics

Living Edition
| Editors: Laurence R. Young, Jeffrey P. Sutton

Muscle Wasting in Space and Countermeasures

  • Vincent J. CaiozzoEmail author
  • Kenneth M. Baldwin
Living reference work entry
DOI: https://doi.org/10.1007/978-3-319-10152-1_116-1

The Mechanisms of Skeletal Muscle Wasting: Role of Protein Gene Transcription, Translation, and Degradation Processes

Skeletal muscle fiber atrophy occurs in response to states of unloading such as during space flight (Adams et al. 2003) and ground-based analogues such as hind limb suspension and space flight in rodents (Caiozzo et al. 1994, 1996) and bedrest in humans (Adams et al. 2003). Unloading-induced atrophy appears to involve both components of the protein balance equation, which is defined as the ratio of protein synthesis rate divided by the protein degradation rate (synthesis/degradation rate) (Thomason and Booth 1990). When the degradation rate exceeds the synthesis rate, net protein loss (atrophy) occurs. While the equation is rather simple, the mechanisms are rather complex. The research emphasis during the past 10–15 years has focused heavily on understanding the upstream events regulating these protein processes.

Protein Synthesis Alterations

There is accumulated evidence, as depicted in Fig. 1, that the IGF-I signaling pathway involving Akt/mTOR/p70SK cascade becomes repressed in unloaded muscle (Sandri et al. 2004; Stitt et al. 2004; Caiozzo et al. 1996; Hornberger et al. 2001; Kandarian and Jackman 2006). Furthermore, to make matters worse, there is evidence that transcription of key myofibrillar protein genes (e.g., myosin and actin) is severely repressed in unloaded muscle (see Fig. 2). For instance, Giger et al. (2009) recently found that one of the early responses contributing to the rapid atrophy of slow skeletal muscle motor units during HS of adult rats involves the transcriptional repression of both the slow-slow type MHC and actin genes. This alteration is manifested as a marked reduction in expression of both their respective pre-RNA and mRNA pools. It is apparent that this response contributes to the very rapid loss in muscle mass that occurs in slow skeletal muscle fibers during the first few days of unloading in which it loses ~35% of muscle mass.
Fig. 1

Schematic illustrating pathways involved in protein synthesis and degradation

Fig. 2

Effects of muscle unloading on muscle mass and pre-mRNA levels for the two key contractile proteins, actin and myosin

Also contributing to this rapid loss of muscle mass involves the rapid loss of total RNA molecules, in which ~90% of the total RNA pool involves the ribosomal fraction. The ribosomal fraction serves as the template for regulating both the rate and amount of protein that is being synthesized for any given protein, such as MHC and actin. Thus, during the early stages of unloading, skeletal muscle protein synthesis is clearly compromised.

Protein Degradation and Global Models of Muscle Atrophy

Given that sarcomeres represent over 80–85% of a muscle fiber’s total cellular volume, it is widely recognized that muscle atrophy occurs primarily because of a loss of sarcomeres/myofibrils in parallel. This loss of sarcomeres/myofibrils occurs in a proportional manner such that the myofibrillar volume density remains unchanged from control conditions. Less attention, however, has been paid to the loss of mitochondria and SR during muscle atrophy and how their loss may or may not be correlated with that of sarcomeres/myofibrils. Such considerations emphasize the need to develop models of muscle atrophy that incorporate key ultrastructural observations.

A unique aspect of the sarcomere is a highly organized lattice structure between thick and thin filaments. This unsurpassed degree of ultrastructural organization extends beyond the highly ordered lattice structure of thick and thin filaments to also include the spatial relationships between the sarcomere, mitochondria, and SR. The tight coupling between these three design constraints suggests that they represent a functional unit, which we refer to as a SMART (Sarcomere, MitochondriA, sarcoplasmic ReTiculum) Unit. As is well-known, the mitochondria are mainly found in two locations: (i) subsarcolemmal (SS) and (ii) intermyofibrillar (IMF). Of these two pools of mitochondria, the IMF mitochondria represent approximately 85–90% of the total mitochondrial volume. Intermyofibrillar mitochondria are typically observed as dyads in association with Z-lines when viewed in a longitudinal plane. This view, however, becomes quite complicated when observing mitochondria in a transverse plane where it becomes obvious that the IMF exists as a reticulum. Nonetheless, the uniformity of IMF dyads associated with Z-lines underscores the high degree of ultrastructural organization found between the mitochondria and sarcomeres. With respect to the SR, it is well-known that the T-tubules and the SR provide an almost immediate source of Ca++ in order for the sarcomeres to contract effectively, while relaxation is rapidly promoted via the uptake of Ca++ by calcium ATPase pumps (SERCAs) located primarily in the lateral sacs of the SR. The location of the T-tubule and triad at the A-I band intersection ensures that Ca++ will rapidly diffuse throughout the thin filament network, maximizing the probability for crossbridge formation. Additionally, the orientation of the lateral sacs overlapping the A-band ensures that the SERCAs of the longitudinal membrane of the SR are strategically located to rapidly take up Ca++ during relaxation.

If there is a global muscle atrophy program that (i) coordinates the breakdown of the SMART Unit and (ii) myofibrillar volume density remains unchanged during muscle atrophy, then it seems reasonable to hypothesize that the mitochondrial and SR volume densities would likewise also be unchanged. So the question arises as to what is currently known about the effects of muscle atrophy on the volume densities of myofibrils, mitochondria, and SR. Ferretti et al. (1997) reported that 42 days of human bedrest without countermeasures produced a 13% reduction in muscle cross-sectional area of the thigh extensors and a decrease in muscle fiber mean cross-sectional area of approximately 15–17% (P <0.06). These observations were associated with no changes in myofibrillar volume density (75% pre bedrest; 77% post bedrest) but were associated with a 17% reduction in IMF volume density. In rats Desplanches et al. (1990) observed that 5 weeks of hind limb suspension of rats produced a relatively small reduction in the volume density of myofibrils (6%) associated with a statistically insignificant change in mitochondrial volume density. Riley et al. (1987) also observed an absence of changes in myofibrillar and IMF volume densities in rodent muscle following 7 days of microgravity. Collectively, these studies suggest that muscle atrophy induced by mechanical unloading alters the volume density of neither the myofibrils nor IMF mitochondria and is consistent with the concept of a global atrophy program that coordinates the disassembly of the SMART Unit. Unfortunately, there is virtually no data with respect to the SR volume density. Some have also argued that muscle unloading is produced by an altered metabolic state that stimulates the mitochondria to undergo mitophagy, producing a loss of myofibrils. Interestingly, however, McDougall et al. (1991) found that prolonged hypoxia produced a reduction in the muscle cross-sectional area of slow type I fibers following operation Everest II, whereby subjects simulated an ascent of Mount Everest over 40 days with a final inspired PO2 of 43 mmHg. This reduction in muscle fiber cross-sectional area, however, was associated with no changes in either myofibrillar or IMF mitochondrial volume density. While it might be assumed that the muscle atrophy observed in this study was simply the result of a reduced inspired PO2, it should also be noted that these subjects had a substantial reduction in diet and had a significant reduction in physical activity due to their confinement to the environmental chamber.

The high degree of ultrastructural organization with respect to the sarcomere, SR, and IMF must be due to the presence of proteins that act to tether these critical design constraints to one another. During the course of the past 10 years, it has become clear that a number of proteins act as scaffolds and determine not only the structure of thick and thin filaments but also the stereotypical association of the IMF mitochondria and SR with the sarcomere. Consistent with this perspective, the localization of the SR with respect to the sarcomere is thought to be mediated by obscurin, which is a large protein that interacts with titin and myomesin at its N-terminus and with small ankyrin proteins at its C-terminus (see Fig. 3a). Small ankyrin 1.5 (Ank 1.5) is thought to bind the lateral sacs of the SR to obscurin, which is thought to act as a tether ensuring that the lateral sacs of the SR are located in close proximity to the A-band. This view is supported by the findings of Lange et al. (2009) who observed that a knockout of the obscurin gene markedly reduced the lateral sac region of the SR. Additionally, the mitochondria are believed to be tethered to the SR via possible candidates such as mitofusin-2 (Ainbinder et al. 2015).
Fig. 3

(Panel a) Schematic illustration of the highly ordered arrangement of thick and thin filaments in sarcomeres, the alignment of Z-lines in register, the stereotypical arrangement of mitochondria into dyads, and the presence of the sarcoplasmic reticulum such that it is in close proximity to the thick and thin filaments and also its spatial association with the mitochondria. Importantly, it should be noted that the mitochondria and SR are located on the surface of sarcomeres rather than within sarcomeres. We refer to this highly ordered arrangement between the sarcomere, mitochondria, and SR as a SMART (Sarcomere, MitochondriA, sarcoplasmic ReTiculum) Unit. This stereotypical alignment between the sarcomere, mitochondria, and SR is to a large extent due to the presence of so-called scaffold proteins such as obscurin, alpha actinin, M-line proteins, and others such as small ankyrin-1 (Ank 1.5), which links the lateral sacs of the SR to the M-line. Additionally, findings suggest that the mitochondria are tethered to the SR via proteins like mitofusin-2. In support of a Unified Muscle Atrophy Program (UMAM; see panel b) which proposes that muscle atrophy leads to the coordinated loss of sarcomeres, mitochondria, and SR (SMART Unit), it is interesting to note atrophy does not result in what might be referred to as “ghost” sarcomeres, whereby the thick and thin filaments are selectively lost without corresponding losses in mitochondria and SR. The simultaneous breakdown of the sarcomere, mitochondria, and SR suggests a highly coordinated set of events that must involve the loss/breakdown of key scaffold/tether proteins responsible for the overall SMART organization. In support of muscle atrophy acting on the SMART Unit as a single entity, the loss of sarcomeres (as represented by one myofibril rather than the two shown in the previous figures) does not appear to result in an increased volume density of mitochondria (as shown in panel d)

The presence of such tightly coupled SMART Units gives rise to a number of interesting questions with respect to muscle atrophy. For instance, does the disassembly of one component of the SMART Unit lead to the disassembly of the other two? For example, since the mitochondria and SR are tethered to the sarcomere at critical sights, then one model of muscle atrophy might propose that the disassembly of mitochondria and/or SR is first preceded by the disassembly of the sarcomere. Alternatively, is it possible that the tight coupling between the mitochondria and SR form a functional unit that plays an integral role in Ca++ homeostasis and, in turn, regulates the actions of calcium-activated proteases? Another hypothesis might be that there is a global muscle atrophy program that promotes the coordinated disassembly of sarcomeres, mitochondria, and the SR.

In recent years considerable insight has accumulated concerning the regulation of the protein degradation cascade, especially in terms of impacting the myofibril fraction. As presented in Fig. 1, when the IGF-1 Akt/mTOR-p70S6K pathway is sufficiently activated, then Akt phosphorylates a transcription factor of the “forkhead family” referred to as FOXO-1. FOXO-1 is a transcription factor that regulates gene expression of key ubiquitin E3 ligase genes such as muscle RING-finger protein-1 (MuRF-1) and atrogin-1/muscle atrophy F box (MAFbx) (Sandri et al. 2004; Stitt et al. 2004). When FOXO1 is phosphorylated, it is transferred out of the nucleus and is no longer capable of activating transcription of atrogin-1 and MuRF1, Ub-E3 ligases, which target degradation of thick and thin filaments. However, when the loading state is reduced as during hind limb suspension involving the rat, Akt signaling pathways are reduced, FOXO1 becomes activated, and the E3 ligases become upregulated to elevate protein degradation processes. Facilitating this degradation cascade also involves the activation of expression of myostatin, an antigrowth factor, which is a member of the transforming growth factor beta (TGFβ) family of proteins. In certain cattle species that possess a nonfunctional myostatin gene, the muscles become huge due to hypertrophy, because of the loss of function of this important gene. Interestingly, during unloading states myostatin is upregulated, and part of its action involves the ability to inhibit the Akt pathway as noted in Fig. 1 (Morissette et al. 2009; Trendelenburg et al. 2009).

While sarcomere disassembly during muscle atrophy appears to be primarily regulated by atrogenes such as atrogin-1 and MuRF1, the loss of mitochondria during muscle atrophy appears to be dependent on altered mitochondrial biogenesis and fusion-fission events controlling mitochondrial morphology. PGC-1a is a transcription coactivator and plays a key role in regulating mitochondrial biogenesis. Wu et al. (1999) were one of the first to demonstrate that PGC-1a controlled mitochondrial biogenesis. Subsequently, Baar et al. (2002) found that physical activity produced a rapid upregulation of PGC-1a, while Sandri et al. (2004) demonstrated that overexpression of PGC-1a could inhibit disuse muscle atrophy. As pointed out by Schiaffino et al. (2013), PGC-1a appears to exert its atrophying sparing effect via actions on both the ubiquitin-proteasome and lysosomal-autophagy pathways. Consistent with the possible role of PGC-1a in mediating muscle atrophy, Oishi et al. (2008) observed that hind limb unloading produced a significant decrease in PGC-1a levels, while reloading produced a large upregulation of PGC-1a levels. More recently, Cannavino et al. (2014, 2015) reported that overexpression of PGC-1a was effective in preventing hind limb suspension-induced muscle atrophy.

Several interesting models of muscle atrophy have recently been proposed that begin to address atrophy at a more global level. Goldberg and colleagues (2015) have proposed a model that describes some of the initial events associated with muscle atrophy. In this model, they propose that one of the earliest events in the atrophy process includes an initial phase during which MuRF1 break downs myosin binding protein-C (MybC) and myosin light chain (MLC). During this initial phase, ubiquitin tripartite motif-containing protein 32 (TRIM32) acts on key organizational proteins like desmin and promotes the disassembly of the Z-line. In a later phase, the loss of thick filament-stabilizing proteins like MyBC and MLC leads to the breakdown of the thick filament by MuRF1. The breakdown of the thick filament is complimented degradation of the thin filament by TRIM32. How might the breakdown of the sarcomere and mitochondria be coordinated? Significant insight has been provided by both the Goldberg (Sandri et al. 2004, 2006; Sacheck et al. 2007; Zhao et al. 2007, 2008, Cohen et al. 2014) and Sandri (2013; Milan et al. 2015; Ratti et al. 2015) groups with their studies focused on the FOXO transcription factor family members (FOXO1, 3, and 4). The coordinated action of FOXO1 and FOXO3 provides a working model to explain an upregulation of both the ubiquitin-protease and lysosomal-autophagy systems. As noted above, muscle unloading is thought to produce nuclear translocation of FOXOs (FOXO1/3), which then activates a number of key atrogenes such as MAFbx1 and MuRF1 initiate disassembly of the sarcomere. Additionally, FOXO3 is thought to play a key role in upregulating autophagic events and may provide a link between the coordinated loss of both sarcomeres and mitochondria. Currently, it is believed that FOXOs control approximately 50% of all atrogenes, so there is still a lot to learn with respect to muscle atrophy. This is especially true with respect to understanding how (if any) scaffold (like obscurin, titin, and nebulin) and tether proteins are degraded in the process and whether their loss might be central to the disassembly of the SMART Unit. Stressing the importance of scaffold proteins like titin, it should be noted that titin contains binding sites for muscle-specific calcium-activated proteases (calpains). This gives rise to the question as to whether/how the activity of calpains might be coordinated with that of FOXOs.

While the concept of FOXOs plays a central role in regulating muscle atrophy via coordinated actions on both the ubiquitin-protease and lysosomal-autophagy pathways, it should be noted that there is evidence that should give pause in accepting this model outright (as is true for any model). For instance, Gustafsson et al. (2010) studied the effects of 3 days of unloading in human subjects and found that the phosphorylation of Akt1, FOXO-1A, FOXO-3A, and p38 was unaltered. Additionally, mRNA levels of FOXO-1A and 3A were unchanged from control values. Gustafsson et al. (2010) also observed that while levels of atrogin-1 and MuRF-1 were elevated in the vastus lateralis muscle, there were no changes seen in the soleus muscle. Clearly, further studies, such as time-course studies, are needed to better understand the role (if any) of FOXOs in coordinating muscle atrophy in humans.

Mechanisms of Slow to Fast MHC Gene Switching During Unloading: Role of Noncoding Antisense RNA

Previously, we described that during space flight and unloading stimuli (HS model), there was a switching of MHC gene expression whereby the slow type I and faster type IIA genes were repressed, while the fast type IIX and IIB genes were expressed de novo in the unloaded soleus muscle of rodents (Caiozzo et al. 1994, 1996). It is important to point out that the MHC gene family in striated muscle comprises at least eight MHC genes: two cardiac genes, alpha and beta, three adult fast MHCs (IIA, IIX, and IIB), two developmental MHCs (embryonic and neonatal), and one specialized type, i.e., the extraocular MHC (EO). Note that the slow cardiac beta MHC is the same as the type I MHC gene that is expressed in slow skeletal muscle fibers.

These MHC genes are arranged into two clusters: (1) the cardiac MHCs on chromosome 15 in the rat and (2) the fast IIA, IIX, and IIB skeletal muscle MHC cluster on chromosome 10. This gene clustering orientation and tandem organization have been conserved through millions of years of mammalian muscle evolution. This conserved configuration raises questions as to whether this particular MHC gene alignment is of functional significance in their patterns of regulation under different physiological states.

Recent evidence has implicated a noncoding RNA transcript in the coordinated regulation of two positioned genes in tandem, which implicates the importance of genomic organization of these MHC genes in their coordinated regulation. For example, Haddad et al. (2003) reported the novel discovery that in normal healthy rodent cardiac muscle, a naturally occurring antisense RNA transcript to the cardiac beta (type 1) MHC gene is involved in cardiac gene regulation, such that the alpha MHC isoform normally is primarily expressed under normal physiological conditions (Haddad et al. 2003). Interestingly, cardiac alpha and beta MHC isoforms are the products of two distinct genes that are organized in tandem in a head to tail position on the same chromosome in the order of beta → alpha (e.g., the beta gene is upstream of the alpha); and they are separated by a ~4.5 kb intergenic DNA space (see Baldwin et al. 2013). In the normal state, a long noncoding antisense RNA is transcribed that is opposite to the beta MHC gene creating a “beta antisense RNA.” This antisense beta sequence was implicated in MHC isoform gene regulation/switching (alpha MHC repression and beta expression enhanced) in the heart in response to both diabetes and hypothyroidism (Haddad et al. 2003). Under conditions of both hypothyroidism and type I diabetes, the antisense beta fragment was repressed allowing the beta MHC gene to dominate cardiac beta MHC compared to the normal heart. Given these findings, studies were subsequently performed on skeletal muscle to ascertain if the noncoding antisense RNA expression in slow and fast skeletal muscle contributes to the patterns of MHC gene expression in response to unloading stimuli.

Recently, Pandorf et al. (2006) published a paper which investigated type II MHC gene regulation in slow type I soleus muscle fibers undergoing a slow to fast MHC transformation in response to 7 days of spinal isolation (SI), a model of inactivity that induces atrophy similar to hind limb suspension. Transcriptional products were examined of both the sense and antisense strands across the IIA-IIX-IIB MHC gene locus. Results showed that the mRNA and pre-mRNA of each MHC gene had a similar response to the SI stimulus, suggesting regulation of these three genes at the transcriptional level. In addition, detection of a previously unknown antisense strand transcription occurred that produced natural antisense transcripts (NATs). RT-PCR mapping of the RNA products revealed that the antisense activity resulted in the formation of three major products: aII, xII, and bII NATs, i.e., antisense products of the IIA, IIX, and IIB genes, respectively. Thus, the key observation of this experiment was that the SI-induced inactivity caused a marked inhibition of both the slow type I and type IIA genes along with upregulation of both the IIX and IIB genes. Therefore, the inactivity model of SI negatively impacts transcription of the type I MHC gene by inhibiting its promoter (27, 49) and induces antisense aII NATS that primarily repress transcription of the IIA MHC gene, thereby creating a switch from slow type I/IIA predominance to a fast IIX fiber of the normally slow soleus muscle. Importantly, this observation explains the existence of type I/IIX hybrid fibers reported previously by Caiozzo et al. (1998), as presented in the earlier section of this entry.

Countermeasure Strategies to Maintain Design Constraints

In recent years, to the authors’ knowledge, few studies have been carried out to ascertain the mechanisms for counteracting the rapid atrophy of animal skeletal muscle as presented in Part I. In 2006 (Haddad et al. 2006; Morissette et al. 2009), performed a study to test the hypothesis that an isometric resistance training paradigm targeting the medial gastrocnemius muscle of adult rodents is effective in preventing muscle atrophy during the early stages of unloading by maintaining normal activation of the insulin receptor substrate-1 (IRS-1)/phospho-inositide-3 kinase (PI3K)/Akt signaling pathway. This pathway has been shown to simultaneously create an anabolic response while inhibiting processes that upregulate catabolic processes involving expression of key enzymes in the ubiquitination of protein for degradation of the myofibril network. The findings of this study showed that during the 5 days of unloading, (i) absolute medial gastrocnemius muscle weight reduction occurred by 20%, but muscle weight corrected to body weight was not different from normal weight-bearing controls, (ii) normalized myofibril concentration and content were decreased, and (iii) a robust isometric training program, known to induce a hypertrophy response, failed to maintain the myofibril protein content. This response occurred despite fully blunting the increases in the mRNA for atrogen-1, MURF-1, and myostatin, e.g., sensitive gene markers that activated the catabolic state. Analyses of the IRS-1/PI3K/Akt markers indicated that abundance IRS-1 and phosphorylation state of Akt and p70S6 kinase were decreased relative to normal controlled rats, and the resistance training failed to maintain these signaling markers at normal regulatory level. These findings were insightful and suggest that to fully prevent muscle atrophy responses affecting the myofibril system (which is the primary target of atrophic stimuli) during unloading, the volume of mechanical stress must be augmented sufficiently to maintain optimal activity of the IRS-1/PI3K/Akt pathway to provide an effective anabolic stimulus for the target muscle groups.

Based on the above information, Adams et al. (2004) undertook a study to determine if resistance training, with increased volume (3-s contractions) along with the incorporation of both static and dynamic contractile components, would be effective in preventing rapid unloading-induced atrophy. Rats were exposed to 5 days of muscle unloading via hind limb suspension (HS). During that time, one leg received electrical stimulated resistance exercise (RE) that included an isometric, concentric, and eccentric contraction phases. The results of this study indicate that this combined-mode RE provided an anabolic stimulus sufficient to maintain the mass and myofibril content of the trained but not the contralateral medial gastrocnemius (MG) muscle. Relative to the contralateral MG, the RE stimulus increased the amount of total RNA (indicative of translational capacity) as well as mRNA for several anabolic/myogenic markers such as insulin-like growth facor-1, myogenin, myoferlin, and collagen III-alpha-1 and decreased that of myostatin, a negative regulator of muscle fiber size. The combined-mode RE also increased the activity of anabolic signaling intermediates such as p70S6 kinase (constituents of the IRS-1/PI3K/Akt pathway). These results indicate that a combination of static- and dynamic-mode RE of sufficient volume provides an effective stimulus to stimulate anabolic/myogenic mechanisms to counter the initial stages of unloading-induced muscle atrophy.

Consistent with this perspective, several approaches for incorporating resistance training as a countermeasure to the effects of microgravity on skeletal muscle have been developed. Some of these include devices such as (i) the advanced resistive exercise device (ARED), (ii) the YoYo flywheel, and (iii) short-arm centrifuges, which allow subjects to perform hypergravity resistance training (see Table 1).
Table 1

Classes of countermeasure devices and some of their key properties related to key physiological systems and spacecraft design criteria

Class of countermeasure device

Potential to protect

Volume requirement

Mass

Electrical power required

Eliminate CV line

Eliminate Muscle line

Eliminate Bone line

CV

Muscle

Bone

Treadmill

  

Moderate

Moderate

Yes

Cycle ergometer

  

Moderate

Moderate

Yes

ARED

 

Large

Moderate

No

Lower body negative pressure

 

Moderate

Moderate

Yes

Human-powered short-arm centrifuge

Large

Moderate

No

M-MED

Moderate

Moderate

No

The ARED device is currently being flown on the International Space Station and incorporates vacuum cylinders (constant resistance) and flywheel assemblies, which provide variable resistance and a free-weight Earth-like experience. Loehr et al. (2011) performed a ground-based study, whereby subjects engaged in either a free-weight or ARED resistance training program (16 weeks), and observed that the ARED device was equally effective as the FW program with respect to increases in muscle function (strength and vertical jump) volume. To our knowledge, there are currently no published flight studies reporting the efficacy of the ARED device. The iRED (interim resistance exercise device) was deployed prior to the ARED system. Unfortunately, the iRED was limited in the amount of resistance it could provide. This might explain why some of the astronauts who used iRED still experienced up to a 20% loss of muscle mass (Trappe et al. 2009).

Perhaps the best studied countermeasure technology, to date, is the YoYo flywheel system developed by Tesch. Some of the key attributes of this system are as follows: (i) it can be used to impose high loading forces on a given muscle group in both a concentric and eccentric fashion; (ii) the loading imposed on the subject is independent of gravity; (iii) it has a relatively low mass and volume requirement; and (iv) recent modifications to this device now allow for a quick transition between resistance and cardiovascular training modes. Importantly, the efficacy of this device has not only been studied under normal physiological states but also under conditions of simulated microgravity.

The results from simulated microgravity are highlighted by several key studies. The first of these (Alkner and Tesch 2004) examined the efficacy of the YoYo device during 90 days of bedrest. Alkner and Tesch (2004) found that bedrest alone produced substantial losses in knee extensor and plantar flexor muscle volume (−18% and 29%, respectively) that was accompanied by large losses in muscle strength in both muscle groups (~30 to 60% losses). In contrast, resistance training with the YoYo device proved to be effective in preventing/mitigating losses in muscle volume both the knee extensors (prevented) and plantar flexors (mitigated; −15% loss). Consistent with muscle volume data, it was also found that the resistance training program was effective in minimizing losses in muscle strength. Subsequently, Carrithers et al. (2002) studied the effects of 5 weeks of unilateral lower limb suspension (ULLS) and examined the effectiveness of flywheel resistance training as a countermeasure to losses in muscle protein content, with a primary focus on both the myosin heavy chain and actin. Consistent with the findings of Alkner and Tesch (2004), Carrithers et al. (2002) reported that flywheel training was effective in preventing loss of muscle mass. Interestingly, changes in MHC and actin content were not observed within any group. Most recently, Cotter et al. (2015) examined the effects of concurrent training on a modified YoYo device. In this study, subjects were exposed to 10 days of ULLS, and subjects were asked to perform both resistance training coupled with aerobic training (concurrent training) using the modified YoYo device. Cotter et al. (2015) found that the concurrent training program (resistance + aerobic training) was effective in mitigating/preventing losses in muscle strength while significantly increases markers of aerobic performance (VO2max and citrate synthase). Collectively, the results using the YoYo device suggest that resistance training can be a highly effective countermeasure to microgravity-induced losses in muscle mass and function.

As Burton noted (Burton 1994a, b), the most obvious countermeasure to microgravity is a centrifuge, yet it has been the least explored. There are some obvious applications of artificial gravity as a countermeasure to microgravity. For instance, artificial gravity could be used to impose orthostatic challenges on the cardiovascular system, possibly preventing the loss of orthostatic tolerance that occurs as a result of microgravity. There are also some potential applications of artificial gravity in a microgravity environment that are not as obvious. As an example, artificial gravity/hypergravity in a microgravity environment could be used as a novel method of performing resistance training under high loading conditions. The novelty of artificial gravity/hypergravity resistance training is that each element of the body is loaded proportionally to the local gravitational field, and under hypergravity conditions, muscles like those of the leg can be made to work against very high loads (e.g., + 2 body weights) without the need for external weights.

Short-arm centrifuges like that of the Space Cycle (Kreitenberg et al. 1998; Caiozzo et al. 2004; Yang et al. 2007b) or the one developed by NASA (Caiozzo et al. 2009) have the potential to produce hypergravity conditions. For example, Yang et al. (2007a, b) found that subjects were able to achieve comparable foot forces during hypergravity squats and 10 RM (repetition maximum). This study provides a key foundational study demonstrating that hypergravity resistance training is easily tolerated and further studies exploring the potential role of hypergravity in mitigating the deconditioning effects of microgravity are needed. In this context, Caiozzo et al. (2009) examined the effects of 21 days of bedrest and the potential role of AG in preventing the loss of muscle mass and function. These investigators found that AG protected the torque-velocity relationships of both the knee extensors and plantar flexors of bedrest subjects. At the morphological level, it was observed that the bedrest subjects had a reduced muscle fiber cross-sectional area, whereas that was not seen in the bedrest subjects who were subjected to AG. With respect to catabolic markers such as atrogin, it was also observed that AG mitigated the response to muscle unloading.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Physiology and BiophysicsUniversity of CaliforniaIrvineUSA
  2. 2.Orthopedics and the Institute for Clinical and Translational Sciences, School of MedicineUniversity of CaliforniaIrvineUSA

Section editors and affiliations

  • Peter Norsk
    • 1
    • 2
  1. 1.Center for Space MedicineBaylor College of MedicineHoustonUSA
  2. 2.Biomedical Research & Environmental Sciences DivisionNASA, Johnson Space CenterHoustonUSA