Adaptation of Mouse Skeletal Muscle to Long-Term Microgravity in the MDS Mission

Abstract

The effect of microgravity on skeletal muscles has so far been examined in rat and mice only after short-term (5–20 day) spaceflights. The mice drawer system (MDS) program, sponsored by Italian Space Agency, for the first time aimed to investigate the consequences of long-term (91 days) exposure to microgravity in mice within the International Space Station. Muscle atrophy was present indistinctly in all fiber types of the slow-twitch soleus muscle, but was only slightly greater than that observed after 20 days of spaceflight. Myosin heavy chain analysis indicated a concomitant slow-to-fast transition of soleus. In addition, spaceflight induced translocation of sarcolemmal nitric oxide synthase-1 (NOS1) into the cytosol in soleus but not in the fast-twitch extensor digitorum longus (EDL) muscle. Most of the sarcolemmal ion channel subunits were up-regulated, more in soleus than EDL, whereas Ca 2+ -activated K + channels were down-regulated, consistent with the phenotype transition. Gene expression of the atrophy-related ubiquitin-ligases was up-regulated in both spaceflown soleus and EDL muscles, whereas autophagy genes were in the control range. Muscle-specific IGF-1 and interleukin-6 were down-regulated in soleus but up-regulated in EDL. Also, various stress-related genes were up-regulated in spaceflown EDL, not in soleus. Altogether, these results suggest that EDL muscle may resist to microgravity-induced atrophy by activating compensatory and protective pathways. Our study shows the extended sensitivity of antigravity soleus muscle after prolonged exposition to microgravity, suggests possible mechanisms accounting for the resistance of EDL, and individuates some molecular targets for the development of countermeasures.

Macrophage deficiency in osteopetrotic (op/op) mice inhibits activation of satellite cells and prevents hypertrophy in single soleus fibers

“…Exposure to microgravity or hind limb unloading of rodents causes passive shortening of soleus muscle due to ankle plantarflexion (20,39,59), which reduces the mechanical stress (20) and neural activity (19,20,39,43). Even though it is well-reported that muscles composed predominantly of slowtwitch fibers are more susceptible to unloading-related atrophy (6,41,42,(45)(46)(47)59), atrophy in soleus muscle of mice composed of fast-twitch fibers mainly was also observed in all types of mice, as was reported elsewhere (40,48,55). The unloading-related decreases in fiber length and sarcomere number may be associated with the remodeling of muscle fibers and sarcomeres, as was reported before (20,59).…”

EUK-134 ameliorates nNOSμ translocation and skeletal muscle fiber atrophy during short-term mechanical unloading

“…Moreover, given that EUK-134 mitigated unloading-related upregulation of oxidative stress, we propose nNOS translocation in response to mechanical unloading in skeletal muscle is a redox-dependent phenomenon. nNOS translocation has previously been associated with increased FoxO3a activation and MuRF-1 activation and muscle atrophy during ground hindlimb unloading (42) and during 91 days of spaceflight (33). In contrast, a new publication indicates that nNOS is necessary in triggering an anabolic signaling pathway involving Nox4 and mTOR, which responds to overloading and regulates muscle hypertrophy (15).…”

Skeletal muscle mass and composition during mammalian hibernation

“…However, at the extremes, a few studies have shown reductions in fiber CSA of between −30% and −55% (Agostini et al, 1991;Steffen et al, 1991). In stark contrast to other models of muscle atrophy (Sandona et al, 2012;Trappe et al, 2004;Widrick et al, 1997), slow oxidative fibers during hibernation do not atrophy more than fast glygolytic fibers. Collectively, these studies indicate that losses of muscle mass, protein and fiber size are typically small during hibernation.…”