ISS study identifies thresholds for muscle atrophy and fiber changes in reduced gravity

It’s well known that spaceflight causes muscle atrophy and other biological changes in reduced gravity, and especially in near-zero gravity (microgravity) environments. However, the gravity threshold needed to maintain sufficient muscle health in space is still unclear.

To gain a better understanding of gravity thresholds capable of mitigating spaceflight-induced changes in muscles, a team of scientists conducted a mouse study on the effects of reduced gravity. The new study, published in Science Advances, measured changes in muscle function and other biomarkers in mice exposed to either microgravity (μG), one-third of Earth’s gravity (0.33g), two-thirds Earth gravity (0.67g) and simulated Earth gravity on the International Space Station (ISS), and compared them to a ground-based control (GC) group.

Muscle changes in mice in reduced gravity

Humans have evolved under Earth’s gravity, with every step and every lift of a finger working to counteract the force of Earth’s gravity on our muscles. Without this gravitational force acting on our bodies, muscles begin to atrophy. This is due to a myriad of changes, including changes in muscle myofiber types, metabolic changes, and even gene expression.

Since NASA hopes to send humans to Mars in the near-future, understanding these changes and how to potentially mitigate them is crucial. While mouse and human anatomies are different, mouse studies can help provide a foundation for understanding biological changes in space.

The team sent 24 male mice to the ISS and exposed them to various levels of gravity for 27–28 days using a centrifuge-equipped habitat, called Multiple Artificial-gravity Research System (MARS). Within several hours after the mice were brought back, the researchers analyzed their muscle mass, grip strength, histology, gene expression, and plasma metabolomics.

“Forelimb grip strength, normalized to body weight, showed a significant decline after spaceflight in both the μG and 0.33g groups compared with preflight levels. In contrast, no significant changes were observed in the 0.67g, 1g, or GC groups, suggesting that higher gravitational loading during spaceflight helps prevent functional decline in forelimb strength,” the study authors wrote.

However, significant changes were not present in the hindlimbs. The soleus muscle, which is known to be highly susceptible to gravitational changes, was found to be significantly atrophied in the μG and 0.33g mice compared with those in the 1g and GC groups. Yet, the team says that the 0.67g group did not differ significantly from the 1g and GC groups, indicating 0.67g was enough gravity to protect against degradation.

There were some protective effects of the 0.33g loading during spaceflight, according to the study. The average cross-sectional area (CSA) of the soleus muscle myofibers was significantly decreased in the μG group compared with that in the 1g and GC groups, but only slightly reduced in the 0.33g and 0.67g mice compared with that shown by the 1g group. This suggests that 0.33g is at least partially sufficient to mitigate muscle atrophy.

Gravity-dependent biomarkers

The team also identified 11 potential biomarkers for determining gravity-dependent muscle changes. Using plasma metabolomic profiling, they found 11 metabolites with a significant gravity-dependent trend. These may be used to predict muscle atrophy or functional decline in reduced gravity or μG conditions in future missions.

“Notably, creatine, lactate, glycerol, and glutamate levels were increased, while the levels of several amino acid–related metabolites, including glycine and betaine, were decreased under low-gravity conditions. The elevation of lactate and glycerol indicated enhanced glycolytic activity and lipolysis. Overall, these findings portray a gravity-associated remodeling of energy and amino acid metabolism, consistent with the observed effects of gravity on skeletal muscle,” the study authors explained.

Gravity-responsive genes were also identified by the team by comparing RNA sequencing results from the μG group with both the 1g and GC groups. Several changes were found between the groups, some suggesting that exposure to μG and 0.33g suppresses protein synthesis and shifts metabolic demand between different processes. Others were indicative of the activation of muscle atrophy pathways and shifts in metabolic features between different types of myofibers. Overall, however, results suggested protective effects at 0.67g and some partial protection at 0.33g, consistent with other observations.

What this means for humans

Assuming humans have similar responses to gravitational effects, a threshold of protective effects at 0.67 is bad news for Mars missions, as Mars’ gravity stands at a mere 0.38g. Of course, there may be some ways around that limitation—artificial gravity and exercise. The moon has even less gravity at 0.17g, so long-term missions there would have even greater biological effects.

This study does have limitations and researchers are still uncertain how well these results would translate to human physiology. Other limitations include a small sample size and only young adult male mice used in the study. Longer-term effects were not studied, so it is also unclear whether effects would worsen or stabilize at some point. Still, after validation studies in humans, the biomarkers found in this study may allow for noninvasive monitoring of muscle health in astronauts, and even patients with muscle diseases.

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