Genetic diversity modulates the physical and transcriptomic response of skeletal muscle to simulated microgravity in male mice

Abstract

Developments in long-term space exploration necessitate advancements in countermeasures against microgravity-induced skeletal muscle loss. Astronaut data shows considerable variation in muscle loss in response to microgravity. Previous experiments suggest that genetic background influences the skeletal muscle response to unloading, but no in-depth analysis of genetic expression has been performed. Here, we placed eight, male, inbred founder strains of the diversity outbred mice (129S1/SvImJ, A/J, C57BL/6J, CAST/EiJ, NOD/ShiLtJ, NZO/HILtJ, PWK/PhJ, and WSB/EiJ) in simulated microgravity (SM) via hindlimb unloading for three weeks. Body weight, muscle morphology, muscle strength, protein synthesis marker expression, and RNA expression were collected. A/J and CAST/EiJ mice were most susceptible to SM-induced muscle loss, whereas NOD/ShiLtJ mice were the most protected. In response to SM, A/J and CAST/EiJ mice experienced reductions in body weight, muscle mass, muscle volume, and muscle cross-sectional area. A/J mice had the highest number of differentially expressed genes (68) and associated gene ontologies (328). Downregulation of immunological gene ontologies and genes encoding anabolic immune factors suggest that immune dysregulation contributes to the response of A/J mice to SM. Several muscle properties showed significant interactions between SM and mouse strain and a high degree of heritability. These data imply that genetic background plays a role in the degree of muscle loss in SM and that more individualized programs should be developed for astronauts to protect their skeletal muscles against microgravity on long-term missions.

Receptors Implicated in Microgravity-Induced Bone Loss

“…Finally, it is worth noting that the loss of bone is variable, suggesting that some people are better suited for long-term missions in low gravity than others [159]. Recent studies of muscle and bone loss in mice in simulated microgravity suggest a genetic basis for differences [188,189], consistent with the idea that bone loss in microgravity may be influenced by genes. In the future, astronaut selection may, in part, depend on genetic characteristics that limit pathological responses to low gravity and other adverse, but unavoidable, elements (radiation for example) of space flight [190].…”

“…Moreover, like on Earth, these may reflect genetic differences. Direct evidence suggests that this is the case with respect to muscle wasting and bone loss in mice [188,189], which have served as a useful model for human musculoskeletal disorders. Currently, astronaut and cosmonaut selection includes numerous characteristics that are genetically linked, including height, correctable vision, allergies, migraines, and colorblindness [244].…”