Hibernation-inspired musculoskeletal resilience: comparative mechanisms of adaptation to disuse and unloading

Prolonged mechanical unloading leads to significant musculoskeletal degradation, posing serious health risks for bedridden patients and astronauts. By contrast, hibernating animals such as Spermophilus dauricus have evolved natural resistance to muscle atrophy and bone loss during extended periods of inactivity. These animals deploy coordinated protective mechanisms, including calpain inhibition, Wingless-related integration site (Wnt)/β-catenin signalling modulation, mitochondrial dynamics regulation, and enhanced antioxidant defences, to maintain musculoskeletal homeostasis. In this study, we systematically compare the molecular adaptations to disuse in both hibernation and unloading models. Our findings reveal both overlapping and distinct regulatory strategies that govern skeletal muscle and bone preservation under mechanical unloading. These insights offer a unique perspective for developing mechanism-based countermeasures against spaceflight-induced musculoskeletal deterioration, and may further inform strategies to combat age-related or disease-associated muscle and bone loss in terrestrial settings. This work underscores the translational potential of hibernation biology for advancing space medicine and human health.