Hibernation as a model for skeletal muscle preservation

Hibernation is an extreme adaptation that enables a diverse array of mammalian species to survive long-term nutrient deprivation. In many seasonal hibernators, winter hibernation is characterized by prolonged periods of immobility and starvation, conditions that induce muscular atrophy in nonhibernating animals. In humans, factors that contribute to muscle atrophy include muscle disuse under conditions of bedrest, casting, paralysis, microgravity, as well as aging. In laboratory mice and rats, muscle disuse can be induced by hindlimb unloading or casting-experimental paradigms that have revealed the molecular basis of muscle atrophy. Remarkably, hibernating mammals experience reduced atrophy and maintain muscle ultrastructure and function despite months of immobility and starvation, serving as excellent models for investigating protective mechanisms for muscular atrophy resistance. In this review, we explore skeletal muscle homeostasis at multiple levels of biological organization, from function, neural innervation, gross anatomy, cellular differentiation, ultrastructure, to biochemical pathways regulating regeneration, growth, and degeneration. At each level, we compare known mechanisms in hibernators, laboratory rodents, and humans. Finally, we highlight gaps in knowledge and propose future areas of investigation for elucidating mechanisms of muscle atrophy resistance in hibernation.