Résumé :
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Maintenance of muscle mass and physiology is essential for general health. Disuse (e.g. immobilization, denervation, and microgravity), inherited neuromuscular disorders, and aging all result in debilitating loss of skeletal muscle. Given the significant tissue plasticity of skeletal muscle, preservation of muscle mass results from efficient muscle regeneration and a homeostatic balance of protein synthesis and degradation. Furthermore, current paradigm dictates that Akt is the major determinant and regulator of skeletal muscle mass and survival. To explore the critical contribution of muscle regeneration and molecular pathways involved in the preservation of muscle mass, the current study provides an innovative approach as we analyzed a naturally occurring, hibernating animal, the 13-lined ground squirrel that is protected from muscle atrophy despite prolonged periods of immobilization and starvation. Remarkably, hibernating, injured squirrel muscles do not actively regenerate, but maintain an afibrotic state that is permissive for muscle regeneration and recovery as soon as the animals arouse from hibernation. Further molecular analyses challenge the major Akt driven paradigm thought to be essential for the maintenance of muscle mass. Here, we find that preservation of skeletal muscle homeostasis is regulated independent of Akt. Instead, we demonstrate that increased expression of serum- and glucocorticoid-inducible kinase, SGK, represents a novel mediator of skeletal muscle mass during hibernation. Insights derived from our hibernating model can be generalized, as we establish a critical role for SGK in regulating muscle size and function in non-hibernating mammals. Our results thus identify a novel therapeutic target to combat loss of skeletal muscle mass in a variety of conditions associated with muscle atrophy and degeneration. The overarching conceptual advance that this work represents is the promise that molecular analyses of naturally occurring extreme physiological states, such as hibernation, can reveal unanticipated pathogenic mechanisms and rational treatment strategies.
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