mTORC1 Promotes Denervation-Induced Muscle Atrophy Through a Mechanism Involving the Activation of FoxO and E3 Ubiquitin Ligases

A kinase complex associated with cellular growth has an unexpected role in muscle atrophy. Preventing Muscle Wasting Denervation causes skeletal muscle to undergo atrophy, a pathological process that involves the activation of the FoxO family of transcription factors. FoxOs stimulate the expression of genes encoding various E3 ubiquitin ligases that mediate the breakdown of proteins, thereby contributing to skeletal muscle atrophy. Tang et al. found that denervation of skeletal muscle in mice led to increased activity of the mammalian target of rapamycin complex 1 (mTORC1). This increase in mTORC1 activity correlated with a decrease in the activity of Akt, a kinase that inhibits FoxO transcription factors. Inhibiting mTORC1 with rapamycin protected mice from denervation-induced muscle atrophy. Furthermore, mice lacking all FoxO isoforms in skeletal muscle showed alterations in normal and denervated muscle mass, demonstrating the importance of FoxO transcription factors in the regulation of muscle biology under physiological and pathological conditions. Although mTORC1 is normally implicated in anabolic processes, this study indicates that it also has a role in the catabolism of denervated muscle. Thus, drugs that inhibit mTORC1 could be promising therapies for attenuating the atrophy of denervated skeletal muscle. Skeletal muscle mass and function are regulated by motor innervation, and denervation results in muscle atrophy. The activity of mammalian target of rapamycin complex 1 (mTORC1) is substantially increased in denervated muscle, but its regulatory role in denervation-induced atrophy remains unclear. At early stages after denervation of skeletal muscle, a pathway involving class II histone deacetylases and the transcription factor myogenin mediates denervation-induced muscle atrophy. We found that at later stages after denervation of fast-twitch muscle, activation of mTORC1 contributed to atrophy and that denervation-induced atrophy was mitigated by inhibition of mTORC1 with rapamycin. Activation of mTORC1 through genetic deletion of its inhibitor TSC1 (tuberous sclerosis complex 1) sensitized mice to denervation-induced muscle atrophy and suppressed the kinase activity of Akt, leading to activation of FoxO transcription factors and increasing the expression of genes encoding E3 ubiquitin ligases atrogin [also known as MAFbx (muscle atrophy F-box protein)] and MuRF1 (muscle-specific ring finger 1). Rapamycin treatment of mice restored Akt activity, suggesting that the denervation-induced increase in mTORC1 activity was producing feedback inhibition of Akt. Genetic deletion of the three FoxO isoforms in skeletal muscle induced muscle hypertrophy and abolished the late-stage induction of E3 ubiquitin ligases after denervation, thereby preventing denervation-induced atrophy. These data revealed that mTORC1, which is generally considered to be an important component of anabolism, is central to muscle catabolism and atrophy after denervation. This mTORC1-FoxO axis represents a potential therapeutic target in neurogenic muscle atrophy.