mTORC1 promotes denervation-induced muscle atrophy through a mechanism involving the activation of FoxO and E3 ubiquitin ligases

• Published in: Science signaling Vol. 7; no. 314; p. ra18
• Main Authors: Tang, Huibin, Inoki, Ken, Lee, Myung, Wright, Erika, Khuong, Andy, Khuong, Amanda, Sugiarto, Sista, Garner, Matthew, Paik, Jihye, DePinho, Ronald A, Goldman, Daniel, Guan, Kun-Liang, Shrager, Joseph B
• Format: Journal Article
• Language: English
• Published: United States 25.02.2014
• Subjects: Animals; Denervation; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gene Deletion; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Transgenic; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Muscle Proteins - genetics; Muscle Proteins - metabolism; Muscular Atrophy - genetics; Muscular Atrophy - metabolism; Muscular Atrophy - pathology; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; SKP Cullin F-Box Protein Ligases - genetics; SKP Cullin F-Box Protein Ligases - metabolism; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Tripartite Motif Proteins; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 1937-9145
• DOI: 10.1126/scisignal.2004809

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.