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

TitlemTORC1 promotes denervation-induced muscle atrophy through a mechanism involving the activation of FoxO and E3 ubiquitin ligases.
Publication TypeJournal Article
Year of Publication2014
AuthorsTang H, Inoki K, Lee M, Wright E, Khuong A, Khuong A, Sugiarto S, Garner M, Paik J, DePinho RA, Goldman D, Guan K-L, Shrager JB
JournalSci Signal
Volume7
Issue314
Paginationra18
Date Published2014 Feb 25
ISSN1937-9145
KeywordsAnimals, Denervation, Forkhead Transcription Factors, Gene Deletion, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Transgenic, Multiprotein Complexes, Muscle Proteins, Muscular Atrophy, Proto-Oncogene Proteins c-akt, SKP Cullin F-Box Protein Ligases, TOR Serine-Threonine Kinases, Tripartite Motif Proteins, Tuberous Sclerosis Complex 1 Protein, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases
Abstract

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.

DOI10.1126/scisignal.2004809
Alternate JournalSci Signal
PubMed ID24570486
Grant ListNS069375 / NS / NINDS NIH HHS / United States
DK083491 / DK / NIDDK NIH HHS / United States
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