title: mTORC1 promotes denervation-induced muscle atrophy through a mechanism involving the activation of FoxO and E3 ubiquitin 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.
authors.affiliation: 1Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Huibin
authors.initials: H
authors.lastname: Tang
authors.forename: Ken
authors.initials: K
authors.lastname: Inoki
authors.forename: Myung
authors.initials: M
authors.lastname: Lee
authors.forename: Erika
authors.initials: E
authors.lastname: Wright
authors.forename: Andy
authors.initials: A
authors.lastname: Khuong
authors.forename: Amanda
authors.initials: A
authors.lastname: Khuong
authors.forename: Sista
authors.initials: S
authors.lastname: Sugiarto
authors.forename: Matthew
authors.initials: M
authors.lastname: Garner
authors.forename: Jihye
authors.initials: J
authors.lastname: Paik
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
authors.forename: Daniel
authors.initials: D
authors.lastname: Goldman
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Shrager
mesh_terms: D000818:Animals; D003714:Denervation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000070584:Tripartite Motif Proteins; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; D046912:Multiprotein Complexes; D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases