title: MTORC1 determines autophagy through ULK1 regulation in skeletal muscle.
abstract: Autophagy impairment has been implicated in several muscle disorders and in age-related dysfunction. Although previous reports pointed to FOXO as a positive regulator of autophagy in skeletal muscle, it remained unclear what is triggering autophagy. We found that TSC muscle knockout (TSCmKO) mice, characterized by specific depletion of TSC1 in skeletal muscle, and thus constant activation of MTORC1, develop a late-onset myopathy marked by the accumulation of autophagic substrates. In those mice, autophagy induction is blocked despite FOXO activation because of constant MTORC1-dependent inhibition of ULK1. Treatment of TSCmKO mice with rapamycin is sufficient to restore autophagy and to alleviate, at least in part, the myopathy. Inversely, inactivation of the MTORC1 pathway in RPTOR-depleted muscles triggers LC3B lipidation in spite of FOXO inhibition. In conclusion, MTORC1 constitutes the master regulator of autophagy induction in skeletal muscle and its deregulation leads to pathologic alterations of muscle homeostasis.
authors.affiliation: Biozentrum; University of Basel; Basel, Switzerland; Neuromuscular Research Center; Departments of Neurology and Biomedicine; Pharmazentrum; Basel University Hospital; Basel, Switzerland.
authors.forename: Perrine
authors.initials: P
authors.lastname: Castets
authors.forename: Markus A
authors.initials: MA
authors.lastname: Rüegg
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D051858:Forkhead Transcription Factors / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D013217:Starvation / Q000201:enzymology / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: FOXO; MTORC1; ULK1; atrophy; autophagy; myopathy; skeletal muscle