title: Sustained activation of mTORC1 in skeletal muscle inhibits constitutive and starvation-induced autophagy and causes a severe, late-onset myopathy.
abstract: Autophagy is a catabolic process that ensures homeostatic cell clearance and is deregulated in a growing number of myopathological conditions. Although FoxO3 was shown to promote the expression of autophagy-related genes in skeletal muscle, the mechanisms triggering autophagy are unclear. We show that TSC1-deficient mice (TSCmKO), characterized by sustained activation of mTORC1, develop a late-onset myopathy related to impaired autophagy. In young TSCmKO mice, constitutive and starvation-induced autophagy is blocked at the induction steps via mTORC1-mediated inhibition of Ulk1, despite FoxO3 activation. Rapamycin is sufficient to restore autophagy in TSCmKO mice and improves the muscle phenotype of old mutant mice. Inversely, abrogation of mTORC1 signaling by depletion of raptor induces autophagy regardless of FoxO inhibition. Thus, mTORC1 is the dominant regulator of autophagy induction in skeletal muscle and ensures a tight coordination of metabolic pathways. These findings may open interesting avenues for therapeutic strategies directed toward autophagy-related muscle diseases.
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Perrine
authors.initials: P
authors.lastname: Castets
authors.forename: Shuo
authors.initials: S
authors.lastname: Lin
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rion
authors.forename: Sabrina
authors.initials: S
authors.lastname: Di Fulvio
authors.forename: Klaas
authors.initials: K
authors.lastname: Romanino
authors.forename: Maitea
authors.initials: M
authors.lastname: Guridi
authors.forename: Stephan
authors.initials: S
authors.lastname: Frank
authors.forename: Lionel A
authors.initials: LA
authors.lastname: Tintignac
authors.forename: Michael
authors.initials: M
authors.lastname: Sinnreich
authors.forename: Markus A
authors.initials: MA
authors.lastname: Rüegg
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009135:Muscular Diseases / Q000378:metabolism / Q000503:physiopathology*; D013217:Starvation / Q000503:physiopathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D046912:Multiprotein Complexes; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases