title: Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy.
abstract: Mammalian target of rapamycin (mTOR) is a key regulator of cell growth that associates with raptor and rictor to form the mTOR complex 1 (mTORC1) and mTORC2, respectively. Raptor is required for oxidative muscle integrity, whereas rictor is dispensable. In this study, we show that muscle-specific inactivation of mTOR leads to severe myopathy, resulting in premature death. mTOR-deficient muscles display metabolic changes similar to those observed in muscles lacking raptor, including impaired oxidative metabolism, altered mitochondrial regulation, and glycogen accumulation associated with protein kinase B/Akt hyperactivation. In addition, mTOR-deficient muscles exhibit increased basal glucose uptake, whereas whole body glucose homeostasis is essentially maintained. Importantly, loss of mTOR exacerbates the myopathic features in both slow oxidative and fast glycolytic muscles. Moreover, mTOR but not raptor and rictor deficiency leads to reduced muscle dystrophin content. We provide evidence that mTOR controls dystrophin transcription in a cell-autonomous, rapamycin-resistant, and kinase-independent manner. Collectively, our results demonstrate that mTOR acts mainly via mTORC1, whereas regulation of dystrophin is raptor and rictor independent.
authors.affiliation: Laboratoire de Biologie Moléculaire de la Cellule, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5239, IFR128, Université de Lyon, Equipe Différenciation Neuromusculaire, Ecole Normale Supérieure, 69364 Lyon Cedex 07, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Risson
authors.forename: Laetitia
authors.initials: L
authors.lastname: Mazelin
authors.forename: Mila
authors.initials: M
authors.lastname: Roceri
authors.forename: Hervé
authors.initials: H
authors.lastname: Sanchez
authors.forename: Vincent
authors.initials: V
authors.lastname: Moncollin
authors.forename: Claudine
authors.initials: C
authors.lastname: Corneloup
authors.forename: Hélène
authors.initials: H
authors.lastname: Richard-Bulteau
authors.forename: Alban
authors.initials: A
authors.lastname: Vignaud
authors.forename: Dominique
authors.initials: D
authors.lastname: Baas
authors.forename: Aurélia
authors.initials: A
authors.lastname: Defour
authors.forename: Damien
authors.initials: D
authors.lastname: Freyssenet
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Tanti
authors.forename: Yannick
authors.initials: Y
authors.lastname: Le-Marchand-Brustel
authors.forename: Bernard
authors.initials: B
authors.lastname: Ferrier
authors.forename: Agnès
authors.initials: A
authors.lastname: Conjard-Duplany
authors.forename: Klaas
authors.initials: K
authors.lastname: Romanino
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bauché
authors.forename: Daniel
authors.initials: D
authors.lastname: Hantaï
authors.forename: Matthias
authors.initials: M
authors.lastname: Mueller
authors.forename: Sara C
authors.initials: SC
authors.lastname: Kozma
authors.forename: George
authors.initials: G
authors.lastname: Thomas
authors.forename: Markus A
authors.initials: MA
authors.lastname: Rüegg
authors.forename: Arnaud
authors.initials: A
authors.lastname: Ferry
authors.forename: Mario
authors.initials: M
authors.lastname: Pende
authors.forename: Xavier
authors.initials: X
authors.lastname: Bigard
authors.forename: Nathalie
authors.initials: N
authors.lastname: Koulmann
authors.forename: Laurent
authors.initials: L
authors.lastname: Schaeffer
authors.forename: Yann-Gaël
authors.initials: YG
authors.lastname: Gangloff
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000367:Age Factors; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism*; D018274:Electroporation; D004734:Energy Metabolism; D004789:Enzyme Activation; D005260:Female; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000201:enzymology; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D009154:Mutation; D010084:Oxidation-Reduction; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D051381:Rats; D000076223:Regulatory-Associated Protein of mTOR; D012720:Severity of Illness Index; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014161:Transduction, Genetic; D049411:Utrophin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D016189:Dystrophin; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; C540162:Rptor protein, mouse; D049411:Utrophin; C525637:rictor protein, mouse; D006003:Glycogen; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005947:Glucose; D020123:Sirolimus