Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy.
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.
Risson
Valérie
V
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.
Mazelin
Laetitia
L
Roceri
Mila
M
Sanchez
Hervé
H
Moncollin
Vincent
V
Corneloup
Claudine
C
Richard-Bulteau
Hélène
H
Vignaud
Alban
A
Baas
Dominique
D
Defour
Aurélia
A
Freyssenet
Damien
D
Tanti
Jean-François
JF
Le-Marchand-Brustel
Yannick
Y
Ferrier
Bernard
B
Conjard-Duplany
Agnès
A
Romanino
Klaas
K
Bauché
Stéphanie
S
Hantaï
Daniel
D
Mueller
Matthias
M
Kozma
Sara C
SC
Thomas
George
G
Rüegg
Markus A
MA
Ferry
Arnaud
A
Pende
Mario
M
Bigard
Xavier
X
Koulmann
Nathalie
N
Schaeffer
Laurent
L
Gangloff
Yann-Gaël
YG
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
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