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Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy

The Journal of cell biology, 2009-12, Vol.187 (6), p.859-874 [Peer Reviewed Journal]

Copyright Rockefeller University Press Dec 14, 2009 ;Distributed under a Creative Commons Attribution 4.0 International License ;2009 Risson et al. 2009 ;ISSN: 0021-9525 ;EISSN: 1540-8140 ;DOI: 10.1083/jcb.200903131 ;PMID: 20008564 ;CODEN: JCLBA3

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Title:
Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy
Author: Risson, Valérie ; Mazelin, Laetitia ; Roceri, Mila ; Sanchez, Hervé ; Moncollin, Vincent ; Corneloup, Claudine ; Richard-Bulteau, Hélène ; Vignaud, Alban ; Baas, Dominique ; Defour, Aurélia ; Freyssenet, Damien ; Tanti, Jean-François ; Le-Marchand-Brustel, Yannick ; Ferrier, Bernard ; Conjard-Duplany, Agnès ; Romanino, Klaas ; Bauché, Stéphanie ; Hantaï, Daniel ; Mueller, Matthias ; Kozma, Sara C ; Thomas, George ; Rüegg, Markus A ; Ferry, Arnaud ; Pende, Mario ; Bigard, Xavier ; Koulmann, Nathalie ; Schaeffer, Laurent ; Gangloff, Yann-Gaël
Subjects: Adaptor Proteins, Signal Transducing ; Age Factors ; Animals ; Biochemistry ; Birds of prey ; Carrier Proteins - antagonists & inhibitors ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; Cell growth ; Cells, Cultured ; Dystrophin - genetics ; Dystrophin - metabolism ; Electroporation ; Energy Metabolism ; Enzyme Activation ; Female ; Gene expression regulation ; Glucose - metabolism ; Glycogen ; Glycogen - metabolism ; Insulin ; Kinases ; Life Sciences ; Messenger RNA ; Metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria, Muscle - enzymology ; Muscle Contraction ; Muscle fibers ; Muscle, Skeletal - drug effects ; Muscle, Skeletal - enzymology ; Muscle, Skeletal - physiopathology ; Muscles ; Muscular Dystrophy, Animal - enzymology ; Muscular Dystrophy, Animal - genetics ; Muscular Dystrophy, Animal - physiopathology ; Mutation ; Oxidation ; Oxidation-Reduction ; Pathology ; Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors ; Phosphotransferases (Alcohol Group Acceptor) - deficiency ; Phosphotransferases (Alcohol Group Acceptor) - genetics ; Phosphotransferases (Alcohol Group Acceptor) - metabolism ; Proteins ; Proto-Oncogene Proteins c-akt - metabolism ; Rapamycin-Insensitive Companion of mTOR Protein ; Rats ; Regulatory-Associated Protein of mTOR ; Severity of Illness Index ; Sirolimus - pharmacology ; Skeletal muscle ; Stem cells ; TOR Serine-Threonine Kinases ; Transduction, Genetic ; Utrophin - metabolism
Is Part Of: The Journal of cell biology, 2009-12, Vol.187 (6), p.859-874
Description: 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.
Publisher: United States: The Rockefeller University Press
Language: English
Identifier: ISSN: 0021-9525
EISSN: 1540-8140
DOI: 10.1083/jcb.200903131
PMID: 20008564
CODEN: JCLBA3
Source: GFMER Free Medical Journals
MEDLINE
PubMed Central

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Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy

Copyright Rockefeller University Press Dec 14, 2009 ;Distributed under a Creative Commons Attribution 4.0 International License ;2009 Risson et al. 2009 ;ISSN: 0021-9525 ;EISSN: 1540-8140 ;DOI: 10.1083/jcb.200903131 ;PMID: 20008564 ;CODEN: JCLBA3

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