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

Authors: Risson, V  Mazelin, L  Roceri, M  Sanchez, H  Moncollin, V  Corneloup, C  Richard-Bulteau, H  Vignaud, A  Baas, D  Defour, A  Freyssenet, D  Tanti, JF  Le-Marchand-Brustel, Y  Ferrier, B  Conjard-Duplany, A  Romanino, K  Bauche, S  Hantai, D  Mueller, M  Kozma, SC  Thomas, G  Ruegg, MA  Ferry, A  Pende, M  Bigard, X  Koulmann, N  Schaeffer, L  Gangloff, YG 
Citation: Risson V, etal., J Cell Biol. 2009 Dec 14;187(6):859-74. doi: 10.1083/jcb.200903131.
Pubmed: (View Article at PubMed) PMID:20008564
DOI: Full-text: DOI:10.1083/jcb.200903131

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.


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RGD Object Information
RGD ID: 10040985
Created: 2015-05-07
Species: All species
Last Modified: 2015-05-07
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.