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

Risson, Valérie and Mazelin, Laetitia and Roceri, Mila and Sanchez, Hervé and Moncollin, Vincent and Corneloup, Claudine and Richard-Bulteau, Hélène and Vignaud, Alban and Baas, Dominique and Defour, Aurélia and Freyssenet, Damien and Tanti, Jean-François and Le-Marchand-Brustel, Yannick and Ferrier, Bernard and Conjard-Duplany, Agnès and Romanino, Klaas and Bauché, Stéphanie and Hantaï, Daniel and Mueller, Matthias and Kozma, Sara C. and Thomas, George and Rüegg, Markus A. and Ferry, Arnaud and Pende, Mario and Bigard, Xavier and Koulmann, Nathalie and Schaeffer, Laurent and Gangloff, Yann-Gaël. (2009) Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy. The Journal of cell biology, Vol. 187, H. 6. pp. 859-874.

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)
UniBasel Contributors:Rüegg, Markus A.
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Rockefeller University Press
ISSN:0021-9525
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:31 Dec 2015 10:49
Deposited On:08 Jun 2012 06:48

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