Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy
Valérie Risson,Laetitia Mazelin,Mila Roceri,Hervé Sanchez,Vincent Moncollin,Claudine Corneloup,Hélène Richard-Bulteau,Alban Vignaud,Dominique Baas,Aurelia Defour,Damien Freyssenet,Jean-François Tanti,Jean-François Tanti,Yannick Le-Marchand-Brustel,Yannick Le-Marchand-Brustel,Bernard Ferrier,Agnès Conjard-Duplany,Klaas Romanino,S. Bauche,Daniel Hantaï,Matthias Mueller,Sara C. Kozma,George Thomas,Markus A. Rüegg,Arnaud Ferry,Mario Pende,Xavier Bigard,Nathalie Koulmann,Laurent Schaeffer,Yann-Gaël Gangloff +29 more
Reads0
Chats0
TLDR
mTor, acting mainly via mTORC1, controls dystrophin transcription in a raptor- and rictor-independent mechanism.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.read more
Citations
More filters
Journal ArticleDOI
mTOR Signaling in Growth, Metabolism, and Disease.
TL;DR: Recent advances in understanding of mTOR function, regulation, and importance in mammalian physiology are reviewed and how the mTOR signaling network contributes to human disease is highlighted.
mTOR Signaling in Growth, Metabolism, and Disease
TL;DR: Recent advances in understanding of mTOR function, regulation, and importance in mammalian physiology are reviewed and how the mTOR-signaling network contributes to human disease is highlighted.
Journal ArticleDOI
Mechanisms regulating skeletal muscle growth and atrophy
TL;DR: Two major protein degradation pathways, the proteasomal and the autophagic–lysosomal pathways, are activated during muscle atrophy and variably contribute to the loss of muscle mass.
Journal ArticleDOI
Cellular and molecular mechanisms of muscle atrophy
Paolo Bonaldo,Marco Sandri +1 more
TL;DR: This paper reviews the key mechanisms that regulate the turnover of contractile proteins and organelles in muscle tissue, and discusses how impairments in these mechanisms can contribute to muscle atrophy.
Journal ArticleDOI
Rapamycin passes the torch: a new generation of mTOR inhibitors
TL;DR: A new generation of ATP-competitive inhibitors that directly target the mTOR catalytic site display potent and comprehensive mTOR inhibition and are in early clinical trials.
References
More filters
Journal ArticleDOI
TOR signaling in growth and metabolism.
TL;DR: The physiological consequences of mammalianTORC1 dysregulation suggest that inhibitors of mammalian TOR may be useful in the treatment of cancer, cardiovascular disease, autoimmunity, and metabolic disorders.
Journal ArticleDOI
Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB.
Dos D. Sarbassov,Siraj M. Ali,Siraj M. Ali,Shomit Sengupta,Shomit Sengupta,Joon Ho Sheen,Joon Ho Sheen,Peggy P. Hsu,Peggy P. Hsu,Alex F. Bagley,Alex F. Bagley,Andrew L. Markhard,Andrew L. Markhard,David M. Sabatini,David M. Sabatini +14 more
TL;DR: It is shown that rapamycin inhibits the assembly of mTORC2 and that, in many cell types, prolongedRapamycin treatment reduces the levels of m TORC2 below those needed to maintain Akt/PKB signaling.
Journal ArticleDOI
Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton.
Dos D. Sarbassov,Siraj M. Ali,Do Hyung Kim,David A. Guertin,Robert R. Latek,Hediye Erdjument-Bromage,Paul Tempst,David M. Sabatini +7 more
TL;DR: It is found that the rictor-mTOR complex modulates the phosphorylation of Protein Kinase C alpha (PKCalpha) and the actin cytoskeleton, suggesting that this aspect of TOR signaling is conserved between yeast and mammals.
Journal ArticleDOI
Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo.
Sue C. Bodine,Trevor Stitt,Michael Gonzalez,William O. Kline,Gretchen L. Stover,Roy Bauerlein,Elizabeth Zlotchenko,Angus Scrimgeour,John C. Lawrence,David J. Glass,George D. Yancopoulos +10 more
TL;DR: It is concluded that the activation of the Akt/mTOR pathway and its downstream targets, p70S6K and PHAS-1/4E-BP1, is requisitely involved in regulating skeletal muscle fibre size, and that activation of this pathway can oppose muscle atrophy induced by disuse.
Journal ArticleDOI
Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive
Estela Jacinto,Robbie Loewith,Anja Schmidt,Shuo Lin,Markus A. Rüegg,Alan Hall,Michael N. Hall +6 more
TL;DR: Two distinct TOR complexes constitute a primordial signalling network conserved in eukaryotic evolution to control the fundamental process of cell growth.