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

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; Hantaı̈, Daniel; Müeller, Matthias; Kozma, Sara C.; Thomas, George; Rüegg, Markus A.; Ferry, Arnaud; Pende, Mario; Bigard, Xavier; Koulmann, Nathalie; Schaeffer, Laurent; Gangloff, Yann-Gaël

doi:10.1083/jcb.200903131

Cited by 328 publications

(333 citation statements)

References 52 publications

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“…Moreover, since neither myotube size or total number were reduced with rapamycin treatment, and were not different over the final 5 days of culture, the increase in force is likely due to other mTOR dependent processes leading to maturation of the myotubes. Indeed, in mice where mTOR is specifically knocked out in skeletal muscle maximal force production was reduced even when accounting for the loss of muscle size, and this force decrement was associated with reduced expression of components of the dystrophin‐dystroglycan complex (Risson et al, 2009). While this was not a primary outcome of the present study, it would be interesting in the future to determine the reasons for blunted force production in engineered skeletal muscle treated with rapamycin.…”

Section: Discussionmentioning

confidence: 99%

Leucine elicits myotube hypertrophy and enhances maximal contractile force in tissue engineered skeletal muscle in vitro

Martin

Turner

Farrington

et al. 2017

Journal Cellular Physiology

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The amino acid leucine is thought to be important for skeletal muscle growth by virtue of its ability to acutely activate mTORC1 and enhance muscle protein synthesis, yet little data exist regarding its impact on skeletal muscle size and its ability to produce force. We utilized a tissue engineering approach in order to test whether supplementing culture medium with leucine could enhance mTORC1 signaling, myotube growth, and muscle function. Phosphorylation of the mTORC1 target proteins 4EBP‐1 and rpS6 and myotube hypertrophy appeared to occur in a dose dependent manner, with 5 and 20 mM of leucine inducing similar effects, which were greater than those seen with 1 mM. Maximal contractile force was also elevated with leucine supplementation; however, although this did not appear to be enhanced with increasing leucine doses, this effect was completely ablated by co‐incubation with the mTOR inhibitor rapamycin, showing that the augmented force production in the presence of leucine was mTOR sensitive. Finally, by using electrical stimulation to induce chronic (24 hr) contraction of engineered skeletal muscle constructs, we were able to show that the effects of leucine and muscle contraction are additive, since the two stimuli had cumulative effects on maximal contractile force production. These results extend our current knowledge of the efficacy of leucine as an anabolic nutritional aid showing for the first time that leucine supplementation may augment skeletal muscle functional capacity, and furthermore validates the use of engineered skeletal muscle for highly‐controlled investigations into nutritional regulation of muscle physiology.

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Section: Discussionmentioning

confidence: 99%

Leucine elicits myotube hypertrophy and enhances maximal contractile force in tissue engineered skeletal muscle in vitro

Martin

Turner

Farrington

et al. 2017

Journal Cellular Physiology

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“…This differs from previous tissue-specific gene knockout studies that focused on the endpoint, i.e., myofiber number and size, consequently failing to monitor the early steps of myogenesis. Thus, the atrophy that is a common feature of skeletal muscle in which mTORC (12) or Raptor (13) has been knocked out could be a consequence of either reduced cellular growth or delayed differentiation of myogenic precursors. Studies of the effect of rapamycin on muscle regeneration (10,33) have similarly focused on myofiber maturation.…”

Section: Discussionmentioning

confidence: 99%

“…It was shown early that the mTORC inhibitor rapamycin inhibits growth of myofibers in regenerating adult muscle (10); such inhibition was overcome by expression of a rapamycin-resistant mTORC gene (11). Genetic ablation of mTORC (12), or of the mTORC1 subunit Raptor (13), or of the mTORC1 target S6K (14) results in severe muscle atrophy. These studies indicate that myofiber growth and maturation are regulated by mTORC1 acting through S6K in vivo but provide no information on the specific effect, if any, of mTORC1 on the early stages of myogenesis.…”

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confidence: 99%

Role of the mTORC1 Complex in Satellite Cell Activation by RNA-Induced Mitochondrial Restoration: Dual Control of Cyclin D1 through MicroRNAs

Jash

Dhar

Ghosh

et al. 2014

Molecular and Cellular Biology

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During myogenesis, satellite stem cells (SCs) are induced to proliferate and differentiate to myogenic precursors. The role of energy sensors such as the AMP-activated protein kinase (AMPK) and the mammalian Target of Rapamycin (mTOR) in SC activation is unclear. We previously observed that upregulation of ATP through RNA-mediated mitochondrial restoration (MR) accelerates SC activation following skeletal muscle injury. We show here that during regeneration, the AMPK-CRTC2-CREB and Raptor-mTORC-4EBP1 pathways were rapidly activated. The phosho-CRTC2-CREB complex was essential for myogenesis and activated transcription of the critical cell cycle regulator cyclin D1 (Ccnd1). Knockdown (KD) of either mTORC or its subunit Raptor delayed SC activation without influencing the differentiation program. KD of 4EBP1 had no effect on SC activation but enhanced myofiber size. mTORC1 positively regulated Ccnd1 translation but destabilized Ccnd1 mRNA. These antithetical effects of mTORC1 were mediated by two microRNAs (miRs) targeted to the 3= untranslated region (UTR) of Ccnd1 mRNA: miR-1 was downregulated in mTORC-KD muscle, and depletion of miR-1 resulted in increased levels of mRNA without any effect on Ccnd1 protein. In contrast, miR-26a was upregulated upon mTORC depletion, while anti-miR-26a oligonucleotide specifically stimulated Ccnd1 protein expression. Thus, mTORC may act as a timer of satellite cell proliferation during myogenesis. R egeneration of skeletal muscle following injury involves formation of new myofibers as well as patch repair of old injured fibers by fusion of satellite cell-derived myoblasts (1). The program of differentiation of satellite cells involves sequential expression of myogenic regulatory factors (MRFs) and their target genes (2-5). Mitochondrial biogenesis occurs at a specific time prior to the formation of myofibers (4, 6), suggesting an energy-requiring step, but the specific role of ATP in differentiation remains unknown. Eukaryotic cells contain a number of enzymes that sense the energy status, particularly, the pools of AMP and ADP (AMPactivated protein kinase [AMPK]) or of ATP (mammalian Target of Rapamycin [mTOR] kinases) (7,8). It is possible that mitochondrial activity, through modulation of the adenylate pool, impacts these energy sensors, thereby activating or inhibiting downstream pathways.Although energy sensors such as AMPK and mTORC are known to regulate cellular energy homeostasis and cell growth (9), there are indications that they could also modulate specific developmental processes. It was shown early that the mTORC inhibitor rapamycin inhibits growth of myofibers in regenerating adult muscle (10); such inhibition was overcome by expression of a rapamycin-resistant mTORC gene (11). Genetic ablation of mTORC (12), or of the mTORC1 subunit Raptor (13), or of the mTORC1 target S6K (14) results in severe muscle atrophy. These studies indicate that myofiber growth and maturation are regulated by mTORC1 acting through S6K in vivo but provide no information on the specific eff...

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“…In order to identify the physiological function of mTOR in various tissues, an mTOR conditional KO (knockout) mouse model was generated to specifically ablate the mTOR gene in muscle (Figure 2). These mice display severe myopathy and premature death due to impaired oxidative metabolism and glycogen accumulation [38], further indicating a critical role for mTOR in regulating the development and metabolism processes.…”

Section: The Roles Of the Mtor Signaling Pathway Components In Tummentioning

confidence: 99%

mTOR signaling in tumorigenesis

Liu

Wei

2014

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

127

126

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mTOR (the mechanistic target of rapamycin) is an atypical serine/threonine kinase involved in regulating major cellular functions including growth and proliferation. Deregulations of the mTOR signaling pathway is one of the most commonly observed pathological alterations in human cancers. To this end, oncogenic activation of the mTOR signaling pathway contributes to cancer cell growth, proliferation and survival, highlighting the potential for targeting the oncogenic mTOR pathway members as an effective anti-cancer strategy. In order to do so, a thorough understanding of the physiological roles of key mTOR signaling pathway components and upstream regulators would guide future targeted therapies. Thus, in this review, we summarize available genetic mouse models for mTORC1 and mTORC2 components, as well as characterized mTOR upstream regulators and downstream targets, and assign a potential oncogenic or tumor suppressive role for each evaluated molecule. Together, our work will not only facilitate the current understanding of mTOR biology and possible future research directions, but more importantly, provide a molecular basis for targeted therapies aiming at key oncogenic members along the mTOR signaling pathway.

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

Abstract: mTor, acting mainly via mTORC1, controls dystrophin transcription in a raptor- and rictor-independent mechanism.

Cited by 328 publications

References 52 publications

Leucine elicits myotube hypertrophy and enhances maximal contractile force in tissue engineered skeletal muscle in vitro

Leucine elicits myotube hypertrophy and enhances maximal contractile force in tissue engineered skeletal muscle in vitro

Role of the mTORC1 Complex in Satellite Cell Activation by RNA-Induced Mitochondrial Restoration: Dual Control of Cyclin D1 through MicroRNAs

mTOR signaling in tumorigenesis

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