Distinct amino acid–sensing mTOR pathways regulate skeletal myogenesis

Sep 27, 2013Molecular biology of the cell

Separate amino acid-sensing mTOR pathways control muscle formation

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Abstract

Knockdown of RagA/B enhances myogenic differentiation, while overexpression of active RagB/C mutants impairs it.

Both Rag GTPases and Vps34 mediate amino acid activation of mTOR complex 1 (mTORC1) in myoblasts.
RagA/B knockdown leads to enhanced differentiation, suggesting a positive role in this process.
Overexpression of active RagB/C mutants suppresses differentiation, indicating an inhibitory function.
The inhibitory effect of Rag on differentiation is linked to mTORC1 suppression of the IRS1-PI3K-Akt pathway.
Vps34 is essential for myogenic differentiation through an amino acid-activated pathway involving insulin-like growth factor II.
The phosphatidic acid produced by phospholipase D1 (PLD1) activates the Igf2 muscle enhancer in a manner that is sensitive to rapamycin but independent of mTOR kinase.

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Signaling through the mammalian target of rapamycin (mTOR) in response to amino acid availability controls many cellular and developmental processes. mTOR is a master regulator of myogenic differentiation, but the pathways mediating amino acid signals in this process are not known. Here we examine the Rag GTPases and the class III phosphoinositide 3-kinase (PI3K) Vps34, two mediators of amino acid signals upstream of mTOR complex 1 (mTORC1) in cell growth regulation, for their potential involvement in myogenesis. We find that, although both Rag and Vps34 mediate amino acid activation of mTORC1 in C2C12 myoblasts, they have opposing functions in myogenic differentiation. Knockdown of RagA/B enhances, whereas overexpression of active RagB/C mutants impairs, differentiation, and this inhibitory function of Rag is mediated by mTORC1 suppression of the IRS1-PI3K-Akt pathway. On the other hand, Vps34 is required for myogenic differentiation. Amino acids activate a Vps34-phospholipase D1 (PLD1) pathway that controls the production of insulin-like growth factor II, an autocrine inducer of differentiation, through the Igf2 muscle enhancer. The product of PLD, phosphatidic acid, activates the enhancer in a rapamycin-sensitive but mTOR kinase-independent manner. Our results uncover amino acid-sensing mechanisms controlling the homeostasis of myogenesis and underline the versatility and context dependence of mTOR signaling.

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Distinct amino acid–sensing mTOR pathways regulate skeletal myogenesis

Abstract

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