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The mTORC2 Complex Regulates Terminal Differentiation of C2C12 Myoblasts

机译：mTORC2复合物调节C2C12成肌细胞的终末分化

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Rapamycin, a selective inhibitor of mTORC1 signaling, blocks terminal myoblast differentiation. We found that downregulation of rictor, a component of the mTORC2 complex, but not downregulation of raptor, a component of the mTORC1 complex, prevented terminal differentiation (fusion) of C2C12 myoblasts. Both rapamycin and rictor downregulation suppressed the phosphorylation of AKT(S473), and rapamycin treatment of C2C12 myoblasts disrupted the mTORC2 complex. Importantly, downregulation of rictor inhibited TORC2 signaling without inhibiting mTORC1 signaling, suggesting that inhibition of mTORC1 by rapamycin may not be the cause of arrested differentiation. In support of this, expression of a phosphomimetic mutant AKT(S473D) in rictor-deficient cells rescued myoblast fusion even in the presence of rapamycin. mTORC2 signaling to AKT appears necessary for downregulation of the Rho-associated kinase (ROCK1) that occurs during myogenic differentiation. Rapamycin treatment prevented ROCK1 inactivation during differentiation, while suppression of ROCK1 activity during differentiation and myoblast fusion was restored through expression of AKT(S473D), even in the presence of rapamycin. Further, the ROCK inhibitor Y-27632 restored terminal differentiation in rapamycin-treated myoblasts. These results provide the first evidence of a specific role for mTORC2 signaling in terminal myogenic differentiation.
机译：雷帕霉素，mTORC1信号的选择性抑制剂，阻止终末成肌细胞分化。我们发现，rictor，mTORC2复合物的组成部分的下调，但不是猛禽，mTORC1复合物的组成部分的下调，则阻止了C2C12成肌细胞的终末分化（融合）。雷帕霉素和rictor下调均抑制了AKT（S 473 ）的磷酸化，雷帕霉素处理C2C12成肌细胞破坏了mTORC2复合物。重要的是，rictor的下调在不抑制mTORC1信号转导的情况下抑制了TORC2信号转导，这表明雷帕霉素对mTORC1的抑制可能不是引起分化停止的原因。支持这一点的是，即使在雷帕霉素存在的情况下，在拟南芥缺乏的细胞中，模拟磷酸化突变体AKT（S473D）的表达也能拯救成肌细胞融合。 AKT的mTORC2信号似乎是下调在成肌分化过程中发生的Rho相关激酶（ROCK1）所必需的。雷帕霉素治疗可防止ROCK1在分化过程中失活，而ROCK1活性在分化和成肌细胞融合过程中的抑制则通过AKT（S473D）的表达得以恢复，即使在雷帕霉素存在的情况下也是如此。此外，ROCK抑制剂Y-27632恢复了雷帕霉素处理的成肌细胞的终末分化。这些结果提供了mTORC2信号在终末成肌分化中特定作用的第一个证据。

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