Rapamycin and mTORC2 inhibition synergistically reduce contraction-stimulated muscle protein synthesis
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Protein synthesis increases following muscle contractions. Previous studies showed that the mechanistic target of rapamycin complex 1 (mTORC1) inhibition suppressed the early but not late muscle protein synthesis-response, while the inhibition of both mTORC1 and mTORC2 abolished both effects. Therefore, we hypothesized that mTORC2 regulates muscle protein synthesis following muscle contractions. To test this, we investigated the effect of mTORC2 inhibition by mouse muscle-specific Rictor knockout (Rictor mKO) on muscle protein synthesis 3h post-contraction. The right gastrocnemius muscles of Rictor mKO mice and wild-type (WT) mice were isometrically contracted using percutaneous electrical stimulation, while the left gastrocnemius muscles served as controls. Vehicle or the mTORC1 inhibitor rapamycin (1.5 mg/kg) was injected intraperitoneally 1 h before contraction. Treatment of WT mice with rapamycin and Rictor mKO lowered protein synthesis in general, but the response to contractions was intact 3h post contractions in both conditions. Rapamycin treatment in Rictor mKO prevented contraction-stimulated muscle protein synthesis. Notably, signalling traditionally associated with mTORC1 was increased by muscle contractions despite rapamycin treatment. In rapamycin-treated Rictor mKO mice, the same mTORC1 signalling was blocked following contractions. Our results indicate that although neither rapamycin-sensitive mTOR/mTORC1 nor mTORC2 regulates contraction-induced muscle protein synthesis, combined inhibition of rapamycin-sensitive mTOR/mTORC1 and mTORC2 synergistically inhibits contraction-induced muscle protein synthesis.
|Journal||Journal of Physiology|
|Publication status||E-pub ahead of print - 7 Sep 2020|
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- Faculty of Science - mTORC1, mTORC2, Protein translation, Exercise, Cell signaling