Rapamycin and mTORC2 inhibition synergistically reduce contraction-stimulated muscle protein synthesis
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Rapamycin and mTORC2 inhibition synergistically reduce contraction-stimulated muscle protein synthesis. / Ogasawara, Riki; Knudsen, Jonas Roland; Li, Jingwen; Ato, Satoru; Jensen, Thomas Elbenhardt.
In: Journal of Physiology, Vol. 598, No. 23, 2020, p. 5453-5466.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Rapamycin and mTORC2 inhibition synergistically reduce contraction-stimulated muscle protein synthesis
AU - Ogasawara, Riki
AU - Knudsen, Jonas Roland
AU - Li, Jingwen
AU - Ato, Satoru
AU - Jensen, Thomas Elbenhardt
N1 - This article is protected by copyright. All rights reserved.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Faculty of Science
KW - mTORC1
KW - mTORC2
KW - Protein translation
KW - Exercise
KW - Cell signaling
U2 - 10.1113/JP280528
DO - 10.1113/JP280528
M3 - Journal article
C2 - 32893874
VL - 598
SP - 5453
EP - 5466
JO - The Journal of Physiology
JF - The Journal of Physiology
SN - 0022-3751
IS - 23
ER -
ID: 248194985