Feeding-induced muscle mTORC1 signaling regulates postprandial protein synthesis and endurance but not muscle size
- 1Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
- 2Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Abstract
Activation of the mechanistic target of rapamycin (mTOR) complex1 (mTORC1) promotes muscle protein synthesis, mass, and function. Muscle mTORC1 can be activated by feeding and contraction. Here, muscle mTORC1 signaling, protein synthesis, mass, and function are characterized in a genetic mouse model that separates these 2 major modes of muscle mTORC1 regulation. AKT signaling is required for feeding-induced muscle mTORC1 signaling and protein synthesis, and mice expressing a mutant of tuberous sclerosis complex 2 (TSC2) that cannot be phosphorylated by AKT specifically in skeletal muscle (SkM-TSC2-5A) attenuate these effects of feeding. Despite this loss of postprandial protein synthesis, SkM-TSC2-5A mice have similar muscle and myofiber size compared with SkM-TSC2-WT mice. SkM-TSC2-5A mice maintain normal muscle mTORC1 activation in response to contraction and exhibit no differences in atrophy-related gene expression or ribosomal content. SkM-TSC2-5A mice exhibit improved maximal endurance capacity without changes in muscle contractile function. This phenotype occurs without alterations in muscle glycogen content or myofiber type, but it does coincide with a modest increase in muscle mitochondrial content. Therefore, AKT-mediated phosphorylation of TSC2 is required for postprandial mTORC1 activation and the induction of protein synthesis; however, these are dispensable for the development and maintenance of muscle mass in sedentary mice.
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BibTeX
@article{lapp2026feedinginduced,
title = {{Feeding-induced muscle mTORC1 signaling regulates postprandial protein synthesis and endurance but not muscle size}},
author = {Samuel C. Lapp and Krystle C. Kalafut and Madi Y. Cissé and Khaled Tighanimine and Dean M. Rosenthal and Will Doxsey and Sheng Hui and Karen E. Inouye and Claire E. Morrow and Yann Cormerais and Brendan D. Manning},
journal = {JCI Insight},
year = {2026},
month = sep,
doi = {10.1172/jci.insight.210523},
url = {https://doi.org/10.1172/jci.insight.210523},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Feeding-induced muscle mTORC1 signaling regulates postprandial protein synthesis and endurance but not muscle size
AU - Samuel C. Lapp
AU - Krystle C. Kalafut
AU - Madi Y. Cissé
AU - Khaled Tighanimine
AU - Dean M. Rosenthal
AU - Will Doxsey
AU - Sheng Hui
AU - Karen E. Inouye
AU - Claire E. Morrow
AU - Yann Cormerais
AU - Brendan D. Manning
PY - 2026
DA - 2026/09/10
JO - JCI Insight
DO - 10.1172/jci.insight.210523
UR - https://doi.org/10.1172/jci.insight.210523
AB - Activation of the mechanistic target of rapamycin (mTOR) complex1 (mTORC1) promotes muscle protein synthesis, mass, and function. Muscle mTORC1 can be activated by feeding and contraction. Here, muscle mTORC1 signaling, protein synthesis, mass, and function are characterized in a genetic mouse model that separates these 2 major modes of muscle mTORC1 regulation. AKT signaling is required for feeding-induced muscle mTORC1 signaling and protein synthesis, and mice expressing a mutant of tuberous sclerosis complex 2 (TSC2) that cannot be phosphorylated by AKT specifically in skeletal muscle (SkM-TSC2-5A) attenuate these effects of feeding. Despite this loss of postprandial protein synthesis, SkM-TSC2-5A mice have similar muscle and myofiber size compared with SkM-TSC2-WT mice. SkM-TSC2-5A mice maintain normal muscle mTORC1 activation in response to contraction and exhibit no differences in atrophy-related gene expression or ribosomal content. SkM-TSC2-5A mice exhibit improved maximal endurance capacity without changes in muscle contractile function. This phenotype occurs without alterations in muscle glycogen content or myofiber type, but it does coincide with a modest increase in muscle mitochondrial content. Therefore, AKT-mediated phosphorylation of TSC2 is required for postprandial mTORC1 activation and the induction of protein synthesis; however, these are dispensable for the development and maintenance of muscle mass in sedentary mice.
SN - 2379-3708
ER -