Feeding-induced muscle mTORC1 signaling regulates postprandial protein synthesis and endurance but not muscle size

Samuel C. Lapp; Krystle C. Kalafut; Madi Y. Cissé; Khaled Tighanimine; Dean M. Rosenthal; Will Doxsey; Sheng Hui; Karen E. Inouye; Claire E. Morrow; Yann Cormerais; Brendan D. Manning

doi:10.1172/jci.insight.210523

Feeding-induced muscle mTORC1 signaling regulates postprandial protein synthesis and endurance but not muscle size

Samuel C. Lapp,¹ Krystle C. Kalafut,¹ Madi Y. Cissé,¹ Khaled Tighanimine,¹ Dean M. Rosenthal,¹ Will Doxsey,¹ Sheng Hui,¹ Karen E. Inouye,¹ Claire E. Morrow,¹ Yann Cormerais,¹ and Brendan D. Manning¹

Published September 10, 2026 - More info

View PDF

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 two 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 to 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 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.

Feeding-induced muscle mTORC1 signaling regulates postprandial protein synthesis and endurance but not muscle size

Samuel C. Lapp,¹ Krystle C. Kalafut,¹ Madi Y. Cissé,¹ Khaled Tighanimine,¹ Dean M. Rosenthal,¹ Will Doxsey,¹ Sheng Hui,¹ Karen E. Inouye,¹ Claire E. Morrow,¹ Yann Cormerais,¹ and Brendan D. Manning¹

Article tools

Metrics

Go to

Feeding-induced muscle mTORC1 signaling regulates postprandial protein synthesis and endurance but not muscle size

Samuel C. Lapp,1 Krystle C. Kalafut,1 Madi Y. Cissé,1 Khaled Tighanimine,1 Dean M. Rosenthal,1 Will Doxsey,1 Sheng Hui,1 Karen E. Inouye,1 Claire E. Morrow,1 Yann Cormerais,1 and Brendan D. Manning1

Article tools

Metrics

Go to

Sign up for email alerts

Samuel C. Lapp,¹ Krystle C. Kalafut,¹ Madi Y. Cissé,¹ Khaled Tighanimine,¹ Dean M. Rosenthal,¹ Will Doxsey,¹ Sheng Hui,¹ Karen E. Inouye,¹ Claire E. Morrow,¹ Yann Cormerais,¹ and Brendan D. Manning¹