Kinetic modeling of leucine-mediated signaling and protein metabolism in human skeletal muscle

Taylor J McColl; David C Clarke

doi:10.1016/j.isci.2023.108634

Kinetic modeling of leucine-mediated signaling and protein metabolism in human skeletal muscle

iScience. 2023 Dec 5;27(1):108634. doi: 10.1016/j.isci.2023.108634. eCollection 2024 Jan 19.

Authors

Taylor J McColl^{1

2}, David C Clarke^{1

2}

Affiliations

¹ Department of Biomedical Physiology and KinesiologySimon Fraser University, Burnaby, BC V5A 1S6, Canada.
² Centre for Cell Biology, Development and Disease, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.

Abstract

Skeletal muscle protein levels are governed by the relative rates of muscle protein synthesis (MPS) and breakdown (MPB). The mechanisms controlling these rates are complex, and their integrated behaviors are challenging to study through experiments alone. The purpose of this study was to develop and analyze a kinetic model of leucine-mediated mTOR signaling and protein metabolism in the skeletal muscle of young adults. Our model amalgamates published cellular-level models of the IRS1-PI3K-Akt-mTORC1 signaling system and of skeletal-muscle leucine kinetics with physiological-level models of leucine digestion and transport and insulin dynamics. The model satisfactorily predicts experimental data from diverse leucine feeding protocols. Model analysis revealed that total levels of p70S6K are a primary determinant of MPS, insulin signaling substantially affects muscle net protein balance via its effects on MPB, and p70S6K-mediated feedback of mTORC1 signaling reduces MPS in a dose-dependent manner.

Keywords: Biological sciences; Protein.