Kinetic Modeling of Leucine-mediated Signaling and Protein Metabolism in Human Skeletal Muscle

Overview

Journal iScience

Publisher Cell Press

Date 2024 Jan 8

PMID 38188514

Authors

Taylor J McColl

David C Clarke

Affiliations

Soon will be listed here.

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.

Citing Articles

A Preliminary Study of Nutrients Related to the Risk of Relative Energy Deficiency in Sport (RED-S) in Top-Performing Female Amateur Triathletes: Results from a Nutritional Assessment.

Langa D, Naczyk M, Szymczak R, Karbowska J, Kochan Z Nutrients. 2025; 17(2).

PMID: 39861337 PMC: 11767317. DOI: 10.3390/nu17020208.

References

Stipanuk M . Leucine and protein synthesis: mTOR and beyond. Nutr Rev. 2007; 65(3):122-9. DOI: 10.1111/j.1753-4887.2007.tb00289.x. View

Janssen I, Shepard D, Katzmarzyk P, Roubenoff R . The healthcare costs of sarcopenia in the United States. J Am Geriatr Soc. 2003; 52(1):80-5. DOI: 10.1111/j.1532-5415.2004.52014.x. View

Everman S, Meyer C, Tran L, Hoffman N, Carroll C, Dedmon W . Insulin does not stimulate muscle protein synthesis during increased plasma branched-chain amino acids alone but still decreases whole body proteolysis in humans. Am J Physiol Endocrinol Metab. 2016; 311(4):E671-E677. PMC: 5241558. DOI: 10.1152/ajpendo.00120.2016. View

Anthony J, Yoshizawa F, Anthony T, Vary T, Jefferson L, Kimball S . Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathway. J Nutr. 2000; 130(10):2413-9. DOI: 10.1093/jn/130.10.2413. View

Atherton P, Etheridge T, W Watt P, Wilkinson D, Selby A, Rankin D . Muscle full effect after oral protein: time-dependent concordance and discordance between human muscle protein synthesis and mTORC1 signaling. Am J Clin Nutr. 2010; 92(5):1080-8. DOI: 10.3945/ajcn.2010.29819. View

Moore D, Atherton P, Rennie M, Tarnopolsky M, Phillips S . Resistance exercise enhances mTOR and MAPK signalling in human muscle over that seen at rest after bolus protein ingestion. Acta Physiol (Oxf). 2010; 201(3):365-72. DOI: 10.1111/j.1748-1716.2010.02187.x. View

Tremblay F, Gagnon A, Veilleux A, Sorisky A, Marette A . Activation of the mammalian target of rapamycin pathway acutely inhibits insulin signaling to Akt and glucose transport in 3T3-L1 and human adipocytes. Endocrinology. 2004; 146(3):1328-37. DOI: 10.1210/en.2004-0777. View

Anthony J, Anthony T, Kimball S, Jefferson L . Signaling pathways involved in translational control of protein synthesis in skeletal muscle by leucine. J Nutr. 2001; 131(3):856S-860S. DOI: 10.1093/jn/131.3.856S. View

Sturis J, Polonsky K, Mosekilde E, Van Cauter E . Computer model for mechanisms underlying ultradian oscillations of insulin and glucose. Am J Physiol. 1991; 260(5 Pt 1):E801-9. DOI: 10.1152/ajpendo.1991.260.5.E801. View

10.

Saxton R, Knockenhauer K, Wolfson R, Chantranupong L, Pacold M, Wang T . Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. Science. 2015; 351(6268):53-8. PMC: 4698039. DOI: 10.1126/science.aad2087. View

11.

Sonntag A, Dalle Pezze P, Shanley D, Thedieck K . A modelling-experimental approach reveals insulin receptor substrate (IRS)-dependent regulation of adenosine monosphosphate-dependent kinase (AMPK) by insulin. FEBS J. 2012; 279(18):3314-28. DOI: 10.1111/j.1742-4658.2012.08582.x. View

12.

Mitchell W, Phillips B, Williams J, Rankin D, Lund J, Smith K . A dose- rather than delivery profile-dependent mechanism regulates the "muscle-full" effect in response to oral essential amino acid intake in young men. J Nutr. 2015; 145(2):207-14. PMC: 4304023. DOI: 10.3945/jn.114.199604. View

13.

Dalle Pezze P, Sonntag A, Thien A, Prentzell M, Godel M, Fischer S . A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation. Sci Signal. 2012; 5(217):ra25. DOI: 10.1126/scisignal.2002469. View

14.

Rabinowitz J, White E . Autophagy and metabolism. Science. 2010; 330(6009):1344-8. PMC: 3010857. DOI: 10.1126/science.1193497. View

15.

Moxon T, Gouseti O, Bakalis S . modelling of mass transfer & absorption in the human gut. J Food Eng. 2016; 176:110-120. PMC: 4767037. DOI: 10.1016/j.jfoodeng.2015.10.019. View

16.

Ogasawara R, Kobayashi K, Tsutaki A, Lee K, Abe T, Fujita S . mTOR signaling response to resistance exercise is altered by chronic resistance training and detraining in skeletal muscle. J Appl Physiol (1985). 2013; 114(7):934-40. DOI: 10.1152/japplphysiol.01161.2012. View

17.

Kraemer W, Ratamess N . Fundamentals of resistance training: progression and exercise prescription. Med Sci Sports Exerc. 2004; 36(4):674-88. DOI: 10.1249/01.mss.0000121945.36635.61. View

18.

Atrih A, Turnock D, Sellar G, Thompson A, Feuerstein G, Ferguson M . Stoichiometric quantification of Akt phosphorylation using LC-MS/MS. J Proteome Res. 2009; 9(2):743-51. PMC: 2816933. DOI: 10.1021/pr900572h. View

19.

Pearce L, Alton G, Richter D, Kath J, Lingardo L, Chapman J . Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1). Biochem J. 2010; 431(2):245-55. DOI: 10.1042/BJ20101024. View

20.

Dyachok J, Earnest S, Iturraran E, Cobb M, Ross E . Amino Acids Regulate mTORC1 by an Obligate Two-step Mechanism. J Biol Chem. 2016; 291(43):22414-22426. PMC: 5077182. DOI: 10.1074/jbc.M116.732511. View