A Modular Mathematical Model of Exercise-Induced Changes in Metabolism, Signaling, and Gene Expression in Human Skeletal Muscle.

Ilya R Akberdin,Ilya N Kiselev,Alexander Yu Vertyshev,Daniil V Popov,Sergey S Pintus,Ruslan N Sharipov,Olga L Vinogradova,Fedor A Kolpakov

doi:10.3390/ijms221910353

Abstract

Skeletal muscle is the principal contributor to exercise-induced changes in human metabolism. Strikingly, although it has been demonstrated that a lot of metabolites accumulating in blood and human skeletal muscle during an exercise activate different signaling pathways and induce the expression of many genes in working muscle fibres, the systematic understanding of signaling–metabolic pathway interrelations with downstream genetic regulation in the skeletal muscle is still elusive. Herein, a physiologically based computational model of skeletal muscle comprising energy metabolism, Ca2+, and AMPK (AMP-dependent protein kinase) signaling pathways and the expression regulation of genes with early and delayed responses was developed based on a modular modeling approach and included 171 differential equations and more than 640 parameters. The integrated modular model validated on diverse including original experimental data and different exercise modes provides a comprehensive in silico platform in order to decipher and track cause–effect relationships between metabolic, signaling, and gene expression levels in skeletal muscle.

Highlights

Skeletal muscle tissue comprises about 40% of total body mass in lean adult humans and plays a crucial role in the control of whole-body metabolism and exercise tolerance
To validate the metabolic part of the model, we investigated the dynamic behaviour of the system in response to diverse acute aerobic exercises and compared them with published experimental data
It is worth noting that qualitative validation of the model was conducted on the basis of the comparison of the simulation and experimental data for three indicators: time period to achieve the maximal level of the species concentrations (e.g., PCr, ATP, glycogen) at the corresponding value of the exercise intensity and time to reach the steady-state value in recovery as well as the multiplicity of concentration changes

Summary

Introduction

Skeletal muscle tissue comprises about 40% of total body mass in lean adult humans and plays a crucial role in the control of whole-body metabolism and exercise tolerance. Regular low-intensity exercise (aerobic or endurance training) strongly increases vascular and mitochondrial density and oxidative capacity, improving fat and carbohydrate metabolism. These adaptations lead to an enhancement of muscle endurance performance and reduce the risk associated with the morbidity and premature mortality of chronic cardiovascular and metabolic diseases [1,2]. Acute aerobic exercise induces significant metabolic changes in the working skeletal muscle, which in turn activate numerous signaling molecules. Changes in the content of Ca2+ ions in skeletal muscle play a fundamental role in the regulation of the activity of contractile proteins and enzymes involved in energy metabolism. Ca2+ and AMPK play a key role in the regulation of various intracellular signaling cascades, as well as the gene expression induced by exercise

Methods

Results

Conclusion