A computational model of dynamics of pH, phosphoenergetics and glycogenolysis in mouse skeletal muscle: acidosis does not inhibit resting glycogenolysis

Abstract

pH changes in muscle cell cytoplasm are a consequence of proton fluxes from biochemical reactions in the intracellular milieu and proton transport across the sarcolemma. These pH changes and the effects of pH on the biochemical reaction kinetics and equilibria influence the overall system behavior. In this study we integrated a previously published model of anaerobic glycogenolysis (Vinnakota et al. Biophys J 91: 1264-87) with an empirical model of oxidative phosphorylation in the intact muscle as an open system with proton transport, metabolic proton load computation, and proton buffering systems i.e., fixed buffers, metabolite buffering and bicarbonate buffering. The model was validated by fitting magnetic resonance spectroscopic data for time courses of PCr, Pi and pH in mouse EDL and SOL in anoxia transient experiments, and pH time course in the SOL in a PCO2 transient experiment. Our model analysis shows that proton fluxes due to ATP hydrolysis, creatine kinase, oxidative phosphorylation, carbon dioxide hydration and lactate efflux reactions are the major determinants of the pH transient; ATP hydrolysis is the main source of protons during anoxia; acidosis due to a transient increase in PCO2 does not inhibit glycogenolysis.