Each-step activation of oxidative phosphorylation is necessary to explain muscle metabolic kinetic responses to exercise and recovery in humans.

Key Points: The basic control mechanisms of oxidative phosphorylation (OXPHOS) and glycolysis during work transitions in human skeletal muscle are still a matter of debate. We used simulations of skeletal muscle bioenergetics to identify key system features that contribute to this debate, by comparing kinetic model outputs with experimental human data, including phosphocreatine, pH, pulmonary oxygen uptake and fluxes of ATP production by OXPHOS (vOX), anaerobic glycolysis and creatine kinase in moderate and severe intensity exercise transitions. We found that each-step activation of particular OXPHOS complexes, NADH supply and glycolysis, and strong (third-order) glycolytic inhibition by protons was required to reproduce observed phosphocreatine, pH and vOX kinetics during exercise.