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. A slow decay of each‐step activation during recovery, which was slowed further following severe exercise, was necessary to reproduce the experimental findings. Well‐tested computer models offer new insight in the control of the human skeletal muscle bioenergetic system during physical exercise. To better understand muscle bioenergetic regulation, a previously‐developed model of the skeletal muscle cell bioenergetic system was used to simulate the influence of: (1) each‐step activation (ESA) of NADH supply (including glycolysis) and oxidative phosphorylation (OXPHOS) complexes and (2) glycolytic inhibition by protons on the kinetics of ATP synthesis from OXPHOS, anaerobic glycolysis and creatine kinase. Simulations were fitted to previously published experimental data of ATP production fluxes and metabolite concentrations during moderate and severe intensity exercise transitions in bilateral knee extension in humans. Overall, the computer simulations agreed well with experimental results. Specifically, a large (>5‐fold) direct activation of all OXPHOS complexes was required to simulate measured phosphocreatine and OXPHOS responses to both moderate and severe intensity exercise. In addition, slow decay of ESA was required to fit phosphocreatine recovery kinetics, and the time constant of ESA decay was slower following severe (180 s) than moderate (90 s) exercise. Additionally, a strong inhibition of (anaerobic) glycolysis by protons (glycolytic rate inversely proportional to the cube of proton concentration) provided the best fit to the experimental pH kinetics, and may contribute to the progressive increase in oxidative ATP supply during acidifying contractions. During severe‐int