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

Abstract

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-intensity exercise, an 'additional' ATP usage (a 27% increase at 8 min, above the initial ATP supply) was necessary to explain the observed V˙O2 slow component. Thus, parallel activation of ATP usage and ATP supply (ESA), and a strong inhibition of ATP supply by anaerobic glycolysis, were necessary to simulate the kinetics of muscle bioenergetics observed in humans.