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

Abstract

Key pointsr The basic control mechanisms of oxidative phosphorylation (OXPHOS) and glycolysis during work transitions in human skeletal muscle are still a matter of debate.r 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.r 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.r A slow decay of each-step activation during recovery, which was slowed further following severe exercise, was necessary to reproduce the experimental findings.r Well-tested computer models offer new insight in the control of the human skeletal muscle bioenergetic system during physical exercise.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 observedV O 2 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. , stoichiometry of proton production/consumption by CK; TCA, tricarboxylic acid cycle; vCK, muscle ATP production by creatine kinase; vGL, muscle ATP production by anaerobic glycolysis; v...

Hyperoxia speeds pulmonary oxygen uptake kinetics and increases critical power during supine cycling

“…During high‐intensity exercise (i.e. above the GET), there is an additional increase in ATP hydrolysis with time, such that the ATP cost of the work increases above that predicted from the linear relationship between ATP usage and power output below the GET (Grassi, Rossiter, & Zoladz, ; Korzeniewski, ; Korzeniewski & Rossiter, ). Given the sigmoidal relationship between [ADP] and in vivo (Wüst et al., ), this additional ATP breakdown during high‐intensity exercise would push [ADP] further towards the flatter portion of the curve, leading to a progressively smaller response for a given elevation in [ADP].…”

Reproducibility of NIRS assessment of muscle oxidative capacity in smokers with and without COPD

“…However, recent studies suggest that control of oxidative phosphorylation in skeletal muscle in humans is not first order, and that allosteric or ‘each step’ activation of mitochondrial oxidative pathways is required to activate the enzymes limiting cellular ${\dot{\mathrm{V}}\mathrm{normalO}}_{2\text{max}}$ (Korzeniewski and Rossiter, 2015; Wüst et al, 2011). Thus, accurate measurement of oxidative capacity by NIRS relies on competing demands to achieve a sufficiently high level of muscle activity and ${\mathrm{normalm}\dot{\mathrm{V}}\mathrm{normalO}}_{\mathrm{2}}$ to release mitochondrial oxidative enzyme regulation, but to limit muscle activity to a sufficiently low level such that muscle mitochondrial O 2 delivery does not become a limiting variable.…”

“…The method relies on two competing assumptions: 1) that exercise is sufficiently intense to maximally activate mitochondrial oxidative enzymes and elicit a sufficient increase in ${\mathrm{normalm}\dot{\mathrm{V}}\mathrm{normalO}}_{\mathrm{2}}$ (Korzeniewski and Rossiter, 2015; Wüst et al, 2011, 2013); 2) that O 2 delivery is not limiting to k (Haseler et al, 2004). This latter condition is especially important in COPD where poor systemic O 2 delivery, muscle capillary rarefaction and brief arterial occlusions may combine to reduce TSI below some critical threshold, thereby slowing ${\mathrm{normalm}\dot{\mathrm{V}}\mathrm{normalO}}_{\mathrm{2}}$ recovery kinetics.…”

Speeding of oxygen uptake kinetics is not different following low‐intensity blood‐flow‐restricted and high‐intensity interval training

“…The potential mechanisms responsible for increased and exercise tolerance are debated, but include the following: increased stroke volume and cardiac output (Park et al., ); increased muscle capillarity and diffusive oxygen transport (Esbjörnsson et al., ; Evans, Vance, & Brown, ; Kacin & Strazar, ); and increased muscle oxidative enzyme activity (Esbjörnsson et al., ; Kaijser et al., ). Training‐induced speeding of moderate‐intensity on‐kinetics (Berger, Tolfrey, Williams, & Jones, ; Gibala et al., ; Jones & Carter, ; Laursen & Jenkins, ) is thought particularly to reflect adaptations in the activation and capacity for muscular oxidative phosphorylation (Korzeniewski & Rossiter, ). Therefore, intramuscular adaptations to mitochondrial function can be revealed in the moderate‐intensity on‐kinetics response (Barstow, Jones, Nguyen, & Casaburi, ; McKay, Paterson, & Kowalchuk, ; Zoladz et al., ) and in the associated kinetics of carbon dioxide output () and ventilation () (Whipp, ).…”