Dynamic balance of myoplasmic energetics, redox state and protons in a fast‐twitch oxidative glycolytic skeletal muscle fibre

To investigate the mechanisms governing energy and redox balance in skeletal muscle, we developed a computational model describing the coupled biochemical reaction network of glycolysis and mitochondrial oxidative phosphorylation (OxPhos) in fast-twitch oxidative glycolytic (FOG) muscle fibres. The model was identified against dynamic in vivo recordings of phosphocreatine (PCr), inorganic phosphate (Pi) and pH in rodent hindlimb muscle and verified against independent data from in vivo experiments and muscle biopsies. Step response testing reveals that mass action kinetics in combination with feedback control are sufficient to accomplish myoplasmic ATP homeostasis over a 100-fold range of ATP turnover rates. This vital emergent property of the metabolic model is associated with intermediary metabolite dynamics typical of a second-order underdamped system, which has been previously reported for the glycolytic pathway. Lactate dehydrogenase (LDH) knockout simulations suggest that the contribution of the LDH reaction to redox balance is more fundamental to muscle function than its role in counteracting myoplasmic acidification across the physiological range of ATP demands in this myofibre phenotype. Furthermore, LDH knockout simulations confirm that mitochondrial uptake of myoplasmic NADH and H⁺ in and by itself is sufficient to maintain redox balance and proton balance over ATP turnover rates in the range of mitochondrial ATP synthesis. We conclude that aerobic lactate production in working muscles is a by-product of the metabolic flexibility of FOG myofibres afforded by expression of high levels of LDH and OxPhos enzymes to support continual myoplasmic redox balance and ATP synthesis under conditions of high-intensity mechanical work. KEY POINTS: Feedback regulation suffices to accomplish myoplasmic ATP homeostasis over a 100-fold range of ATP turnover. Second-order underdamped behaviour is predicted to arise as a generic trait of the ATP metabolic network in mammalian cells. Aerobic lactate is a by-product of the metabolic and functional flexibility. LDH's role in maintaining redox balance is more important than its role in counteracting cellular acidification.