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