Role of NADH/NAD(+) transport activity and glycogen store on skeletal muscle energy metabolism during exercise: in silico studies

Li Y, Dash RK, Kim J, Saidel GM, Cabrera ME. Role of NADH/NAD(+) transport activity and glycogen store on skeletal muscle energy metabolism during exercise: in silico studies. Am J Physiol Cell Physiol 296: C25-C46, 2009. First published October 1, 2008; doi:10.1152/ajpcell.00094.2008.-Skeletal muscle can maintain ATP concentration constant during the transition from rest to exercise, whereas metabolic reaction rates may increase substantially. Among the key regulatory factors of skeletal muscle energy metabolism during exercise, the dynamics of cytosolic and mitochondrial NADH and NAD(+) have not been characterized. To quantify these regulatory factors, we have developed a physiologically based computational model of skeletal muscle energy metabolism. This model integrates transport and reaction fluxes in distinct capillary, cytosolic, and mitochondrial domains and investigates the roles of mitochondrial NADH/NAD(+) transport (shuttling) activity and muscle glycogen concentration (stores) during moderate intensity exercise (60% maximal O-2 consumption). The underlying hypothesis is that the cytosolic redox state (NADH/NAD(+)) is much more sensitive to a metabolic disturbance in contracting skeletal muscle than the mitochondrial redox state. This hypothesis was tested by simulating the dynamic metabolic responses of skeletal muscle to exercise while altering the transport rate of reducing equivalents (NADH and NAD(+)) between cytosol and mitochondria and muscle glycogen stores. Simulations with optimal parameter estimates showed good agreement with the available experimental data from muscle biopsies in human subjects. Compared with these simulations, a 20% increase (or similar to 20% decrease) in mitochondrial NADH/NAD(+) shuttling activity led to an similar to 70% decrease (or similar to 3-fold increase) in cytosolic redox state and an similar to 35% decrease (or similar to 25% increase) in muscle lactate level. Doubling (or halving) muscle glycogen concentration resulted in an similar to 50% increase (or similar to 35% decrease) in cytosolic redox state and an similar to 30% increase (or similar to 25% decrease) in muscle lactate concentration. In both cases, changes in mitochondrial redox state were minimal. In conclusion, the model simulations of exercise response are consistent with the hypothesis that mitochondrial NADH/NAD(+) shuttling activity and muscle glycogen stores affect primarily the cytosolic redox state. Furthermore, muscle lactate production is regulated primarily by the cytosolic redox state.