Submitted on February 16, 2008
Revised on August 20, 2008
Accepted on September 18, 2008
Role of NADH/NAD+ Transport Activity and Glycogen Store on Skeletal Muscle Energy Metabolism during Exercise - In Silico Studies
Yanjun Li1, Ranjan K. Dash2, Jaeyeon Kim1, Gerald M. Saidel1, and Marco E Cabrera1*
1 Case Western Reserve University
2 Medical College of Wisconsin
* To whom correspondence should be addressed. E-mail: marco.cabrera{at}case.edu.
Skeletal muscle can maintain [ATP] constant during the transition from rest to exercise, while 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 developed here 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% VO2max). 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 esti-mates showed good agreement with the available experimental data from muscle biopsies in hu-man subjects. Compared with these simulations, a 20% increase (or ~20% decrease) in mito-chondrial NADH/NAD+ shuttling activity led to ~70% decrease (or ~3-fold increase) in cytosolic redox state and ~35% decrease (or ~25% increase) in muscle lactate level. Doubling (or halving) muscle glycogen concentration resulted in ~50% increase (or ~35% decrease) in cytosolic redox state and ~30% increase (or ~25% decrease) in muscle lactate concentration. In both cases, changes in mitochondrial redox state were minimal. In conclusion, the model simulations of ex-ercise response are consistent with the hypothesis that mitochondrial NADH/NAD+ shuttling ac-tivity and muscle glycogen stores affect primarily the cytosolic redox state. Furthermore, muscle lactate production is regulated primarily by the cytosolic redox state.
