Computational modeling of in vivo metabolic processes in skeletal muscle

Metabolic disorders of skeletal muscle are associated with various diseases, e.g., type 2 diabetes. To maintain the normal physiological function of skeletal muscle, intracellular metabolism is strictly regulated. To elucidate the regulatory mechanisms of cellular metabolism of skeletal muscle, it is necessary to quantitatively analyze its metabolic processes in vivo. This requires a combination of mechanistic, mathematical modeling and experimental measurements. Model simulations that describe and predict the dynamics of tissue metabolism provide important insights for evaluating regulatory mechanisms and identifying the pathological components.;In this study, a multi-scale, multi-domain mathematical model of skeletal muscle with several variations was developed to represent the most important metabolic pathways/reactions and metabolites in blood, cytosolic, and mitochondrial domains. Also, the model incorporates the transport processes between these domains. Consequently, this model can simulate the in vivo dynamics of intramuscular metabolic activities in response to physiological stimuli. Model simulations correspond to available experimental data including the dynamics of tissue metabolism during moderate intensity exercise (~60% VO2max) and intracellular metabolites (e.g., glycogen and lactate) and transport fluxes (e.g., lactate release rate). From perturbations of the NADH transport capacity between cytosol and mitochondria, model simulations showed that the cytosolic redox state (NADH/NAD+) is much more sensitive than mitochondrial redox state to lactate production.;With minor modifications, the basic model simulated metabolic responses of skeletal muscle to insulin infusion (euglycemic-hyperinsulinemic clamp) under different hypotheses. Model simulations demonstrated that when just a few key enzymes (i.e., hexokinase, glycogen synthase and pyruvate dehydrogenase) were stimulated by insulin via insulin signaling, the experimental metabolic responses could not be explained. Instead, most of the metabolic reactions must be stimulated in accord with the parallel activation hypothesis.;Further model developments incorporated the distinctive functions of two major types of muscle fibers. Consequently, this modified model can simulate the metabolic responses in each muscle fiber during submaximal intensity exercise. Model simulations were consistent with experimental data that showed glycogen and PCr decreased predominantly in type I fiber, which accounts for most of the energy supply of working muscle.