Activation of ATP Consumption Is Necessary to Stimulate Glycogenolysis in Skeletal Muscle

Glycogenolysis is an important contributor to ATP production in contracting skeletal muscle. However, the activation of glycogen phosphorylase in resting muscle does not by itself trigger significant glycogenolysis. To elucidate the mechanisms underlying this regulation, we analyzed the functional coupling between glycogenolysis and glycolysis using a mathematical model of energy metabolism in mammalian fast-twitch (white) skeletal muscle. A system-level analysis of the model reveals an important role for inorganic phosphate (a substrate for glycogen phosphorylase) in regulating glycogenolysis rates in both resting and contracting muscle. In contracting muscle, at sufficiently high concentrations of inorganic phosphate, the activation of glycogen phosphorylase markedly increases the rate of glycogenolysis, thereby enhancing ATP production and stabilizing the cellular energy charge. In contrast, glycogen phosphorylase activation in resting muscle is unable to support glycogen breakdown due to a significant decrease in inorganic phosphate levels. Moreover, the analysis shows that forced acceleration of the glycogen phosphorylase reaction under resting conditions does not increase ATP production; instead, it promotes the accumulation of phosphorylated glycolytic intermediates, which may induce osmotic stress and cause damage to muscle cells.