Regulation of ATP Supply in Muscle: Implications for Importance of Flux Control Coefficients and for the Genesis of Mitochondrial Myopathies

Abstract

There is a huge increase in the demand for ATP during exercise of skeletal muscle, and the rate of ATP production by oxidative phosphorylation must be adjusted in some way to meet the increased energy demand. Different mechanisms of an adequate activation of respiration in mitochondria have been proposed. According to the traditional view (Chance & Williams, 1955), an intracellular messenger (Ca²⁺) only activates directly ATP usage (mainly actomyosin-ATPase), various steps of the ATP-producing system being activated indirectly via changes in the ATP/ADP ratio and the concentrations of other metabolites. This mechanism can be called output activation (Fig. 1a). The discovery of the activation in vitro of the irreversible dehydrogenases of the tricarboxylate cycle by Ca²⁺ led to the proposal that the substrate dehydrogenation block is also activated directly (Denton & McCormack, 1980; McCormack & Denton, 1990). This would be equivalent to parallel activation of the input and output of oxidative phosphorylation (input/output activation, Fig. 1b). On the other hand, computer simulations of the dynamic model of oxidative phosphorylation in skeletal muscle mitochondria developed previously and tested for large-scale changes in fluxes and metabolite concentrations (Korzeniewski & Mazat, 1996) suggest (Korzeniewski, 1998) that only direct activation by an external effector of each step (enzyme, carrier) of oxidative phosphorylation can explain the experimental changes in the respiration rate and ATP/ADP ratio after onset of maximal exercise of skeletal muscle measured, for example an 18-fold increase in the respiration rate and 3-fold decrease in ATP/ADP (Hochachka, 1994).