In muscle, energy supply is finely tuned to energy demand. Ca2+-activated ATP hydrolysis in the cytosol provides ADP to the mitochondrion to stimulate oxidative phosphorylation by acceptor control of mitochondrial respiration. Although mitochondria are responsive to increased concentrations of ADPin vitro, oxygen extraction in cardiac muscle may increase independently of any significant alterations in cellular ADP levels or of dramatic changes in cellular phosphate metabolites as determined by P-31 NMR. Alterations in ATP/ADP ratios in skeletal muscle with aerobic exercise may be dependent on fiber type, with maintained ATP levels seen in oxidative fibers during muscle work. These data are consistent with increased rates of NADH generation by mitochondrial dehydrogenases, so that ATP production keeps pace with ATP hydrolysis in the cytosol. The mechanism of increased ATP synthesis in muscle mitochondria is termed “stimulus-response-metabolism coupling.” Ca2+ion increases in the muscle cytosol enhance contractility and glycogen breakdown. The Ca2+signal is then transmitted to the mitochondria to provide matrix Ca2+concentrations, which activate Ca2+-sensitive dehydrogenase activities, leading to accelerated rates of NAD reduction and oxidative phosphorylation. Thus, Ca2+signaling to the mitochondria may explain the lack of dramatic fluctuations in the cytosolic phosphorylation potential over a large range of contractile activities in cardiac muscle.