The Role of Calcium in the Energetics of Contracting Skeletal Muscle

In its second messenger role in skeletal muscle, calcium coordinates the function of muscle (contractile activity) with its overall energetics, thereby controlling the provision of ATP in a time of need. Not only is ATP required for crossbridge turnover in the myofibrils, but it is also needed for the maintenance of ion pumps, nuclear activity, and so forth. When oxygen is limiting, the sustained contractions of both fast and slow muscle (after the immediate burst of activity) is primarily supported by glycogenolysis and the glycolytic pathway (anaerobic). Calcium is important to this process, and the compartmentation of the glycogen particle and some of the enzymes associated with the glycolytic pathway in the terminal cisternae of the sarcoplasmic reticulum ensures that the provision of glucose-6-phosphate to the glycolytic pathway for the generation of the needed ATP proceeds rapidly. The activation of phosphorylase and glycogenolysis by calcium-troponin-C is another example of the tight control of cellular energetics deemed possible by compartmentation within the cell. The regulation by calcium, therefore, is only dependent on the diffusion of calcium rather than diffusion of substrate. When oxygen is not limiting (i.e. when a new steady-state is reached), the aerobic metabolism of pyruvate and fatty acids may be regulated in part by calcium at least in slow skeletal muscle. Oxidative phosphorylation, where ADP is phosphorylated to ATP, is thought to be controlled by the concentration of ADP in skeletal muscle. However, because of the obvious compartmentation of the mitochondria within the slow muscle fibre and the higher free calcium required for peak force development (5 μmol/L), the kinetics are theoretically favourable for the calcium cycle in slow muscle mitochondria to play an important role in the regulation of aerobic substrate oxidation, as it does in the heart. Although this hypothesis is attractive based on the available data, the direct demonstration of a major role for calcium as a regulator of substrate oxidation in slow muscle awaits experimentation.