Invited Review HIGHLIGHTED TOPIC Fatigue Mechanisms Determining Exercise Performance Impaired calcium release during fatigue

doi:10.1152/japplphysiol.00908.2007.—Impaired calcium release from the sarco-plasmic reticulum (SR) has been identified as a contributor to fatigue in isolated skeletal muscle fibers. The functional importance of this phenomenon can be quantified by the use of agents, such as caffeine, which can increase SR Ca2 release during fatigue. A number of possible mechanisms for impaired calcium release have been proposed. These include reduction in the amplitude of the action potential, potentially caused by extracellular K accumulation, which may reduce voltage sensor activation but is counteracted by a number of mechanisms in intact animals. Reduced effectiveness of SR Ca2 channel opening is caused by the fall in intracellular ATP and the rise in Mg2 concentrations that occur during fatigue. Reduced Ca2 available for release within the SR can occur if inorganic phosphate enters the SR and precipitates with Ca2. Further progress requires the develop-ment of methods that can identify impaired SR Ca2 release in intact, blood-perfused muscles and that can distinguish between the various mechanisms pro-posed