Skeletal muscle fatigue – regulation of excitation–contraction coupling to avoid metabolic catastrophe

Abstract

ATP provides the energy in our muscles to generate force, through its use by myosin ATPases, and helps to terminate contraction by pumping Ca(2+) back into the sarcoplasmic reticulum, achieved by Ca(2+) ATPase. The capacity to use ATP through these mechanisms is sufficiently high enough so that muscles could quickly deplete ATP. However, this potentially catastrophic depletion is avoided. It has been proposed that ATP is preserved not only by the control of metabolic pathways providing ATP but also by the regulation of the processes that use ATP. Considering that contraction (i.e. myosin ATPase activity) is triggered by release of Ca(2+), the use of ATP can be attenuated by decreasing Ca(2+) release within each cell. A lower level of Ca(2+) release can be accomplished by control of membrane potential and by direct regulation of the ryanodine receptor (RyR, the Ca(2+) release channel in the terminal cisternae). These highly redundant control mechanisms provide an effective means by which ATP can be preserved at the cellular level, avoiding metabolic catastrophe. This Commentary will review some of the known mechanisms by which this regulation of Ca(2+) release and contractile response is achieved, demonstrating that skeletal muscle fatigue is a consequence of attenuation of contractile activation; a process that allows avoidance of metabolic catastrophe.