The repeated intense stimulation of skeletal muscle rapidly decreases its force- and motion-generating capacity. This type of
fatigue can be temporally correlated with the accumulation of metabolic by-products, including
phosphate (Pi) and
protons (H). Experiments on skinned single muscle fibers demonstrate that elevated concentrations of these
ions can reduce maximal isometric force, unloaded shortening velocity, and peak power, providing strong evidence for a causative role in the
fatigue process. This seems to be due, in part, to their direct effect on muscle's molecular motor,
myosin, because in assays using isolated
proteins, these
ions directly inhibit
myosin's ability to move actin. Indeed, recent work using a single molecule
laser trap assay has revealed the specific steps in the crossbridge cycle affected by these
ions. In addition to their direct effects, these
ions also indirectly affect
myosin by decreasing the sensitivity of the myofilaments to
calcium, primarily by altering the ability of the muscle regulatory
proteins,
troponin and
tropomyosin, to govern
myosin binding to actin. This effect seems to be partially due to
fatigue-dependent alterations in the structure and function of specific subunits of
troponin. Parallel efforts to understand the molecular basis of muscle contraction are providing new technological approaches that will allow us to gain unprecedented molecular detail of the
fatigue process. This will be crucial to fully understand this ubiquitous phenomenon and develop appropriately targeted
therapies to attenuate the debilitating effects of
fatigue in clinical populations.