Invited Review HIGHLIGHTED TOPIC Fatigue Mechanisms Determining Exercise Performance The cross-bridge cycle and skeletal muscle fatigue

Fitts RH. The cross-bridge cycle and skeletal muscle fatigue. J Appl Physiol 104: 551–558, 2008. First published December 27, 2007; doi:10.1152/ japplphysiol.01200.2007.—The functional correlates of fatigue observed in both animals and humans during exercise include a decline in peak force (P0), maximal velocity, and peak power. Establishing the extent to which these deleterious functional changes result from direct effects on the myofilaments is facilitated through understanding the molecular mechanisms of the cross-bridge cycle. With actin-myosin binding, the cross-bridge transitions from a weakly bound low-force state to a strongly bound high-force state. Low pH reduces the number of high-force cross bridges in fast fibers, and the force per cross bridge in both fast and slow fibers. The former is thought to involve a direct inhibition of the forward rate constant for transition to the strong cross-bridge state. In contrast, inorganic phosphate (Pi) is thought to reduce P0 by accelerating the reversal of this step. Both H and Pi decrease myofibrillar Ca sensitivity. This effect is particularly important as the amplitude of the Ca transient falls with fatigue. The inhibitory effects of low pH and high Pi on P0 are reduced as temperature increases from 10 to 30°C. However, the H -induced depression of peak power in the slow fiber type, and Pi inhibition of myofibrillar Ca sensitivity in slow and fast fibers, are greater at high compared with low temperature. Thus the depressive effects of H and Pi at in vivo temperatures cannot easily be predicted from data collected below 25° C. In vitro, reactive oxygen species reduce myofibrillar Ca sensitivity; however, the importance of this mechanism during in vivo exercise is unknown.