Effect of intracellular and extracellular ion changes on E-C coupling and skeletal muscle fatigue.

The causative factors in muscle fatigue are multiple, and vary depending on the intensity and duration of the exercise, the fibre type composition of the muscle, and the individual's degree of fitness. Regardless of the aetiology, fatigue is characterized by the inability to maintain the required power output and the decline in power can be attributed to a reduced force and velocity. Following high-intensity exercise, peak force has been shown to recover biphasically with an initial rapid (2 min) recovery followed by a slower (50 min) return to the pre-fatigued condition. The resting membrane potential depolarizes by 10-15 mV, while the action potential overshoot declines by a similar magnitude. Following high-frequency stimulation of the frog semitendinous muscle, we observed intracellular potassium [K+]1 decrease from 142 +/- 5 to 97 +/- 8 mM, while sodium [Na+]i rose from 16 +/- 1 to 49 +/- 6 mM. The [K+]i loss was similar to that observed in fatigued mouse and human skeletal muscle, which suggests that there may be a limit to which [K+]i can decrease before the associated depolarization begins to limit the action potential frequency. Fibre depolarization to- 60 mV (a value observed in some cells) caused a significant reduction in the t-tubular charge movement, and the extent of the decline was inversely related to the concentration of extracellular Ca2+. A decrease in intracellular pH (pHi) to 6.0 was observed, and it has been suggested by some that low pH may disrupt E-C coupling by directly inhibiting the SR Ca2+ release channel. However, Lamb at al. (1992) observed that low pH had no effect on Ca2+ release, and we found low pHi to have no effect on t-tubular charge movement (Q) or the Q vs. Vm relationship. The Ca2+ released from the SR plays three important roles in the regulation of E-C coupling. As Ca2+ rises, it binds to the inner surface of the t-tubular charge sensor to increase charge (Q gamma) and thus Ca2+ release, it opens SR Ca2+ channels that are not voltage-regulated, and as [Ca2+]i increases further it feeds back to close the same channels. The late stages of fatigue have been shown to be in part caused by a reduced SR Ca2+ release. The exact cause of the reduced release is unknown, but the mechanism appears to involve a direct inhibition of the SR Ca2+ channel.