EC coupling in skeletal muscle: implications for fatigue

G.D. Lamb, D.G. Stephenson, Zoology, La Trobe University, Bundoora, Vic, Australia

Skeletal muscle fibres are activated by a sequence of events referred to as excitation-contraction (EC) coupling. The action potential (AP) passes along the sarcolemma and into the transverse tubular (T-) system where it activates voltage-sensor molecules (VS) that in turn open the Ca²⁺ release channels in the sarcoplasmic reticulum (SR). The Ca²⁺ released into the cytoplasm activates the contractile apparatus, producing force. When skeletal muscles are stimulated repeatedly, they fatigue, that is there is a decrease in force and power output. There can be various causes of muscle fatigue, depending on the type of muscle and type of stimulation¹. It can result from failure of AP propagation in the T-system, caused by a build-up of K⁺ and consequent depolarization². Using electrically-stimulated skinned muscle fibres³, we found that intracellular acidification counters this effect by reducing T-system chloride conductance, thus helping prevent the fibre from fatiguing⁴. Muscle fatigue also occurs with repeated stimulation because of effects on the contractile apparatus and, more importantly, a reduction in Ca²⁺ release from the SR¹. The latter can be due to inorganic phosphate precipitating with Ca²⁺ in the SR, reducing the amount of Ca²⁺ available for rapid release^5,6. It also seems likely that the fastest contracting fibre types may fatigue because the [ATP] in the cytoplasm drops to very low levels. This decrease, together with the concomitant rise in free [Mg²⁺] and ATP metabolites, has strong inhibitory effects on the Ca²⁺ release channels, which interferes with their activation by the VS⁷. Finally, repeated increases in cytoplasmic [Ca²⁺] may cause fatigue lasting more than a day because of Ca²⁺-dependent damage to the coupling between the VS and the release channels⁸, likely due to activation of calpain.

(1) Westerblad et al, News Physiol Sci 17, 17, 2002.

(2) Fryer et al, J Physiol 482, 123, 1995.

(3) Pedersen et al, Science 305, 1144, 2004.

(4) Posterino et al, J Physiol 527, 131, 2000.

(5) Sejersted & Sjøgaard, Physiol Rev 80, 1411, 2000.

(6) Allen et al, Exp Physiol 80, 497, 1995.

(7) Dutka & Lamb, J Physiol (In Press), 2004

(8) Lamb et al, J Physiol 489, 349, 1995.