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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 release5,6. 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.