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Effects of oxidation and cytosolic redox conditions on excitation-contraction coupling in rat skeletal muscle

G. S. Posterino, M. A. Cellini and G. D. Lamb

In this study the effects of oxidation and reduction on various steps in the excitation-contraction (E-C) coupling sequence was examined in mammalian skeletal muscle. In mechanically skinned fast-twitch fibres, electric field stimulation was used to generate action potentials in the sealed transverse-tubular (T-) system, thereby eliciting twitch responses, which are a sensitive measure of Ca²⁺ release. Treatment of fibres with the oxidant H₂O₂ (200 µM and 10 mM) for 2-5 min markedly potentiated caffeine-induced Ca²⁺ release and the force response to partial depolarisation of the T-system (by solution substitution). Importantly, such H₂O₂ treatment had no effect at all on any aspect of the twitch response (peak amplitude, rate of rise, decay rate constant and half-width), except in cases where it interfered with the T-system potential or voltage-sensor activation, resulting in a reduction or abolition of the twitch response. Exposure to strong thiol reductants, dithiothreitol (DTT, 10 mM) and reduced glutathione (GSH, 5 mM), did not affect the twitch response over 5 min, nor did varying the glutathione ratio (reduced to oxidised glutathione) from the level present endogenously in the cytosol of a rested fibre (30:1) to the comparatively oxidised level of 3:1. In fibres that had been oxidised by H₂O₂ (10 mM) (or by 2,2'-dithiodipyridine, 100 µM), exposure to GSH (5 mM) caused potentiation of twitch force (by ~20 % for H₂O₂); this effect was due to the increase in the Ca²⁺ sensitivity of the contractile apparatus that occurs under such circumstances and was fully reversed by subsequent exposure to 10 mM DTT. We conclude that: (a) the redox potential across the sarcomplamsic reticulum has no noticeable direct effect on normal E-C coupling in mammalian skeletal muscle, (b) oxidising the Ca²⁺-release channels and greatly increasing their sensitivity to Ca²⁺-induced Ca²⁺ release does not alter the amount of Ca²⁺ released by an action potential and (c) oxidation potentiates twitches by a GSH-mediated increase in the Ca²⁺ sensitivity of the contractile apparatus.

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