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Effects of oxidation and reduction on contractile function in skeletal muscle fibres of the rat

G. D. Lamb and G. S. Posterino

This study investigated the effects of the oxidants hydrogen peroxide (H₂O₂) and 2,2'-dithiodipyridine (DTDP), and reductants, glutathione (GSH) and dithiothreitol (DTT), on the properties of the contractile apparatus of rat fast- and slow-twitch skeletal muscle fibres, in order to assess how oxidation affects muscle function. Skinned muscle fibres were activated in heavily-buffered Ca²⁺ solutions. The force-[Ca²⁺] relationship before and after various treatments was fitted by a Hill curve described by the maximum Ca²⁺-activated force, pCa₅₀ (-log₁₀[Ca²⁺] giving half-maximum force) and n_H (the Hill coefficient). Exposing freshly skinned fibres to strong reducing conditions (i.e. 10 mM DTT or 5 mM GSH) had little if any effect on Ca²⁺ sensitivity (pCa₅₀ or n_H). The effect of oxidants H₂O₂ and DTDP depended on whether the fibre was relaxed (in pCa > 9) or activated during the exposure. In both fast- and slow-twitch fibres a 5 min exposure to 10 mM H₂O₂ at pCa > 9 had no effect on pCa₅₀, causing only a reduction in n_H. In contrast, when fast-twitch fibres were activated in the presence of 10 mM H₂O₂ (or 100 µM DTDP) there was a substantial increase in pCa₅₀ (by ~0.06 and 0.1, respectively), as well as larger decreases in n_H than occurred in relaxed fibres, with all effects being reversed by DTT (10 mM, 10 min). In slow-twitch soleus fibres, the activation-dependent effect of DTDP was even greater (pCa₅₀ increased by ~0.35), and it was found that the rate of reversal in DTT was also increased by activation. A separate important phenomenon was that fast-twitch fibres that had been oxidised with H₂O₂ or DTDP (while either relaxed or activated) showed a paradoxical increase in Ca²⁺ sensitivity (~0.04 and 0.25 increase in pCa₅₀, respectively) when briefly exposed to the endogenous reductant GSH (5 mM, 2 min). This effect was reversed by DTT or longer (> 20 min) exposure to GSH, did not occur in slow-twitch soleus fibres, and may contribute to post-tetanic potentiation in fast-twitch muscle. Maximum force was not affected by any of the above treatments, whereas exposure to a high concentration of DTDP (1 mM) did greatly reduce force production. These findings reveal a number of novel and probably important effects of oxidation on the contractile apparatus in skeletal muscle fibres.

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