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Low [ATP] and elevated [Mg²⁺] reduce depolarization-induced Ca²⁺ release in rat skinned skeletal muscle fibres

R. Blazev and G. D. Lamb

This study examined whether reduced [ATP], raised [Mg²⁺] and the presence of the metabolites AMP and inosine monophosphate (IMP) affected depolarization-induced Ca²⁺ release from the sarcoplasmic reticulum (SR) in mechanically skinned skeletal muscle fibres of the rat. The amount of Ca²⁺ released was determined from the extent of SR Ca²⁺ depletion following a depolarization in the specified conditions with 2 mM free EGTA present to chelate released Ca²⁺.

In the presence of 8 mM total ATP and 1 mM free Mg²⁺, most of the SR Ca²⁺ could be released by a single (2-3 s) depolarization. Paired comparisons in the same fibres showed that raising the [Mg²⁺] from 1 to 3 mM reduced the total amount of Ca²⁺ released by a single depolarization by ~40 %. At 1 mM Mg²⁺, lowering the [ATP] to 0·5 mM did not cause a detectable change in the total amount of Ca²⁺ released, but when the release rate was reduced by the presence of 3 mM Mg²⁺, lowering the [ATP] to 0·5 mM resulted in a further (~20 %) reduction in the total amount of Ca²⁺ released.

At 1 mM Mg²⁺ and 0·5 mM ATP, neither the presence of 3 mM AMP alone nor 3 mM AMP plus 3 mM IMP caused a significant change in total Ca²⁺ release. Furthermore, at 1 mM Mg²⁺, the combined effect of lowering the [ATP] from 8 to 0·5 mM and simultaneously adding 3 mM AMP and 3 mM IMP did not significantly alter total Ca²⁺ release. However, when Ca²⁺ release was already reduced by the presence of 3 mM Mg²⁺ and 0·5 mM ATP (to ~50 %), addition of 3 mM AMP and 3 mM IMP significantly reduced the amount of Ca²⁺ released a further 2-fold.

These results show that depolarization-induced Ca²⁺ release in mammalian muscle fibres is modulated by the concentration of ATP and its metabolic products, as well as by the free [Mg²⁺]. Consequently, the (reversible) reduction in Ca²⁺ release occurring in a muscle fibre after prolonged exercise could result not only from raised [Mg²⁺] but also from a severe reduction in [ATP] locally near the Ca²⁺ release channels, with the accompanying build-up of AMP and IMP further exacerbating this effect.

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