Ca2+ leakage out of the sarcoplasmic reticulum is increased in type I skeletal muscle fibres in aged humans

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Abstract

The present study examined whether the lower Ca(2+) storage levels in the sarcoplasmic reticulum (SR) in vastus lateralis muscle fibres in Old (70 ± 4 years) relative to Young (24 ± 4 years) human subjects is the result of increased leakage of Ca(2+) out of the SR through the Ca(2+) release channels/ryanodine receptors (RyRs) and due to oxidative modification of the RyRs. SR Ca(2+) accumulation in mechanically skinned muscle fibres was examined in the presence of 1, 3 or 10 mm cytoplasmic Mg(2+) because raising [Mg(2+)] strongly inhibits Ca(2+) efflux through the RyRs. In type I fibres of Old subjects, SR Ca(2+) accumulation in the presence of 1 mm Mg(2+) approached saturation at shorter loading times than in Young subjects, consistent with Ca(2+) leakage limiting net uptake, and raising [Mg(2+)] to 10 mm in such fibres increased maximal SR Ca(2+) accumulation. No significant differences were seen in type II fibres. Treatment with dithiothreitol (10 mm for 5 min), a strong reducing agent, also increased maximal SR Ca(2+) accumulation at 1 mm Mg(2+) in type I fibres of Old subjects but not in other fibres. The densities of dihydropyridine receptors and RyRs were not significantly different in muscles of Old relative to Young subjects. These findings indicate that Ca(2+) leakage from the SR is increased in type I fibres in Old subjects by reversible oxidative modification of the RyRs; this increased SR Ca(2+) leak is expected to have both direct and indirect deleterious effects on Ca(2+) movements and muscle function.

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