Coupling of excitation to Ca2+ release is modulated by dysferlin

Abstract

Dysferlin concentrates in the transverse tubules of skeletal muscle and stabilizes Ca²⁺ transients when muscle fibres are subjected to osmotic shock injury (OSI). We show here that voltage-induced Ca²⁺ transients elicited in dysferlin-null A/J myofibers are smaller than control A/WySnJ fibres. Regional expression of Venus-dysferlin chimeras in A/J fibres restores the full amplitude of the Ca²⁺ transients and protects against OSI. We also show that drugs that target ryanodine receptors (RyR1: dantrolene, tetracaine, S107) and L-type Ca²⁺ channels (LTCC: nifedipine, verapamil, diltiazem) prevent the decrease in Ca²⁺ transients in A/J fibres following OSI. Diltiazem specifically increases transients by ∼20% in uninjured A/J fibres, restoring them to control values. The fact that both RyR1s and LTCCs are involved in OSI-induced damage suggests that damage is mediated by increased Ca²⁺ leak from the sarcoplasmic reticulum (SR) through the RyR1. Congruent with this, injured A/J fibres produced Ca²⁺ sparks and Ca²⁺ waves. S107 (stabilizer of RyR1-FKBP coupling that reduces Ca²⁺ leak) or local expression of Venus-dysferlin prevented OSI-induced Ca²⁺ waves. Our data suggest that dysferlin modulates SR Ca²⁺ release in skeletal muscle, and that in its absence OSI causes increased RyR1-mediated Ca²⁺ leak from the SR into the cytoplasm.

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