Abstract
The mouse model of Duchenne muscular dystrophy, the mdx mouse, displays changes in Ca2+ homeostasis that may lead to the pathology of the muscle. Here we examine the activation of store overload-induced Ca2+ release (SOICR) in mdx muscle. The activation of SOICR is associated with the depolymerization of the sarcoplasmic reticulum (SR) Ca2+ buffer calsequestrin and the reduction of SR Ca2+ buffering power (B-SR). The role of SOICR in healthy and dystrophic muscle is unclear. Using skinned fibers we show that lowering the Mg2+ concentration can activate discrete Ca2+ release events that did not necessarily lead to activation of SOICR. However, SOICR waves could propagate into these fiber segments. The average delay to activation of SOICR in mdx fibers was longer than in wild-type (WT) fibers. In the lowered Ca2+-buffered environment following large SOICR events, brief waves in mdx fibers displayed a low amplitude and propagation rate, in contrast to WT fibers that showed a range of amplitudes correlated with wave propagation rate. The distinct properties of SOICR in mdx fibers were consistent with a ryanodine receptor (RyR) that was leakier to Ca2+ than in WT. The consequence of delayed SOICR and leaky RyRs is prolonged high BSR and a reduction in free Ca2+ concentration inside the SR as total SR calcium drops. We present a hypothesis that SOICR activation is required in healthy muscle and that this mechanism works suboptimally in mdx fibers to fail to limit the activation of store-operated Ca2+ entry.