Reduced voltage-activated Ca²⁺ release flux in muscle fibers from a rat model of Duchenne dystrophy

The potential pathogenic role of disturbed Ca²⁺ homeostasis in Duchenne muscular dystrophy (DMD) remains a complex, unsettled issue. We used muscle fibers isolated from 3-mo-old DMD^mdx rats to further investigate the case. Most DMD^mdx fibers exhibited no sign of trophic or morphology distinction as compared with WT fibers and mitochondria and t-tubule membrane networks also showed no stringent discrepancy. Under voltage clamp, values for holding current were similar in the two groups, whereas values for capacitance were larger in DMD^mdx fibers, suggestive of enhanced amount of t-tubule membrane. The Ca²⁺ current density across the channel carried by the EC coupling voltage sensor (Ca_V1.1) was unchanged. The maximum rate of voltage-activated sarcoplasmic reticulum (SR) Ca²⁺ release was reduced by 25% in the DMD^mdx fibers, with no change in voltage dependency. Imaging resting Ca²⁺ revealed rare spontaneous local SR Ca²⁺ release events with no sign of elevated activity in DMD^mdx fibers. Under current clamp, DMD^mdx fibers generated similar trains of action potentials as WT fibers. Results suggest that reduced peak amplitude of SR Ca²⁺ release is an inherent feature of this DMD model, likely contributing to muscle weakness. This occurs despite a preserved amount of releasable Ca²⁺ and with no change in excitability, Ca_V1.1 channel activity, and SR Ca²⁺ release at rest. Although we cannot exclude that fibers from the 3-mo-old animals do not yet display a fully developed disease phenotype, results provide limited support for pathomechanistic concepts frequently associated with DMD such as membrane fragility, excessive Ca²⁺ entry, or enhanced SR Ca²⁺ leak.