Dysferlin and the Regulation of Ca²⁺ Release in Skeletal Muscle

Dysferlin is a large transmembrane protein that is mutated or absent in Limb Girdle Muscular Dystrophy Type R2 (LGMD R2). Although it may have several functions in healthy skeletal muscle, most research on dysferlin has addressed its roles in repair of the sarcolemma and in maintaining proper control of Ca²⁺ homeostasis at the triad junction, where it concentrates. Here, we review the literature on the role of dysferlin in both membrane repair and in Ca²⁺ homeostasis, with a focus on the latter. We propose that pathophysiology in LGMD R2 is in part the result of increased leak of Ca²⁺ at the triad junction, which in turn reduces the amplitude of Ca²⁺ transients and, by activating Ca²⁺-induced Ca²⁺ release, or CICR, at the triad junction, induces Ca²⁺ waves. We discuss the mechanisms that regulate Ca²⁺ leak and Ca²⁺ levels at the triad junction under physiological and pathophysiological conditions. Our results suggest that suppression of abnormal leak and CICR may be therapeutic for LGMD R2 and other diseases of muscle linked to dysregulation of Ca²⁺ homeostasis.