Dysferlin pathophysiology in LGMD R2 involves increased Ca2+ leak at the triad junction, suggesting that suppressing abnormal leak and Ca2+-induced Ca2+ release may be therapeutic.
Suppression of abnormal Ca2+ leak and calcium-induced calcium release may be a therapeutic strategy for LGMD R2 and other muscle diseases linked to Ca2+ dysregulation.
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.
Bloch et al. (Mon,) conducted a review in Limb Girdle Muscular Dystrophy Type R2 (LGMD R2). Dysferlin was evaluated. Dysferlin pathophysiology in LGMD R2 involves increased Ca2+ leak at the triad junction, suggesting that suppressing abnormal leak and Ca2+-induced Ca2+ release may be therapeutic.