Dysferlin at transverse tubules regulates Ca(2+) homeostasis in skeletal muscle

Abstract

The class of muscular dystrophies linked to the genetic ablation or mutation of dysferlin, including Limb Girdle Muscular Dystrophy 2B (LGMD2B) and Miyoshi Myopathy (MM), are late-onset degenerative diseases. In lieu of a genetic cure, treatments to prevent or slow the progression of dysferlinopathy are of the utmost importance. Recent advances in the study of dysferlinopathy have highlighted the necessity for the maintenance of calcium handling in altering or slowing the progression of muscular degeneration resulting from the loss of dysferlin. This review highlights new evidence for a role for dysferlin at the transverse (t-) tubule of striated muscle, where it is involved in maintaining t-tubule structure and function.

Keywords: calcium; excitation-contraction coupling; muscular dystrophy; myopathy.

Figure 1

Proposed model of t-tubule dysferlin. Dysferlin is anchored in the t-tubule membrane by its transmembrane domain, with its extreme C-terminus exposed to the lumen of the t-tubule. In close proximity to dysferlin are proteins of the triad junction, the L-type Ca²⁺ channel (DHPR) in the t-tubule and the ryanodine receptor (RyR) in the sarcoplasmic reticulum. Caveolin 3 (Cav3) and Bin1, both important for the development of t-tubules, are known binding partners of dysferlin. Dysferlin also associates with annexins, which respond to changes in intracellular Ca²⁺ to promote wound repair.

Figure 2

Pathophysiology of dysferlin deficiency. Dysferlin is hypothesized to respond to influxes of Ca²⁺ and promote wound repair of the t-tubule membrane. Mechanical stress or membrane injury results in influx of Ca²⁺, mediated by the L-type Ca²⁺ channel, and this Ca²⁺ influx does not cause significant muscle injury in wild type muscle cells. However, in the absence of dysferlin, Ca²⁺ influx to the cytosol is greatly exaggerated, disrupting Ca²⁺ homeostasis and EC-coupling. This activates a cascade of Ca²⁺-mediated events that promote further damage to the muscle fiber, including Ca²⁺-induced proteolysis and oxidative stress. Together, these processes contribute to the eventual myopathy, spurring increased necrosis and inflammation.