Dysferlin in Membrane Trafficking and Patch Repair

Abstract

The muscular dystrophies are a heterogeneous group of inherited disorders, defined by progressive muscle weakness and atrophy. Following the discovery of dystrophin, remarkable progress has been made in defining the molecular properties of proteins involved in the various dystrophies. This has underlined the importance of the dystrophin‐associated protein complex as a cell membrane scaffold, providing structural stability to muscle cells (McNeil PL, Khakee R. Disruptions of muscle fiber plasma membranes. Role in exercise‐induced damage. Am J Pathol 1992;140:1097–1109). While the dystrophies linked to loss of function of dystrophin and its associated proteins are caused by diminished membrane integrity, it is now believed that a new class of dystrophies arises because of a diminished capacity for rapid muscle membrane repair after injury. Dysferlin is the first identified member of a putative muscle‐specific repair complex that permits rapid resealing of membranes disrupted by mechanical stress. Membrane resealing is a function conserved by most cells and is mediated by a mechanism closely resembling regulated, Ca2+‐dependent exocytosis. A primary role for dysferlin in this pathway, as a Ca2+‐regulated fusogen, has been suggested, and a number of candidate partner proteins have been identified. This review outlines the current understanding of the role of dysferlin in membrane repair and the evolving picture of dysferlin‐related signaling pathways in muscle cell physiology and pathology.

Dysferlin Deficiency Enhances Monocyte Phagocytosis

“…3,4 However, dysferlin is also expressed in many other cell types, including CD14 ϩ monocytes. 5,6 Thus, nonmyofiber cells may possibly contribute to the disease process.…”

Membrane wounding triggers ATP release and dysferlin-mediated intercellular calcium signaling

“…In a direct role dysferlin might allow a wounded cell to survive an injury. It has been proposed that Ca 2+ influx through a plasma membrane breach triggers dysferlin-mediated membrane fusion to seal the lesion (Bansal et al, 2003;Glover and Brown, 2007;Lennon et al, 2003;McNeil and Kirchhausen, 2005). Alternatively, an indirect role for dysferlin in wound repair may involve intercellular signaling (Chiu et al, 2009).…”

Unmasking Potential Intracellular Roles For Dysferlin through Improved Immunolabeling Methods

“…Since its discovery, dysferlin has been referred to as a plasma membrane protein that is also found in cytoplasmic vesicles (Anderson et al 1999;Bansal et al 2003), largely because it appears enriched at the sarcolemma in cross sections of snap-frozen, unfixed muscle. The accumulation of subsarcolemmal vesicles in dysferlinopathic muscle, and studies of muscle fibers cultured from mice lacking dysferlin that involve laser wounding or other damaging treatments, have suggested that dysferlin's function is to repair disrupted plasma membranes (Bansal and Campbell, 2004;Glover and Brown, 2007;Han and Campbell, 2007).…”