The potential of sarcospan in adhesion complex replacement therapeutics for the treatment of muscular dystrophy

Abstract

Three adhesion complexes span the sarcolemma and facilitate critical connections between the extracellular matrix and the actin cytoskeleton: the dystrophin- and utrophin-glycoprotein complexes and α7β1 integrin. Loss of individual protein components results in a loss of the entire protein complex and muscular dystrophy. Muscular dystrophy is a progressive, lethal wasting disease characterized by repetitive cycles of myofiber degeneration and regeneration. Protein-replacement therapy offers a promising approach for the treatment of muscular dystrophy. Recently, we demonstrated that sarcospan facilitates protein-protein interactions amongst the adhesion complexes and is an important potential therapeutic target. Here, we review current protein-replacement strategies, discuss the potential benefits of sarcospan expression, and identify important experiments that must be addressed for sarcospan to move to the clinic. Sarcospan facilitates interactions between the adhesion glycoprotein complexes, dystrophin- and utrophin-glycoprotein complexes and α7β1 integrin, which protect the sarcolemma during muscle contraction. Over-expression of sarcospan ameliorates dystrophic pathology in mdx muscle by upregulating integrins and the utrophin-glycoprotein complex, Akt phosphorylation, and glycosylation of the dystroglycans. These mechanisms result in stabilization of the sarcolemmal membrane by restoring connections to laminin. © 2013 FEBS.