Mice lacking the a-Dystrobrevin or Dystrophin proteins of the DGC exhibit dystrophic characteristics in skeletal muscle

Abstract

Muscular dystrophies are a group of genetic disorders that primarily affect skeletal muscle and are characterized by progressive muscle wasting and a shortened life span. Within skeletal muscle, the dystrophin-glycoprotein complex (DGC) links the extracellular matrix and the muscle cell cytoskeleton. Major forms of muscular dystrophy have been linked to abnormalities of the DGC proteins. Due to this, mice with mutations affecting the DGC are significant models for studying muscular dystrophy and its pathology. In this study we examined MDX mice, which do not express the Dystrophin protein, a-Dystrobrevin knockout mice (a-dbn- /-), which do not express the a-Dystrobrevin scaffolding protein, a-Syntrophin knockout mice (a-syn-/-), which do not express the a-Syntrophin signaling protein, and double knockout (DKO) (a-dbn-/- , a-syn-/-) mice. We performed histological analyses of their skeletal muscle in search of dystrophic characteristics and inspected the morphology of their neuromuscular junctions (NMJs) to look for denervation. We found that the expression of the Dystrophin and a- Dystrobrevin proteins of the DGC are both significant determinants of skeletal muscle integrity and innervation. The expression of a-Syntrophin proved to be insignificant in determining the health of skeletal muscle. This study expanded our understanding of the DGC in both healthy and diseased muscle as well as how mutations of the DGC proteins influence the health of muscle fibers and contribute to characteristics of muscular dystrophy.