Expression of Dp260 in muscle tethers the actin cytoskeleton to the dystrophin-glycoprotein complex and partially prevents dystrophy

Dystrophin forms a mechanical link between the actin cytoskeleton and the extracellular matrix in muscle that helps maintain sarcolemmal integrity. Two regions of dystrophin have been shown to bind actin: the N-terminal domain and rod domain repeats 11-17. To better understand the roles of these two domains and whether the rod domain actin-binding domain alone can support a mechanically functional link with actin, we constructed transgenic mice expressing Dp260 in skeletal muscle. Dp260, the retinal isoform of dystrophin, lacks the N-terminal domain and a significant portion of the rod domain, but retains the rod domain actin-binding domain. Our results indicate that Dp260 expression restores a stable association between costameric actin and the sarcolemma, assembles the dystrophin-glycoprotein complex, and significantly slows the progression of the dystrophy in the dystrophin-deficient mdx mouse. We assessed the functional integrity of the mechanical link in Dp260 transgenic mdx mice and found that Dp260 muscles showed normal resistance to contraction-induced injury, but dramatic reductions in force generation similar to those found with mdx muscles. Morphologically, Dp260 muscles displayed reduced amounts of inflammation and fibrosis, but still showed a significant, albeit reduced, amount of degeneration/regeneration. These data demonstrate that protection from contraction-induced injury can dramatically ameliorate, but not completely halt, the dystrophic process. We suggest that a non-mechanical defect, attributed to the loss of the N terminus of dystrophin, is likely responsible for the residual dystrophy observed.