Bidirectional role of Costameres in the pathophysiology of mdx skeletal muscles.

Skeletal muscles in Duchenne Muscular Dystrophy (DMD) are most susceptible to injury at a point in maturation when dystrophin is absent and utrophin dissipates from the membrane. The lack of the dystrophin glycoprotein complex (DGC) leaves a residual costameric scaffold that structurally connects the peripheral sarcomeres to the sarcolemma. However, the residual costameres are weak and transmit less lateral force making it unclear how they contribute to the pathophysiology of DMD. Here we found that costameres were near absent in mature mdx4cv:desmin double knockout (dko) fast 2b myofibers where the compensating utrophin protein is not upregulated at costameres. The lack of costameres decoupled sarcomere strain injury from tearing the membrane leading to isolated necrotic myofibers. Despite a 30% reduction in the proportion of myofibers with centrally located nuclei (a marker of degenerating/regenerating myofibers), the fast 2b dko muscles were atrophic and profoundly weakened by the sarcomere strain injury. Thus, our data is consistent with the DGC protecting the membrane and peripheral sarcomeres from the bidirectional forces that propagate through the desmin-fortified costameres.