Abstract 12884: Connexin-43 Reduction Rescues Cardiac and Skeletal Muscle Pathology in a Mouse Model of Duchenne Muscular Dystrophy Symptomatic Carriers

Duchenne Muscular Dystrophy (DMD) and its associated cardiomyopathy is a severe x-linked neuromuscular degenerative disorder that primarily affects males. However, 8% of female carriers of DMD are symptomatic and under-represented in research due to the lack of a faithful mouse model. To generate a symptomatic mouse model of DMD carriers, we injected mdx (murine DMD) embryonic stem cells (ESCs) into wild-type (WT) blastocysts (mdx/WT chimera). We found that mdx/WT chimeras develop cardiomyopathy, arrhythmias, and fibrosis as measured by echocardiography, electrocardiography, and histological staining. Also, forelimb grip strength declined and we found evidence of skeletal muscle weakness, fibrosis, and inflammation characteristic of DMD female carriers. Furthermore, we discovered that levels of Connexin-43 (Cx43), the primary gap junctional protein in the heart, was pathologically increased and mislocalized in mdx/WT chimeras. Genetic reduction of Cx43 copy number protected mdx/WT chimeras from cardiac, and unexpectedly, skeletal muscle fiber damage, where Cx43 is not expressed. However, Cx43 expression is seen in the mononuclear cells invading the dystrophic skeletal muscle as seen by immunofluorescence and in Fluorescence-activated cell sorted (FACS) F4/80/Cd11b double-positive macrophages by western blot. Ethidium bromide uptake in FACS-macrophages confirmed functional activity of Cx43 in this population. Because excess of Cx43 has been associated with cell death, we believe that Cx43 reduction represents a strong therapeutic opportunity for the treatment of understudied DMD carriers in the myopathic heart and - via invading macrophages - the dystrophic skeletal muscle.