Abstract 16468: A Microtubule-Connexin 43 Regulatory Link Suppresses Cardiac Fibrosis and Arrhythmias in Duchenne Muscular Dystrophy Mice

Abstract

Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular degenerative disorder that leads to premature death in the teens because of multiple dysfunctions in the heart and skeletal muscle. DMD is caused by the absence of dystrophin, a sarcolemma protein encoded by the dmd gene, located on the X chromosome. 1:5,000 boys are diagnosed with DMD annually, and there is no cure. Clinically, steroid-based treatments reduce inflammation and thus, palliate skeletal muscle pathology. With improvements in the skeletal muscle, DMD-associated cardiomyopathy has become the leading cause of mortality because nearly all patients develop cardiac disease by age 20. Connexin 43 (Cx43) is a gap junction protein and is responsible for the electrical propagation of signals in the heart; it is upregulated and undergoes pathological remodeling, away from the intercalated disc in the heart of DMD mice (mdx) and patients. Hypo-phosphorylation of a specific triplet of serines in Cx43 had been found in mdx and DMD hearts. To study a potential rescue role for Cx43 phosphorylation in DMD, the triplet of serine residues was replaced by glutamic acid or alanine residues to create a phospho-mimic (Cx43-S3E) or a phospho-dead (Cx43-S3A) version of Cx43 respectively. We found that Cx43-S3E but not Cx43-S3A prevents Cx43 remodeling and development of fibrotic cardiomyopathy, arrhythmias, and heart failure in mdx mice. Remarkably, inhibition of hyperdensified, dystrophic microtubule (MT) polymerization by treatment with colchicine (Colch) enhances Cx43 phosphorylation and reduces Cx43 remodeling in dystrophic hearts, suggesting the presence of a MT-Cx43 regulatory connection. This connection could play an important role in the development of dystrophic cardiomyopathy. Our studies explore the electrophysiological properties of Cx43-S3E in DMD cardiomyocytes, and investigate a requirement for Cx43-S3A in the Colch-dependent improvement of the MT dynamics, uncovering a novel link between phospho-Cx43 and MT organization. Furthermore, the results suggest a novel target for the treatment of DMD-cardiomyopathy.