Key result
Phospho-mimicking Connexin-43 (S3E) normalized microtubule organization and protected against arrhythmias and fibrosis in Duchenne muscular dystrophy mice, while phospho-dead Cx43 (S3A) abolished the protective effects of Colchicine.
Why the study?
Dilated cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy patients, and Connexin-43 phosphorylation status drives arrhythmias and fibrosis.
Does Colchicine treatment or Cx43 phosphorylation mimicry improve microtubule organization and reduce arrhythmias and fibrosis in DMD mice?
Does Colchicine treatment or Cx43 phosphorylation mimicry improve microtubule organization and reduce arrhythmias and fibrosis in DMD mice?
Modulating Connexin-43 phosphorylation and microtubule organization may offer a novel therapeutic pathway for treating Duchenne muscular dystrophy-associated cardiomyopathy and arrhythmias.
Dilated cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD) patients due to advancements in skeletal muscle therapies yet limited presence of cardiac treatments. The phosphorylation status of gap junction protein Connexin-43 (Cx43) drives Cx43 remodeling and the development of arrhythmias and fibrosis. Based on evidence that Colchicine drug treatment improves Cx43 phosphorylation and remodeling, we compared the microtubule cytoskeleton in DMD mice (mdx) versus mdx mice genetically altered to be Cx43-phosphorylation-deficient (mdxS3A). Reciprocally, we analyzed the microtubule cytoskeleton in mdx mice genetically altered to be Cx43-phospho-mimicking (mdxS3E). We found a link between the phospho-status of Connexin-43 and regulation of microtubule organization, in which phospho-dead Cx43 (S3A) inhibits improvements seen with Colchicine treatment in mdx mice, and phospho-mimic S3E promotes microtubule reorganization in mdx mice. A reduction in arrhythmias and fibrosis suggests an unsuspecting Cx43-microtubule link for translational corrective activities for DMD cardiomyopathy.
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Himelman et al. (2022) studied Duchenne muscular dystrophy cardiomyopathy. Colchicine and Cx43 genetic modifications (S3E/S3A) vs. Saline or unmodified mdx mice was evaluated on Microtubule organization, Cx43 remodeling, and arrhythmia severity. Phospho-mimicking Connexin-43 (S3E) normalized microtubule organization and protected against arrhythmias and fibrosis in Duchenne muscular dystrophy mice, while phospho-dead Cx43 (S3A) abolished the protective effects of Colchicine.
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