Voltage-gated ion channel dysfunction precedes cardiomyopathy development in the dystrophic heart

• Published in: PloS one Vol. 6; no. 5; p. e20300
• Main Authors: Koenig, Xaver, Dysek, Sandra, Kimbacher, Stefanie, Mike, Agnes K, Cervenka, Rene, Lukacs, Peter, Nagl, Katrin, Dang, Xuan B, Todt, Hannes, Bittner, Reginald E, Hilber, Karlheinz
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.05.2011; Public Library of Science (PLoS)
• Subjects: Abnormalities; Action potential; Action Potentials - physiology; Analysis; Animals; Animals, Newborn; Arrhythmia; Barium - metabolism; Biology; Calcium; Calcium channels; Calcium Channels, L-Type - metabolism; Cardiomyocytes; Cardiomyopathies - pathology; Cardiomyopathies - physiopathology; Cardiomyopathy; Cells, Cultured; Channel gating; Complications; Deactivation; Developmental stages; Duchenne's muscular dystrophy; Dystrophin; Dystrophin - genetics; Dystrophy; EKG; Electric potential; Electrocardiography; Gene mutation; Genetic aspects; Heart; Heart diseases; Humans; Inactivation; Ion channels; Kinases; Medical research; Medicine; Mice; Mice, Inbred C57BL; Mice, Inbred mdx; Muscular dystrophy; Muscular Dystrophy, Duchenne - genetics; Muscular Dystrophy, Duchenne - pathology; Muscular Dystrophy, Duchenne - physiopathology; Mutation; Myocardial diseases; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Neonates; Newborn infants; Patch-Clamp Techniques; Pathology; Reduction; Rodents; Sodium; Sodium - metabolism; Sodium channels; Sodium Channels - metabolism; Utrophin; Utrophin - deficiency; Voltage; Austria
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0020300

Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, is associated with severe cardiac complications including cardiomyopathy and cardiac arrhythmias. Recent research suggests that impaired voltage-gated ion channels in dystrophic cardiomyocytes accompany cardiac pathology. It is, however, unknown if the ion channel defects are primary effects of dystrophic gene mutations, or secondary effects of the developing cardiac pathology. To address this question, we first investigated sodium channel impairments in cardiomyocytes derived from dystrophic neonatal mice prior to cardiomyopahty development, by using the whole cell patch clamp technique. Besides the most common model for DMD, the dystrophin-deficient mdx mouse, we also used mice additionally carrying an utrophin mutation. In neonatal cardiomyocytes, dystrophin-deficiency generated a 25% reduction in sodium current density. In addition, extra utrophin-deficiency significantly altered sodium channel gating parameters. Moreover, also calcium channel inactivation was considerably reduced in dystrophic neonatal cardiomyocytes, suggesting that ion channel abnormalities are universal primary effects of dystrophic gene mutations. To assess developmental changes, we also studied sodium channel impairments in cardiomyocytes derived from dystrophic adult mice, and compared them with the respective abnormalities in dystrophic neonatal cells. Here, we found a much stronger sodium current reduction in adult cardiomyocytes. The described sodium channel impairments slowed the upstroke of the action potential in adult cardiomyocytes, and only in dystrophic adult mice, the QRS interval of the electrocardiogram was prolonged. Ion channel impairments precede pathology development in the dystrophic heart, and may thus be considered potential cardiomyopathy triggers.