Decreased Myocardial nNOS, Increased iNOS and Abnormal ECGs in Mouse Models of Duchenne Muscular Dystrophy

• Published in: Journal of molecular and cellular cardiology 1999-10, Vol.31 (10), p.1857-1862
• Main Authors: Bia, Britta L, Cassidy, Paul J, Young, Martin E, Rafael, Jill A, Leighton, Brendan, Davies, Kay E, Radda, George K, Clarke, Kieran
• Format: Article
• Language: English
• Subjects: Aging; Animals; Body Weight; Conduction abnormalities; Cytoskeletal Proteins - genetics; Duchenne muscular dystrophy mdx mouse heart; Dystrophin - genetics; Electrocardiogram; Electrocardiography; Endothelial nitric oxide synthase; Heart - growth & development; Heart - physiopathology; Inducible nitric oxide synthase; Membrane Proteins - genetics; Mice; Mice, Inbred C57BL; Mice, Inbred mdx; Mice, Inbred Strains; Muscular Dystrophy, Animal - enzymology; Muscular Dystrophy, Animal - genetics; Muscular Dystrophy, Animal - physiopathology; Muscular Dystrophy, Duchenne - enzymology; Muscular Dystrophy, Duchenne - physiopathology; Neuronal nitric oxide synthase; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Organ Size; Utrophin
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1006/jmcc.1999.1018

Duchenne muscular dystrophy is a devastating neuromuscular disease caused by lack of the protein, dystrophin, in skeletal muscle and heart, although the biochemical mechanism by which dystrophin loss causes muscle dysfunction is unknown. Here we show that the dystrophin-deficient mdx mouse and a mouse lacking both dystrophin and the dystrophin-related protein, utrophin (dko), have abnormal electrocardiograms (ECGs). In skeletal muscle, dystrophin is normally associated with neuronal nitric oxide synthase (nNOS) at the sarcolemma. Consequently, we have measured NOS isoform activities in hearts from control, mdx and dko mice. In control mouse hearts, eNOS and nNOS activities increased by 120% and 47%, respectively, between 2 and 6 months of age. In mdx mice, myocardial nNOS activity was decreased by 60%, 84% and 80% at 2, 6 and 12 months of age, respectively. Similarly, hearts from dko mice showed a 65% decrease in nNOS activity compared to controls at 2 months of age. Endothelial NOS (eNOS) activity was not affected by dystrophin loss, but inducible NOS (iNOS) activity was seven-fold higher than control in the mdx mouse heart by 12 months of age. We conclude that lack of dystrophin in the mdx mouse results in abnormal ECGs that are associated with decreased myocardial nNOS and increased iNOS activities.