Subcellular Localization of Dystrophin Isoforms in Cardiomyocytes and Phenotypic Analysis of Dystrophin-deficient Mice Reveal Cardiac Myopathy is Predominantly Caused by a Deficiency in Full-length Dystrophin

• Published in: Experimental Animals Vol. 62; no. 3; pp. 211 - 217
• Main Authors: Masubuchi, Nami, Shidoh, Yuichi, Kondo, Shunzo, Takatoh, Jun, Hanaoka, Kazunori
• Format: Journal Article
• Language: English
• Published: Japan Japanese Association for Laboratory Animal Science 2013
• Subjects: Animals; Cardiomyopathies - genetics; cardiomyopathy; dp427; dp71; dystrophin; Dystrophin - deficiency; Dystrophin - genetics; Fibrosis; heart; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Inbred Strains; Myocardium - cytology; Myocardium - pathology; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Original; Phenotype; Protein Isoforms - genetics; Sarcolemma - metabolism
• ISSN: 1341-1357; 1881-7122
• DOI: 10.1538/expanim.62.211

Duchenne muscular dystrophy (DMD) is an X-linked recessive progressive muscle degenerative disorder that causes dilated cardiomyopathy in the second decade of life in affected males. Dystrophin, the gene responsible for DMD, encodes full-length dystrophin and various short dystrophin isoforms. In the mouse heart, full-length dystrophin Dp427 and a short dystrophin isoform, Dp71, are expressed. In this study, we intended to clarify the functions of these dystrophin isoforms in DMD-related cardiomyopathy. We used two strains of mice: mdx mice, in which Dp427 was absent but Dp71 was present, and DMD-null mice, in which both were absent. By immunohistochemical staining and density-gradient centrifugation, we found that Dp427 was located in the cardiac sarcolemma and also at the T-tubules, whereas Dp71 was specifically located at the T-tubules. In order to determine whether T tubule-associated Dp71 was involved in DMD-related cardiac disruption, we compared the cardiac phenotypes between DMD-null mice and mdx mice. Both DMD-null mice and mdx mice exhibited severe necrosis, which was followed by fibrosis in cardiac muscle. However, we could not detect a significant difference in myocardial fibrosis between mdx mice and DMD-null mice. Based on the present results, we have shown that cardiac myopathy is caused predominantly by a deficiency of full-length dystrophin Dp427.