title: Uniform low-level dystrophin expression in the heart partially preserved cardiac function in an aged mouse model of Duchenne cardiomyopathy.
abstract: Dystrophin deficiency results in Duchenne cardiomyopathy, a primary cause of death in Duchenne muscular dystrophy (DMD). Gene therapy has shown great promise in ameliorating the cardiac phenotype in mouse models of DMD. However, it is not completely clear how much dystrophin is required to treat dystrophic heart disease. We and others have shown that mosaic dystrophin expression at the wild-type level, depending on the percentage of dystrophin positive cardiomyocytes, can either delay the onset of or fully prevent cardiomyopathy in dystrophin-null mdx mice. Many gene therapy strategies will unlikely restore dystrophin to the wild-type level in a cardiomyocyte. To determine whether low-level dystrophin expression can reduce the cardiac manifestations in DMD, we examined heart histology, ECG and hemodynamics in 21-m-old normal BL6 and two strains of BL6-background dystrophin-deficient mice. Mdx3cv mice show uniform low-level expression of a near full-length dystrophin protein in every myofiber while mdx4cv mice have no dystrophin expression. Immunostaining and western blot confirmed marginal level dystrophin expression in the heart of mdx3cv mice. Although low-level expression did not reduce myocardial histopathology, it significantly ameliorated QRS prolongation and normalized diastolic hemodynamic deficiencies. Our study demonstrates for the first time that low-level dystrophin can partially preserve heart function.
authors.affiliation: Department of Molecular Microbiology and Immunology, School of Medicine, The University of Missouri, Columbia, MO 65212, USA.
authors.forename: Nalinda B
authors.initials: NB
authors.lastname: Wasala
authors.affiliation: Department of Molecular Microbiology and Immunology, School of Medicine, The University of Missouri, Columbia, MO 65212, USA.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Yue
authors.affiliation: Department of Molecular Microbiology and Immunology, School of Medicine, The University of Missouri, Columbia, MO 65212, USA.
authors.forename: Jenna
authors.initials: J
authors.lastname: Vance
authors.affiliation: Department of Molecular Microbiology and Immunology, School of Medicine, The University of Missouri, Columbia, MO 65212, USA; Department of Neurology, School of Medicine, The University of Missouri, Columbia, MO 65212, USA; Department of Bioengineering, The University of Missouri, Columbia, MO 65212, USA; Department of Biomedical Sciences, College of Veterinary Medicine, The University of Missouri, Columbia, MO 65212, USA. Electronic address: duand@missouri.edu.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Duan
mesh_terms: D000367:Age Factors; D000818:Animals; D015415:Biomarkers; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002155:Calsequestrin / Q000235:genetics / Q000378:metabolism; D009202:Cardiomyopathies / Q000175:diagnosis / Q000209:etiology* / Q000503:physiopathology*; D003971:Diastole; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism; D004562:Electrocardiography; D015870:Gene Expression; D051379:Mice; D020388:Muscular Dystrophy, Duchenne / Q000150:complications* / Q000235:genetics / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D016276:Ventricular Function; D000099211:Phospholamban
chemical_list: D015415:Biomarkers; D002135:Calcium-Binding Proteins; D002155:Calsequestrin; D016189:Dystrophin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban
keywords: AAV; Adeno-associated virus; DMD; Dilated cardiomyopathy; Duchenne cardiomyopathy; Duchenne muscular dystrophy; Dystrophin; ECG; Gene therapy; Heart; Hemodynamics; Low-level expression