Low dystrophin levels in heart can delay heart failure in mdx mice.
Duchenne muscular dystrophy is caused by mutations that prevent synthesis of functional dystrophin. All patients develop dilated cardiomyopathy. Promising therapeutic approaches are underway that successfully restore dystrophin expression in skeletal muscle. However, their efficiency in the heart is limited. Improved quality and function of only skeletal muscle potentially accelerate the development of cardiomyopathy. Our study aimed to elucidate which dystrophin levels in the heart are required to prevent or delay cardiomyopathy in mice. Heart function and pathology assessed with magnetic resonance imaging and histopathological analysis were compared between 2, 6 and 10-month-old female mdx-Xist(Δhs) mice, expressing low dystrophin levels (3-15%) in a mosaic manner based on skewed X-inactivation, dystrophin-negative mdx mice, and wild type mice of corresponding genetic backgrounds and gender. With age mdx mice developed dilated cardiomyopathy and hypertrophy, whereas the onset of heart pathology was delayed and function improved in mdx-Xist(Δhs) mice. The ejection fraction, the most severely affected parameter for both ventricles, correlated to dystrophin expression and the percentage of fibrosis. Fibrosis was partly reduced from 9.8% in mdx to 5.4% in 10 month old mdx-Xist(Δhs) mice. These data suggest that mosaic expression of 4-15% dystrophin in the heart is sufficient to delay the onset and ameliorate cardiomyopathy in mice.
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Maaike
M
van Putten
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Elizabeth M
EM
van der Pijl
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Margriet
M
Hulsker
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Ingrid E C
IE
Verhaart
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Vishna D
VD
Nadarajah
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands; Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
Louise
L
van der Weerd
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: a.m.rus@lumc.nl.
Annemieke
A
Aartsma-Rus
D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D016189:Dystrophin / Q000502:physiology*; D005260:Female; D005355:Fibrosis / Q000517:prevention & control*; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000150:complications* / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000150:complications* / Q000473:pathology
D015415:Biomarkers; D016189:Dystrophin
Cardiomyopathy; Dystrophin; Magnetic resonance imaging; Mouse models; Therapy