Low dystrophin levels in heart can delay heart failure in mdx mice

作者：van Putten Maaike; van der Pijl Elizabeth M; Hulsker Margriet; Verhaart Ingrid E C; Nadarajah Vishna D; van der Weerd Louise; Aartsma Rus Annemieke^*

来源：Journal of Molecular and Cellular Cardiology, 2014, 69: 17-23.

DOI：10.1016/j.yjmcc.2014.01.009

• Dystrophin
• Cardiomyopathy
• Mouse models
• Magnetic resonance imaging
• Therapy

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, Band 10-month-old female mdx-Xist(Delta hs) 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 mcbt mice developed dilated cardiomyopathy and hypertrophy, whereas the onset of heart pathology was delayed and function improved in mdx-Xist(Delta hs) 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(Delta hs) 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.

• 出版日期2014-4