A cure for
dystrophin-deficient
muscular dystrophy requires treating both skeletal muscle and the heart. Whereas mosaic
dystrophin expression has been shown to protect skeletal muscle, controversy exists over whether mosaic expression is protective in the heart. We have shown recently that mosaic
dystrophin expression prevents stress-induced heart damage in young carrier mice. Although an interesting finding, the clinical relevance remains to be established because young
dystrophin-null mdx mice do not have
heart disease. On the other hand,
heart failure has been reported in human carriers. To resolve this mouse/human discrepancy, we evaluated the cardiac phenotype in 21-month-old mdx, carrier, and normal mice. We found
dilated cardiomyopathy in old mdx mice but not in age-matched carrier mice. All anatomical parameters and physiological assay results (ECG and closed-chest Millar
catheter) were within the normal range in old carrier mice. Focal myocardial
inflammation was found in a small fraction of old carrier mice, but it had no major impact on heart function.
Dobutamine stress revealed a near normal hemodynamic profile except for a marginal reduction in systolic pressure in old carrier mice. Immunostaining and Western blot showed
dystrophin expression in 50% cardiomyocytes in old carrier mice. Interestingly,
utrophin was upregulated in
dystrophin-negative heart cells in carrier mice. In summary, we have provided the first clear-cut evidence that
dilated cardiomyopathy in old mdx mice was prevented by mosaic
dystrophin expression or complementary
dystrophin/
utrophin expression. Our results raise the hope for ameliorating dystrophic
cardiomyopathy through partial gene and/or
cell therapy.