Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused, in most cases, by the complete absence of the 427 kDa cytoskeletal
protein,
dystrophin. There is no effective treatment, and affected individuals die from
respiratory failure and
cardiomyopathy by age 30. Here, we investigated whether
cardiomyopathy could be prevented in animal models of DMD by increasing diaphragm
utrophin or
dystrophin expression and thereby restoring diaphragm function. In a transgenic mdx mouse, where
utrophin was over expressed in the skeletal muscle and the diaphragm, but not in the heart, we found cardiac function, specifically right and left ventricular ejection fraction as measured using in vivo magnetic resonance imaging, was restored to wild-type levels. In mdx mice treated with a
peptide-conjugated
phosphorodiamidate morpholino oligomer (PPMO) that resulted in high levels of
dystrophin restoration in the skeletal muscle and the diaphragm only, cardiac function was also restored to wild-type levels. In
dystrophin/
utrophin-deficient double-knockout (dKO) mice, a more severely affected animal model of DMD, treatment with a PPMO again produced high levels of
dystrophin only in the skeletal muscle and the diaphragm, and once more restored cardiac function to wild-type levels. In the dKO mouse, there was no difference in heart function between treatment of the diaphragm plus the heart and treatment of the diaphragm alone. Restoration of diaphragm and other respiratory muscle function, irrespective of the method used, was sufficient to prevent
cardiomyopathy in dystrophic mice. This novel mechanism of treating respiratory muscles to prevent
cardiomyopathy in dystrophic mice warrants further investigation for its implications on the need to directly treat the heart in DMD.