Severe cardiomyopathy in mice lacking dystrophin and MyoD

The mdx mouse, a mouse model of Duchenne muscular dystrophy, carries a loss -of-function mutation in dystrophin, a component of the membrane-associated dystrophin-glycoprotein complex. Unlike humans, mdx mice rarely display ca rdiac abnormalities and exhibit dystrophic changes only in a small number o f heavily heavily used skeletal muscle groups. By contrast, mdx:MyoD(-/-) m ice lacking dystrophin and thew skeletal muscle-specific bHLH transcription factor MyoD display a severe skeletal myopathy leading to widespread dystr ophic changes in skeletal muscle and premature death around 1 year of age. The severely increased phenotype of mdx:MyoD(-/-) muscle is a consequence o f impaired muscle regeneration caused by enhanced satellite cell self-renew al. Here we report that mdx:MyoD(-/-) mice developed a severe cardiac myopa thy with areas of necrosis associated with hypertrophied myocytes. Moreover , heart tissue from mdx:MyoD(-/-) mice exhibited constitutive activation of stress-activated signaling components, similar to in vitro models of cardi ac myocyte adaptation. Taken together, these results support the hypothesis that the progression of skeletal muscle damage is a significant contributi ng factor leading to development of cardiomyopathy.