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 cardiac abnormalities and exhibit dystrophic changes only in a small number of heavily used skeletal muscle groups. By contrast, mdx:MyoD-/- mice lacking dystrophin and the skeletal muscle-specific bHLH transcription factor MyoD display a severe skeletal myopathy leading to widespread dystrophic changes in skeletal muscle and premature death around 1 year of age. The severely increased phenotype of mdx:MyoD-/- muscle is a consequence of impaired muscle regeneration caused by enhanced satellite cell self-renewal. Here we report that mdx:MyoD-/- mice developed a severe cardiac myopathy 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 cardiac myocyte adaptation. Taken together, these results support the hypothesis that the progression of skeletal muscle damage is a significant contributing factor leading to development of cardiomyopathy.
Megeney
L A
LA
Institute for Molecular Biology and Biotechnology, 1280 Main Street West, McMaster University, Hamilton, Ontario, Canada L8S 4K1.
Kablar
B
B
Perry
R L
RL
Ying
C
C
May
L
L
Rudnicki
M A
MA
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D006332:Cardiomegaly; D009202:Cardiomyopathies / Q000150:complications / Q000473:pathology*; D016189:Dystrophin / Q000235:genetics*; D005355:Fibrosis; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D018101:Mice, Inbred mdx; D008817:Mice, Mutant Strains; D020928:Mitogen-Activated Protein Kinases; D018482:Muscle, Skeletal / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000150:complications / Q000473:pathology; D017570:MyoD Protein / Q000235:genetics*; D012038:Regeneration; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases
D016189:Dystrophin; D017570:MyoD Protein; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases