Cardiomyopathy is independent of skeletal muscle disease in muscular dystrophy

Abstract

Dystrophin and its associated proteins, the sarcoglycans, are normally expressed in heart and skeletal muscle. Mutations that alter the expression of these membrane-associated proteins lead to muscular dystrophy (MD) and cardiomyopathy in humans. Because of the timing and nature of the accompanying cardiomyopathy, it has been suggested that cardiomyopathy develops as a secondary consequence of skeletal muscle dysfunction in the muscular dystrophies. To determine whether skeletal muscle dystrophy contributes to the development of sarcoglycan-mediated cardiomyopathy, we used mice lacking gamma-sarcoglycan and inserted a transgene that "rescued" gamma-sarcoglycan expression only in skeletal muscle. Gamma-sarcoglycan was expressed in skeletal muscle under the control of the skeletal muscle-specific myosin light chain 1/3 promoter. Gamma-sarcoglycan-null mice expressing this transgene fully restore gamma-sarcoglycan expression. Furthermore, the transgene-rescued mice lack the focal necrosis and membrane permeability defects that are a hallmark of MD. Despite correction of the skeletal muscle disease, focal degeneration and membrane permeability abnormalities persisted in cardiac muscle, and notably persisted in the right ventricle. Therefore, heart and skeletal muscle defects are independent processes in sarcoglycan-mediated muscular dystrophies and, as such, therapy should target both skeletal and cardiac muscle correction to prevent sudden death due to cardiomyopathy in the muscular dystrophies.