Mechanism of heart failure in cardiomyopathy based on cytoskeletal abnormality

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Disruption of the dystrophin-glycoprotein complex (DGC) caused by genetic defects of dystrophin or sarcoglycans results in muscular dystrophy and/or cardiomyopathy in humans and animal models. However, the key early molecular events leading to myocyte degeneration remain elusive. We have shown in recent work that stretch-sensitive cation-selective channels are active and Ca^<2+> entry is enhanced in resting cultured myotubes prepared from cardiomyopathic hamster (BIO14.6). To identify Ca^<2+> entry mechanisms possibly responsible for the pathogenesis of myocyte degeneration we searched for and cloned a growth factor-regulated channel (GRC) in striated muscle. GRC is a Ca~<2+> -permeable nonselective cation channel belonging to the transient-receptor-potential (TRP) channel family, which translocates from the cell interior to the surface in response to growth factors such as IGF-I and FCS. GRC is elevated in the sarcolemma of δ-sarcoglycan. However, total cell GRC does not differ markedly between normal and dystrophic muscles. Analysis of the properties of myotubes prepared from δ-sarcoglycan-deficient BIO 14.6 hamsters revealed that GRC is activated in response to myocyte stretch and is responsible for enhanced Ca^<2+> influx and resultant cell damage as measured by creatine phosphokinase efflux. We found that cell stretch increased GRC translocation to the sarcolemma, which requires entry of external Ca^<2+>.