Inhibition of tenascin C rescues abnormally reduced Na currents in dystrophin-deficient ventricular cardiomyocytes.

Cardiac arrhythmias significantly contribute to mortality in Duchenne muscular dystrophy (DMD), a severe muscle disease caused by dystrophin deficiency. Using the mdx mouse model for human DMD, we previously showed that the lack of dystrophin induces a significant loss of peak sodium current (INa) in ventricular cardiomyocytes. This provided a mechanistic explanation for ventricular conduction defects and concomitant arrhythmias in the dystrophic heart. The extracellular matrix protein tenascin C (TN-C), a major remodeling factor in the diseased heart, is strongly upregulated in DMD. The consequences of TN-C upregulation in the dystrophic heart, however, are unknown. Here, we tested if TN-C induces electrical remodeling in the dystrophic heart, and if inhibition of TN-C rescues peak INa loss in dystrophin-deficient ventricular cardiomyocytes. We found that cardiomyocytes from TN-C knock-out (KO) mice had increased peak INa. The abnormally reduced peak INa in mdx myocytes was rescued to wild-type level by additional TN-C KO, which was accompanied by enhanced Nav1.5 channel expression. Further, peak INa in mdx myocytes was increased by treatment of mdx mice with TN-C siRNA. 24 h incubation of wild-type myocytes with human recombinant TN-C reduced their peak INa, an effect which could be abolished by blocking antibodies specific for the alpha-7 integrin subunit. Our findings suggest that TN-C induces peak INa loss in the dystrophic heart, and that inhibition of TN-C expression rescues abnormally reduced peak INa in dystrophin-deficient ventricular cardiomyocytes. TN-C inhibition emerges as strategy to counteract ventricular conduction impairments and arrhythmias in DMD patients.