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

ABSTRACT: 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 (I_Na) 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 I_Na loss in dystrophin-deficient ventricular cardiomyocytes. We found that cardiomyocytes from TN-C knockout (KO) mice had increased peak I_Na. The abnormally reduced peak I_Na in mdx myocytes was rescued to wild-type levels by additional TN-C KO, which was accompanied by enhanced Na_v1.5 channel expression. Further, peak I_Na in mdx myocytes was increased by treatment of mdx mice with TN-C siRNA. Twenty-four-hour incubation of wild-type myocytes with human recombinant TN-C reduced their peak I_Na, an effect which could be abolished by blocking antibodies specific for the α-7 integrin subunit. Our findings suggest that TN-C induces peak I_Na loss in the dystrophic heart, and that inhibition of TN-C expression rescues abnormally reduced peak I_Na in dystrophin-deficient ventricular cardiomyocytes. TN-C inhibition emerges as a strategy to counteract ventricular conduction impairments and arrhythmias in patients with DMD.NEW & NOTEWORTHY Dystrophin deficiency in cardiomyocytes leads to abnormally reduced Na currents. These can be rescued by inhibition of the expression of tenascin C.

SUBMITTER: Marksteiner J 

PROVIDER: S-EPMC7618084 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature