Reference - Detail
| RRC ID | 85795 |
|---|---|
| Author | Marksteiner J, Sauer J, Hohenegger M, David FO, Schindler N, Szabó PL, Kiss A, Dostal C, Podesser BK, Lilliu E, Hackl B, Todt H, Koenig X, Hilber K, Schicker K. |
| Title | Inhibition of tenascin C rescues abnormally reduced Na currents in dystrophin-deficient ventricular cardiomyocytes. |
| Journal | Am J Physiol Heart Circ Physiol |
| 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 (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 knockout (KO) mice had increased peak INa. The abnormally reduced peak INa in mdx myocytes was rescued to wild-type levels 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. Twenty-four-hour 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 α-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 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. |
| Volume | 329(3) |
| Pages | H648-H660 |
| Published | 2025-9-1 |
| DOI | 10.1152/ajpheart.00307.2025 |
| PMID | 40789177 |
| PMC | PMC7618084 |
| MeSH | Action Potentials Animals Arrhythmias, Cardiac* / genetics Arrhythmias, Cardiac* / metabolism Arrhythmias, Cardiac* / physiopathology Arrhythmias, Cardiac* / prevention & control Cells, Cultured Disease Models, Animal Dystrophin* / deficiency Dystrophin* / genetics Heart Ventricles / metabolism Male Mice Mice, Inbred C57BL Mice, Inbred mdx Mice, Knockout Muscular Dystrophy, Duchenne* / complications Muscular Dystrophy, Duchenne* / genetics Muscular Dystrophy, Duchenne* / metabolism Muscular Dystrophy, Duchenne* / physiopathology Myocytes, Cardiac* / drug effects Myocytes, Cardiac* / metabolism NAV1.5 Voltage-Gated Sodium Channel / genetics NAV1.5 Voltage-Gated Sodium Channel / metabolism Sodium* / metabolism Tenascin* / antagonists & inhibitors Tenascin* / genetics Tenascin* / metabolism |
| IF | 3.864 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 3 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Mice | RBRC00007 |