| 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
|
| Resource |
| Mice |
RBRC00007 |
