Decreasing microtubule detyrosination by parthenolide restores sodium current in mdx cardiomyocytes

Abstract Funding Acknowledgements Type of funding sources: None. Background The cardiac sodium channel Nav1.5 is transported to the membrane by microtubule network. Alterations in dynamics are known impact on ion trafficking. Pathophysiological conditions such as heart failure and Duchenne muscular dystrophy (DMD) associated with an increase detyrosination well a decreased current (INa) pro-arrhythmia. Parthenolide, compound that decreases fraction detyrosinated microtubules, has been shown have beneficial effects function DMD mice, but its INa not investigated. Methods Results Cardiomyocytes (CMs) from wild type (WT) mdx mice were used investigate effect parthenolide. Cells incubated either 10 µM parthenolide or DMSO for 3-5 hours. action potential (AP) characteristics assessed using patch-clamp technique, while immunofluorescence stochastic optical reconstruction microscopy (STORM), cluster density, respectively. In accordance previous studies, we observed increased levels microtubules CMs compared WT. Treatment significantly magnitude CMs, had no WT CMs. Accordingly, AP maximal upstroke velocity without affecting other properties. Parthenolide did affect gating properties, indicating it enhancing Indeed, STORM analysis showed density at both lateral (crest) intercalated disc region Conclusions restores expression may be benefit pathophysiological reduced INa. Further elucidation identify additional therapeutic targets restoring conduction preventing arrhythmias.