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Alterations in MT dynamics are known to impact on ion channel trafficking. Duchenne muscular dystrophy (DMD), caused by dystrophin deficiency, is associated with an increase in MT detyrosination, decreased sodium current (INa), and arrhythmias. Parthenolide (PTL), a compound that decreases MT detyrosination, has shown beneficial effects on cardiac function in DMD. We here investigated its impact on INa and Nav1.5 subcellular distribution.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Ventricular cardiomyocytes (CMs) from wild-type (WT) and mdx (DMD) mice were incubated with either 10\u2005\u00b5M PTL, 20\u2005\u00b5M EpoY, or dimethylsulfoxide (DMSO) for 3\u20135\u2005h, followed by patch-clamp analysis to assess INa and action potential (AP) characteristics in addition to immunofluorescence and stochastic optical reconstruction microscopy (STORM) to investigate MT detyrosination and Nav1.5 cluster size and density, respectively. In accordance with previous studies, we observed increased MT detyrosination, decreased INa and reduced AP upstroke velocity (Vmax) in mdx CMs compared to WT. PTL decreased MT detyrosination and significantly increased INa magnitude (without affecting INa gating properties) and AP Vmax in mdx CMs, but had no effect in WT CMs. Moreover, STORM analysis showed that in mdx CMs, Nav1.5 clusters were decreased not only in the grooves of the lateral membrane (LM; where dystrophin is localized) but also at the LM crests. PTL restored Nav1.5 clusters at the LM crests (but not at the grooves), indicating a dystrophin-independent trafficking route to this subcellular domain. Interestingly, Nav1.5 cluster density was also reduced at the intercalated disc (ID) region of mdx CMs, which was restored to WT levels by PTL. Treatment of mdx CMs with EpoY, a specific MT detyrosination inhibitor, also increased INa density, while decreasing the amount of detyrosinated MTs, confirming a direct mechanistic link.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Attenuating MT detyrosination in mdx CMs restored INa and enhanced Nav1.5 localization at the LM crest and ID. Hence, the reduced whole-cell INa density characteristic of mdx CMs is not only the consequence of the lack of dystrophin within the LM grooves but is also due to reduced Nav1.5 at the LM crest and ID secondary to increased baseline MT detyrosination. Overall, our findings identify MT detyrosination as a potential therapeutic target for modulating INa and subcellular Nav1.5 distribution in pathophysiological conditions.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvae043","type":"journal-article","created":{"date-parts":[[2024,2,22]],"date-time":"2024-02-22T13:47:38Z","timestamp":1708609658000},"page":"723-734","source":"Crossref","is-referenced-by-count":14,"title":["Decreasing microtubule detyrosination modulates Nav1.5 subcellular distribution and restores sodium current in\n                    <i>mdx<\/i>\n                    cardiomyocytes"],"prefix":"10.1093","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8485-4446","authenticated-orcid":false,"given":"Giovanna","family":"Nasilli","sequence":"first","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam University Medical Center, University of Amsterdam, Heart Centre , Meibergdreef 9, 1105 AZ, Amsterdam , The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias , Meibergdreef 9, 1105 AZ, Amsterdam , The Netherlands"},{"name":"Division of Cardiology, NYU Grossman School of Medicine , 550 First Avenue, New York, NY 10016 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja M","family":"de Waal","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam University Medical Center, University of Amsterdam, Heart Centre , Meibergdreef 9, 1105 AZ, Amsterdam , The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias , Meibergdreef 9, 1105 AZ, Amsterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard A","family":"Marchal","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam University Medical Center, University of Amsterdam, Heart Centre , Meibergdreef 9, 1105 AZ, Amsterdam , The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias , Meibergdreef 9, 1105 AZ, Amsterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Bertoli","sequence":"additional","affiliation":[{"name":"Division of Cardiology, NYU Grossman School of Medicine , 550 First Avenue, New York, NY 10016 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marieke W","family":"Veldkamp","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam University Medical Center, University of Amsterdam, Heart Centre , Meibergdreef 9, 1105 AZ, Amsterdam , The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias , Meibergdreef 9, 1105 AZ, Amsterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eli","family":"Rothenberg","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Pharmacology, NYU Grossman School of Medicine , 450 E 29TH ST Alexandria Center for Life Science, New York, NY 10016 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2672-2779","authenticated-orcid":false,"given":"Simona","family":"Casini","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam University Medical Center, University of Amsterdam, Heart Centre , Meibergdreef 9, 1105 AZ, Amsterdam , The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias , Meibergdreef 9, 1105 AZ, Amsterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0095-0084","authenticated-orcid":false,"given":"Carol Ann","family":"Remme","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam University Medical Center, University of Amsterdam, Heart Centre , Meibergdreef 9, 1105 AZ, 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