ArticleCirculation. Arrhythmia and electrophysiology2026
Decreasing Microtubule Detyrosination Improves Cardiac Mechanics and Sodium Channel Function in Arrhythmogenic Cardiomyopathy.
Article in Circulation. Arrhythmia and electrophysiology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundAlterations in microtubule dynamics have been shown to affect cardiomyocyte membrane stiffness and modulate ion channels, including the cardiac sodium channel. While conditions, such as heart failure and Duchenne muscular dystrophy, are associated with increased detyrosination of microtubules and reduced sodium current, a potential role for microtubule detyrosination in arrhythmogenic cardiomyopathy has not been explored. We here investigated the impact of microtubule detyrosination on membrane stiffness, cardiac sodium channel distribution, and function in mouse and human models of arrhythmogenic cardiomyopathy.
methodsIsolated ventricular cardiomyocytes from mice with cardiomyocyte-specific, tamoxifen-activated knockout of PKP2 (plakophilin-2), as well as
resultsCardiomyocyte-specific, tamoxifen-activated knockout of PKP2 mouse cardiomyocytes displayed increased microtubule detyrosination and membrane stiffness, which were both attenuated by parthenolide treatment. Parthenolide significantly increased whole-cell sodium current density in cardiomyocyte-specific, tamoxifen-activated knockout of PKP2 mouse cardiomyocytes, with macropatch measurements demonstrating that this increase occurred both at the intercalated disc and lateral membrane. Stochastic optical reconstruction microscopy analysis revealed that parthenolide increased cardiac sodium channel cluster density at the intercalated disc of cardiomyocyte-specific, tamoxifen-activated knockout of PKP2 mouse cardiomyocytes. In contrast, parthenolide had no effect on sodium current density, cardiac sodium channel cluster size, or density in cardiomyocytes from control mice.
conclusionsIncreased microtubule detyrosination secondary to loss of PKP2 impacts cardiomyocyte (dys)function beyond the desmosome, contributing to both electrical and mechanical alterations in the setting of arrhythmogenic cardiomyopathy. Our findings identify microtubule detyrosination as a novel therapeutic target in pathophysiological conditions, such as arrhythmogenic cardiomyopathy, aimed at improving both contractile and electrical function.
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