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Microtubule cytoskeleton regulates Connexin 43 localization and cardiac conduction in cardiomyopathy caused by mutation in A-type lamins gene.

  • Macquart, Coline1
  • Jüttner, Rene2
  • Morales Rodriguez, Blanca1
  • Le Dour, Caroline3, 4
  • Lefebvre, Florence5
  • Chatzifrangkeskou, Maria1
  • Schmitt, Alain6
  • Gotthardt, Michael7, 8
  • Bonne, Gisèle1
  • Muchir, Antoine1
  • 1 Sorbonne Université, INSERM, Association Institut de Myologie, Centre de Recherche en Myologie, UMRS974, Paris 75013, France. , (France)
  • 2 Max-Delbrück-Center for Molecular Medicine, DE-13092 Berlin, Germany. , (Germany)
  • 3 Department of Medicine.
  • 4 Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
  • 5 Signaling and Cardiovascular Pathophysiology, UMRS 1180, Université Paris-Sud, INSERM, Chatenay-Malabry 92216, France. , (France)
  • 6 Institut Cochin, INSERM U1016-CNRS UMR 8104, Université Paris Descartes-Sorbonne Paris Cité, Paris F-75014, France. , (France)
  • 7 DZHK (German Centre for Cardiovascular Research), Berlin, Germany. , (Germany)
  • 8 Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany. , (Germany)
Published Article
Human Molecular Genetics
Oxford University Press
Publication Date
Dec 15, 2019
DOI: 10.1093/hmg/ddy227
PMID: 29893868


Mutations in the lamin A/C gene (LMNA) cause an autosomal dominant inherited form of dilated cardiomyopathy associated with cardiac conduction disease (hereafter referred to as LMNA cardiomyopathy). Compared with other forms of dilated cardiomyopathy, mutations in LMNA are responsible for a more aggressive clinical course owing to a high rate of malignant ventricular arrhythmias. Gap junctions are intercellular channels that allow direct communication between neighboring cells, which are involved in electrical impulse propagation and coordinated contraction of the heart. For gap junctions to properly control electrical synchronization in the heart, connexin-based hemichannels must be correctly targeted to intercalated discs, Cx43 being the major connexin in the working myocytes. We here showed an altered distribution of Cx43 in a mouse model of LMNA cardiomyopathy. However, little is known on the molecular mechanisms of Cx43 remodeling in pathological context. We now show that microtubule cytoskeleton alteration and decreased acetylation of α-tubulin lead to remodeling of Cx43 in LMNA cardiomyopathy, which alters the correct communication between cardiomyocytes, ultimately leading to electrical conduction disturbances. Preventing or reversing this process could offer a strategy to repair damaged heart. Stabilization of microtubule cytoskeleton using Paclitaxel improved intraventricular conduction defects. These results indicate that microtubule cytoskeleton contributes to the pathogenesis of LMNA cardiomyopathy and that drugs stabilizing the microtubule may be beneficial for patients. © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected]

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