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ACTIN-MICROTUBULE CYTOSKELETAL INTERPLAY MEDIATED BY MRTF-A/SRF SIGNALING PROMOTES DILATED CARDIOMYOPATHY CAUSED BY LMNA MUTATIONS
Mediada pela sinalização MRTF-A/SRF
Promove cardiomiopatia dilatada
Causada por mutações LMNA
Mediated by MRTF-A/SRF signaling
Promotes dilated cardiomyopath
Caused by LMNA mutations
Author
Le Dour, Caroline
Chatzifrangkeskou, Maria
Macquart, Coline
Magiera, Maria M.
Peccate, Cécile
Jouve, Charlène
Virtanen, Laura
Heliö, Tina
Aalto-Setälä, Katriina
Crasto, Silvia
Cadot, Bruno
Cardoso, Déborah
Mougenot, Nathalie
Adesse, Daniel
Di Pasquale, Elisa
Hulot, Jean-Sébastien
Taimen, Pekka
Janke, Carsten
Muchir, Antoine
Chatzifrangkeskou, Maria
Macquart, Coline
Magiera, Maria M.
Peccate, Cécile
Jouve, Charlène
Virtanen, Laura
Heliö, Tina
Aalto-Setälä, Katriina
Crasto, Silvia
Cadot, Bruno
Cardoso, Déborah
Mougenot, Nathalie
Adesse, Daniel
Di Pasquale, Elisa
Hulot, Jean-Sébastien
Taimen, Pekka
Janke, Carsten
Muchir, Antoine
Affilliation
Centre de recherche en Myologie, U974 SU-INSERM, 75013 Paris, France.
Centre de recherche en Myologie, U974 SU-INSERM, 75013 Paris, France.
Centre de recherche en Myologie, U974 SU-INSERM, 75013 Paris, France.
Institut Curie, Université PSL, CNRSUMR3348, 91401 Orsay, France / Université Paris-Saclay, CNRS UMR3348, 91401 Orsay, France.
Centre de recherche en Myologie, U974 SU-INSERM, 75013 Paris, France.
Université de Paris, Paris Cardiovascular Research Center PARCC, INSERM, 75015 Paris, France.
Institute of Biomedicine and FICAN West Cancer Centre, University of Turku, 20520 Turku, Finland.
Heart and Lung Centre, Helsinki University Central Hospital, University of Helsinki, 00290 Helsinki, Finland.
Faculty of Medicine and Health Technology and BioMediTech Institute, Tampere University, 33520 Tampere, Finland.
Institute of Genetic and Biomedical Research (IRGB), UOS of Milan, National Research Council of Italy, Milan, Italy / Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano (MI), Italy.
Centre de recherche en Myologie, U974 SU-INSERM, 75013 Paris, France.
Centre de recherche en Myologie, U974 SU-INSERM, 75013 Paris, France.
Sorbonne Université, INSERM, UMS28 Phénotypage du petit animal, Paris 75013, France.
Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Biologia Estrutural, Rio de Janeiro, RJ, Brasil.
Institute of Genetic and Biomedical Research (IRGB), UOS of Milan, National Research Council of Italy, Milan, Italy / Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano (MI), Italy.
Université de Paris, Paris Cardiovascular Research Center PARCC, INSERM, 75015 Paris, France.
Institute of Biomedicine and FICAN West Cancer Centre, University of Turku, 20520 Turku, Finland / Department of Pathology, Turku University Hospital, 20520 Turku, Finland.
Institut Curie, Université PSL, CNRSUMR3348, 91401 Orsay, France / Université Paris-Saclay, CNRS UMR3348, 91401 Orsay, France.
Centre de recherche en Myologie, U974 SU-INSERM, 75013 Paris, France.
Centre de recherche en Myologie, U974 SU-INSERM, 75013 Paris, France.
Centre de recherche en Myologie, U974 SU-INSERM, 75013 Paris, France.
Institut Curie, Université PSL, CNRSUMR3348, 91401 Orsay, France / Université Paris-Saclay, CNRS UMR3348, 91401 Orsay, France.
Centre de recherche en Myologie, U974 SU-INSERM, 75013 Paris, France.
Université de Paris, Paris Cardiovascular Research Center PARCC, INSERM, 75015 Paris, France.
Institute of Biomedicine and FICAN West Cancer Centre, University of Turku, 20520 Turku, Finland.
Heart and Lung Centre, Helsinki University Central Hospital, University of Helsinki, 00290 Helsinki, Finland.
Faculty of Medicine and Health Technology and BioMediTech Institute, Tampere University, 33520 Tampere, Finland.
Institute of Genetic and Biomedical Research (IRGB), UOS of Milan, National Research Council of Italy, Milan, Italy / Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano (MI), Italy.
Centre de recherche en Myologie, U974 SU-INSERM, 75013 Paris, France.
Centre de recherche en Myologie, U974 SU-INSERM, 75013 Paris, France.
Sorbonne Université, INSERM, UMS28 Phénotypage du petit animal, Paris 75013, France.
Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Biologia Estrutural, Rio de Janeiro, RJ, Brasil.
Institute of Genetic and Biomedical Research (IRGB), UOS of Milan, National Research Council of Italy, Milan, Italy / Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano (MI), Italy.
Université de Paris, Paris Cardiovascular Research Center PARCC, INSERM, 75015 Paris, France.
Institute of Biomedicine and FICAN West Cancer Centre, University of Turku, 20520 Turku, Finland / Department of Pathology, Turku University Hospital, 20520 Turku, Finland.
Institut Curie, Université PSL, CNRSUMR3348, 91401 Orsay, France / Université Paris-Saclay, CNRS UMR3348, 91401 Orsay, France.
Centre de recherche en Myologie, U974 SU-INSERM, 75013 Paris, France.
Abstract
Mutations in the lamin A/C gene (LMNA) cause dilated cardiomyopathy associated
with increased activity of ERK1/2 in the heart. We recently showed that
ERK1/2 phosphorylates cofilin-1 on threonine 25 (phospho(T25)-cofilin-1) that
in turn disassembles the actin cytoskeleton. Here, we show that inmuscle cells
carrying a cardiomyopathy-causing LMNA mutation, phospho(T25)-cofilin-1
binds to myocardin-related transcription factor A (MRTF-A) in the cytoplasm,
thus preventing the stimulation of serumresponse factor (SRF) in the nucleus.
Inhibiting the MRTF-A/SRF axis leads to decreased α-tubulin acetylation by
reducing the expression of ATAT1 gene encoding α-tubulin acetyltransferase 1.
Hence, tubulin acetylation is decreased in cardiomyocytes derived from male
patients with LMNA mutations and in heart and isolated cardiomyocytes from
Lmnap.H222P/H222P male mice. In Atat1 knockout mice, deficient for acetylated α-
tubulin, we observe left ventricular dilation andmislocalization of Connexin 43
(Cx43) in heart. Increasing α-tubulin acetylation levels in Lmnap.H222P/H222P mice
with tubastatin A treatment restores the proper localization of Cx43 and
improves cardiac function. In summary, we show for the first time an actinmicrotubule
cytoskeletal interplay mediated by cofilin-1 and MRTF-A/SRF,
promoting the dilated cardiomyopathy caused by LMNA mutations. Our
findings suggest that modulating α-tubulin acetylation levels is a feasible
strategy for improving cardiac function.
Keywords in Portuguese
Interação actina-microtúbulos do citoesqueletoMediada pela sinalização MRTF-A/SRF
Promove cardiomiopatia dilatada
Causada por mutações LMNA
Keywords
Actin-microtubule cytoskeletal interplayMediated by MRTF-A/SRF signaling
Promotes dilated cardiomyopath
Caused by LMNA mutations
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