Actin-microtubule cytoskeletal interplay mediated by MRTF-A/SRF signaling promotes dilated cardiomyopathy caused by LMNA mutations

Caroline Le Dour, Maria Chatzifrangkeskou, Coline Macquart, Maria M. Magiera, Cécile Peccate, Charlène Jouve, Laura Virtanen, Tiina Heliö, Katriina Aalto-Setälä, Silvia Crasto, Bruno Cadot, Déborah Cardoso, Nathalie Mougenot, Daniel Adesse, Elisa Di Pasquale, Jean Sébastien Hulot, Pekka Taimen, Carsten Janke, Antoine Muchir

Tutkimustuotos: Artikkelijulkaisu › Artikkeli › Tieteellinen › vertaisarvioitu

Abstrakti

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 in muscle 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 serum response 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 and mislocalization 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 actin-microtubule 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.

Alkuperäiskielienglanti
Artikkeli7886
LehtiNature Communications
Vuosikerta13
Numero1
ISSN2041-1723
DOI - pysyväislinkit
TilaJulkaistu - jouluk. 2022
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

Lisätietoja

Funding Information:
The work of A.M. was supported by the Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, and the Association Française contre les Myopathies, the French National Research Agency (ANR, award ANR-19-CE17-0013), MyoPharm and a grant (PER-SU) provided by Sorbonne Université. C.J. received support from ANR-10-IDEX-0001-02, the LabEx CellNScale ANR-11-LBX-0038, the French National Research Agency (ANR, award ANR-17-CE13-0021), and the Fondation pour la Recherche Medicale (FRM, grant DEQ20170336756). P.T. was supported by research funding provided by the Academy of Finland. We thank the genomic facility at Institut Cochin, Paris, for Affymetrix data acquisition. We thank Dr. Ben Yaou (Institute of Myology Paris) and Dr. Eschenhagen (University Medical Center Hamburg-Eppendorf) for providing the iPSCs carrying the LMNA p.H222P mutation. We thank Dr. Dal Ferro (University of Trieste) for providing the iPSCs carrying the LMNA p.R190W mutation. We thank Dr. Alonso (Universidad Autónoma de Madrid) for providing the ATAT1 CArGs 1–4 construct and Dr. Sadoul (Université Grenoble Alpes) for providing the ATAT knockout mouse strain. We thank Dr. Sotiropoulos (Université de Paris) for providing the SRF-VP16 plasmid. We thank Zoheir Guesmia for his help with imaging and quantification. Parts of Figs. 3 and 4 were drawn using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License. Fig. 7 was created thanks to BioRender.com.

Funding Information:
The work of A.M. was supported by the Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, and the Association Française contre les Myopathies, the French National Research Agency (ANR, award ANR-19-CE17-0013), MyoPharm and a grant (PER-SU) provided by Sorbonne Université. C.J. received support from ANR-10-IDEX-0001-02, the LabEx CellNScale ANR-11-LBX-0038, the French National Research Agency (ANR, award ANR-17-CE13-0021), and the Fondation pour la Recherche Medicale (FRM, grant DEQ20170336756). P.T. was supported by research funding provided by the Academy of Finland. We thank the genomic facility at Institut Cochin, Paris, for Affymetrix data acquisition. We thank Dr. Ben Yaou (Institute of Myology Paris) and Dr. Eschenhagen (University Medical Center Hamburg-Eppendorf) for providing the iPSCs carrying the LMNA p.H222P mutation. We thank Dr. Dal Ferro (University of Trieste) for providing the iPSCs carrying the LMNA p.R190W mutation. We thank Dr. Alonso (Universidad Autónoma de Madrid) for providing the ATAT1 CArGs 1–4 construct and Dr. Sadoul (Université Grenoble Alpes) for providing the ATAT knockout mouse strain. We thank Dr. Sotiropoulos (Université de Paris) for providing the SRF-VP16 plasmid. We thank Zoheir Guesmia for his help with imaging and quantification. Parts of Figs. and were drawn using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License. Fig. was created thanks to BioRender.com.

Publisher Copyright:
© 2022, The Author(s).

Tieteenalat

  • 3111 Biolääketieteet

Pääsy asiakirjaan

    Siteeraa tätä