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

Caroline 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 Pasquale, Jean-Sébastien Hulot, Pekka Taimen, Carsten Janke and Antoine Muchir ()
Additional contact information
Caroline Dour: U974 SU-INSERM
Maria Chatzifrangkeskou: U974 SU-INSERM
Coline Macquart: U974 SU-INSERM
Maria M. Magiera: CNRS UMR3348
Cécile Peccate: U974 SU-INSERM
Charlène Jouve: INSERM
Laura Virtanen: University of Turku
Tiina Heliö: University of Helsinki
Katriina Aalto-Setälä: Tampere University
Silvia Crasto: National Research Council of Italy
Bruno Cadot: U974 SU-INSERM
Déborah Cardoso: U974 SU-INSERM
Nathalie Mougenot: UMS28 Phénotypage du petit animal
Daniel Adesse: Laboratório de Biologia Estrutural
Elisa Pasquale: National Research Council of Italy
Jean-Sébastien Hulot: INSERM
Pekka Taimen: University of Turku
Carsten Janke: CNRS UMR3348
Antoine Muchir: U974 SU-INSERM

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: 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 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-35639-x Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35639-x

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-35639-x

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().