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

• Published in: Nature communications 2022-12, Vol.13 (1), p.7886-7886, Article 7886
• Main Authors: Le Dour, Caroline, Chatzifrangkeskou, Maria, Macquart, Coline, Magiera, Maria M., Peccate, Cécile, Jouve, Charlène, Virtanen, Laura, Heliö, Tiina, 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
• Format: Article
• Language: English
• Subjects: 13/100; 38; 38/61; 631/80/128/1276; 631/80/128/1653; 631/80/304; 64/60; 692/699/75/74; 82/80; 96/1; 96/109; 96/63; 96/95; Acetylation; Acetyltransferase; Actin; Actin Depolymerizing Factors - genetics; Actins - metabolism; Animals; C gene; Cardiac function; Cardiomyocytes; Cardiomyopathy; Cardiomyopathy, Dilated - metabolism; Cofilin; Connexin 43; Connexin 43 - genetics; Cytoplasm; Cytoskeleton; Destabilization; Dilated cardiomyopathy; Gene expression; Heart; Humanities and Social Sciences; Intermediate Filament Proteins - genetics; Lamin Type A - genetics; Lamin Type A - metabolism; Life Sciences; Localization; Male; Males; Mice; Mice, Knockout; Microtubules - metabolism; multidisciplinary; Muscles; Mutation; Myocytes, Cardiac - metabolism; Phosphorylation; Science; Science (multidisciplinary); Serum response factor; Serum Response Factor - genetics; Structure-function relationships; Threonine; Tubulin; Tubulin - genetics; Ventricle
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-35639-x

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 Lmna p.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 Lmna p.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. Lamin A/C gene mutations cause dilated cardiomyopathy associated with cofilin-1 phosphorylation and actin destabilization. Here, the authors show that phosphorylated cofilin-1 blunts the MRTF-A/SRF axis, leading to decreased tubulin acetylation and altered cardiac structure and function.