Caroline Le Dour is a post-doctoral fellow in the Signaling Pathways & Striated Muscles team led by Antoine Muchir, at the Institute’s Myology Centre for Research. She is first author of a paper published in Nature Communications which focuses on the interaction of actin and microtubule cytoskeletons in cardiomyopathy caused by LMNA gene mutations.
What is the context of this work?
Dominant mutations in the LMNA gene encoding nuclear lamins A/C, can cause an early onset dilated cardiomyopathy with an extremely aggressive clinical course (arrhythmias, sudden death and heart failure). This pathology is associated with an overactivation of the ERK1/2 signalling pathway in the heart.
We have recently shown that ERK1/2 phosphorylates cofilin-1 (on threonine 25) which in turn disassembles the actin cytoskeleton. In muscle cells, the actin cytoskeleton acts as a scaffold, regulating the shape of the cell, ensuring its mechanical integrity and strength, and stabilising the contractile units called sarcomeres*.
Our team has also shown that the development of dilated cardiomyopathy caused by mutations in the LMNA gene correlates with alterations in the microtubule cytoskeleton as well as remodelling of a protein of the communicating junctions: connexin43 (Cx43)**. The microtubule cytoskeleton is well known for its role in protein transport and addressing (notably Cx43), and it also functions as a mechanotransducer, converting contraction forces into cellular signals in cardiac myocytes.
What was the aim of this study?
The synergy of the actin and microtubule cytoskeletons is particularly important for the regulation of the mechanical strength of cells. In this article, we sought to elucidate the mechanisms underlying the interaction and possible synergy between actin and microtubules, two components of the cytoskeleton found to be altered in cardiomyopathy caused by LMNA gene mutations.
What results did you obtain?
We showed that :
- Cofilin-1 phosphorylated on T25 binds to MRTF-A and sequesters it in the cytoplasm in muscle cells expressing LMNA mutations, inhibiting the MRTF-A/SRF axis important for muscle homeostasis,
- Inhibition of the MRTF-A/SRF actin-dependent transcriptional circuit regulates α-tubulin acetylation by decreasing the expression of ATAT1, which encodes α-tubulin acetyltransferase 1,
- Reduced α-tubulin acetylation in mice leads to mislocalisation of Cx43 in cardiomyocytes, disrupting contractility and resulting in cardiac dysfunction,
- It is possible to restore the correct localisation of Cx43 in the intercalated discs and improve cardiac function by increasing α-tubulin acetylation via administration of tubastatin A (inhibiting HDAC6, an enzyme that deacetylates α-tubulin).
What conclusions did you draw?
We show for the first time that cofilin-1 and MRTF-A/SRF-mediated interaction of the actin cytoskeleton with microtubules promotes dilated cardiomyopathy caused by LMNA gene mutations. These results open new therapeutic perspectives and suggest that targeting cytoskeleton and MRTF-A/SRF signalling could improve the disease.
Actin-microtubule cytoskeletal interplay mediated by MRTF-A/SRF signaling promotes dilated cardiomyopathy caused by LMNA mutations. Le Dour C, Chatzifrangkeskou M, Macquart C, Magiera MM, Peccate C, Jouve C, Virtanen L, Heliö T, Aalto-Setälä K, Crasto S, Cadot B, Cardoso D, Mougenot N, Adesse D, Di Pasquale E, Hulot JS, Taimen P, Janke C, Muchir A. Nat Commun. 2022 Dec 22;13(1):7886. doi: 10.1038/s41467-022-35639-x. PMID: 36550158 Free PMC article.