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

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.

The actin-binding protein CAP1 represses MRTF-SRF–dependent gene expression in mouse cerebral cortex

“…Although cofilin1 and ADF have been implicated in MRTF-SRF regulation in cardiomyocytes and corneas (53)(54)(55), we found neuronal SRF activity unchanged upon inactivation of cofilin1 or ADF. Instead, SRF activity was moderately increased in ADF/Cfl1-dKO neurons, in line with studies demonstrating overlapping brain functions for both ABPs (22)(23)(24)56).…”

Characterization of cardiac involvement in patients with LMNA splice-site mutation–related dilated cardiomyopathy and sudden cardiac death

“…Unstable sarcomere movement will lead to myocardial contraction disorder and affect intracellular signal transmission. Therefore, skeletal protein defects represent an important mechanism of DCM ( Le Dour et al, 2022 ). However, the molecular pathogenesis of LMNA -related DCM has not yet been clearly clarified.…”

Enhanced cell viscosity: A new phenotype associated with lamin A/C alterations

“… 52 , 53 Several recent studies reported that microtubule network contributes to laminopathy pathophysiology in progeria and in dilated cardiomyopathies (DCM). 20 , 21 , 54 , 55 , 56 This effect is mediated by an increase in alpha-tubulin acetylation when compared to control cells that induce an increased microtubule network stability. 55 , 57 Moreover, the inhibition of acetyltransferase protein 10 (NAT10), responsible for alpha-tubulin acetylation, improves cellular phenotype in progeria and DCM models reinforcing the potential role of microtubule network in laminopathies.…”

“… 17 Few other studies have addressed the effect of missense mutations, mainly mutations involved in cardiomyopathies or progeria. 18 , 19 , 20 , 21 However, the diversity of approaches has resulted in a large panel of results that are rather difficult to compare. 3 , 22 , 23 In addition, the link between lamin A/C structural or functional changes and cell or tissue manifestations in the pathological context of laminopathies remains unclear.…”