Cofilin-1 phosphorylation catalyzed by ERK1/2 alters cardiac actin dynamics in dilated cardiomyopathy caused by lamin A/C gene mutation

Abstract

Hyper-activation of extracellular signal-regulated kinase (ERK) 1/2 contributes to heart dysfunction in cardiomyopathy caused by mutations in the lamin A/C gene (LMNA cardiomyopathy). The mechanism of how this affects cardiac function is unknown. We show that active phosphorylated ERK1/2 directly binds to and catalyzes the phosphorylation of the actin depolymerizing factor cofilin-1 on Thr25. Cofilin-1 becomes active and disassembles actin filaments in a large array of cellular and animal models of LMNA cardiomyopathy. In vivo expression of cofilin-1, phosphorylated on Thr25 by endogenous ERK1/2 signaling, leads to alterations in left ventricular function and cardiac actin. These results demonstrate a novel role for cofilin-1 on actin dynamics in cardiac muscle and provide a rationale on how increased ERK1/2 signaling leads to LMNA cardiomyopathy.

Amelioration of desmin network defects by αB-crystallin overexpression confers cardioprotection in a mouse model of dilated cardiomyopathy caused by LMNA gene mutation

“…These aggregates compromise proper targeting of desmoplakin (in blue) to the desmosomes and consequently their stabilization, thus also affecting indirectly the stability of fascia adherens and gap junctions and their components. In addition, or alternatively, desmin network destabilization could influence, through the linker plectin, the other two cytoskeletal networks, actin microfilaments and microtubules, thus contributing to the observed mislocalization of plakoglobin (in green) or connexin-43 (in yellow), consistent with the previously reported effects in actin [46] and microtubule [47,48] cytoskeleton in the Lmna H222P/H222P mouse cardiomyocytes. Similarly, desmin network destabilization and aggregation leads to the expected mitochondrial defects due to loss of proper desmin function [26] (B).…”

“…cytoskeleton to actin microfilaments and microtubules though plectin at least, it is not surprising to link their defects to the pathology of the Lmna H222P/H222P [46][47][48] or TAC [61] mouse models of cardiomyopathy. We also revealed that in Lmna H222P/H222P hearts desmin exhibits a different PTM status, as indicated by the presence of more acidic desmin isoforms in 2-D Western blot, compatible with increased phosphorylation.…”

Nesprins and Lamins in Health and Diseases of Cardiac and Skeletal Muscles

“…Thus, mutations in genes encoding LINC complex proteins could alter in a tissue-specific manner transcription factors expression and/or alter expression pattern of tissue-specific genes ( Dialynas et al, 2010 ). For example, such alterations are more and more described for laminopathies with the hyperactivation of the ERK (extracellular signal-regulated kinase) pathway in cardiomyopathy caused by LMNA mutations ( Chatzifrangkeskou et al, 2018 ) or the overexpression of SMAD6, an inhibitor of the BMP signaling pathways, as a cause of accelerated myogenic differentiation of LMNA mutated cells ( Janin et al, 2018 ).…”

Alteration of performance in a mouse model of Emery–Dreifuss muscular dystrophy caused by A-type lamins gene mutation

“…We used transthoracic echocardiography to determine the cardiac function of Lmna H222P/H222P male mice. While the cardiac structure and function were not statistically different at 3 months of age, at 6 months of age, Lmna H222P/H222P male mice have increased left ventricular diameters, and decreased fractional shortening (FS) compared with wild type animals ( Figure 1A) (8,9,16). Left ventricular dilatation in Lmna H222P/H222P male mice at 6 months of age was demonstrated by histopathological analysis ( Figure 1B).…”

“…We largely contributed in understanding the metabolic and physiological mechanisms regulating cardiac function and energy balance in EDMD, both in animal models and in patient's tissues. These include abnormal regulation of the mitogenactivated protein kinase (MAPK) signaling cascade (6,7), altered actin dynamics (8), altered Wnt/βcatenin signaling (9), fibrosis (10), NAD signaling (11) and AKT/mTOR signaling (12). Despite the growing understanding of the pathogenesis of EDMD as well as the discovery of novel therapeutic for the disease (7,(9)(10)(11)(12)(13), little is known on the overall benefit of these treatments on the performance of the animals.…”