Activation of MAPK in hearts of EMD null mice: Similarities between mouse models of X-linked and autosomal dominant Emery - Dreifuss muscular dystrophy

Department of Medicine, College of Physicians and Surgeons, Columbia University, New York 10032, USA.
Human Molecular Genetics (Impact Factor: 6.39). 09/2007; 16(15):1884-95. DOI: 10.1093/hmg/ddm137
Source: PubMed


Emery–Dreifuss muscular dystrophy (EDMD) is an inherited disorder characterized by slowly progressive skeletal muscle weakness
in a humero-peroneal distribution, early contractures and prominent cardiomyopathy with conduction block. Mutations in EMD, encoding emerin, and LMNA, encoding A-type lamins, respectively, cause X-linked and autosomal dominant EDMD. Emerin and A-type lamins are proteins
of the inner membrane of the nuclear envelope. Whereas the genetic cause of EDMD has been described and the proteins well
characterized, little is known on how abnormalities in nuclear envelope proteins cause striated muscle disease. In this study,
we analyzed genome-wide expression profiles in hearts from Emd knockout mice, a model of X-linked EDMD, using Affymetrix GeneChips. This analysis showed a molecular signature similar to
that we previously described in hearts from Lmna H222P knock-in mice, a model of autosomal dominant EDMD. There was a common activation of the ERK1/2 branch of the mitogen-activated
protein kinase (MAPK) pathway in both murine models, as well as activation of downstream targets implicated in the pathogenesis
of cardiomyopathy. Activation of MAPK signaling appears to be a cornerstone in the development of heart disease in both X-linked
and autosomal dominant EDMD.

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    • "Activation of these targets might consequently regulate expression of additional genes, including those encoding proteins involved in sarcomere structure, cardiomyofibre organisation, and other aspects of heart function (Gillespie-Brown et al., 1995; Thorburn et al., 1995). Hyperactivation of ERK1/2 also occurs in the hearts of emerin-deficient mice, a model of x-linked EDMD with DCM (Muchir et al., 2007a). The role of ERK1/2 hyperactivation in the pathogenesis of DCM is further supported by the finding that the cardiac impairment in Lmna H222P/H222P mice is blocked by treatment with MAPK signalling inhibitors before the appearance of clinical symptoms (Muchir et al., 2009; Wu et al., 2011). "
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    ABSTRACT: Lamin A/C is a structural protein of the nuclear envelope and cardiac involvement in Lamin A/C mutations was one of the first phenotypes to be reported in humans, suggesting a crucial role of this protein in the cardiomyocytes function. Mutations in LMNA gene cause a class of pathologies generically named ‘Lamanopathies’ mainly involving heart and skeletal muscles. Moreover, the well known disease called Hutchinson-Gilford Progeria Syndrome (HGPS) due to extensive mutations in LMNA gene, in addition to the systemic phenotype of premature aging, is characterized by the death of patients at around 13 typically for a heart attack or stroke, suggesting again the heart as the main site sensitive to Lamin A/C disfunction. Indeed, the identification of the roles of the Lamin A/C in cardiomyocytes function is a key area of exploration.One of the primary biological roles recently conferred to Lamin A/C is to affect contractile cells lineage determination and senescence. Then, in differentiated adult cardiomyocytes both the ‘structural’ and ‘gene expression hypothesis’ could explain the role of Lamin A in the function of cardiomyocytes. In fact, recent advances in the field propose that the structural weakness/stiffness of the NE, regulated by Lamin A/C amount in NE, can ‘consequently’ alter gene expression.This article is protected by copyright. All rights reserved
    Biology of the Cell 07/2014; 106(10). DOI:10.1111/boc.201400033 · 3.51 Impact Factor
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    • "In addition to autosomal EDMD, ERK1/2 has been implicated as contributing to skeletal or cardiac muscle pathology in mdx[39-41], γ-sarcoglycan-deficient [42,43], and Lama2Dy-w[44] mice, respective small animal models of Duchenne, limb girdle type 2C, and a form of congenital muscular dystrophy. ERK1/2 activity is also abnormally increased in hearts of mice with emerin deficiency, which is the genetic alteration in X-linked EDMD [45]. "
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    ABSTRACT: Autosomal Emery-Dreifuss muscular dystrophy is caused by mutations in the lamin A/C gene (LMNA) encoding A-type nuclear lamins, intermediate filament proteins of the nuclear envelope. Classically, the disease manifests as scapulo-humeroperoneal muscle wasting and weakness, early joint contractures and dilated cardiomyopathy with conduction block; however, more variable skeletal muscle can be present. Previously, we demonstrated increased activity of extracellular signal-regulated kinase (ERK) 1/2 in hearts of LmnaH222P/H222P mice, a model of autosomal Emery-Dreifuss muscular dystrophy, and that blocking its activation improved cardiac function. We therefore examined the role of ERK1/2 activity in skeletal muscle pathology. Sections of skeletal muscle from LmnaH222P/H222P mice were stained with hematoxylin and eosin and histological analysis performed using light microscopy. ERK1/2 activity was assessed in mouse tissue and cultured cells by immunoblotting and real-time polymerase chain reaction to measure expression of downstream target genes. LmnaH222P/H222P mice were treated with selumetinib, which blocks mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 that activates ERK1/2, from 16 to 20 weeks of age to assess the effects of treatment on muscle histology, ERK1/2 activity and limb grip strength. We detected enhanced activation of ERK1/2 in skeletal muscle of LmnaH222P/H222P mice. Treatment with selumetinib ameliorated skeletal muscle histopathology and reduced serum creatine phosphokinase and aspartate aminotransferase activities. Selumetinib treatment also improved muscle function as assessed by in vivo grip strength testing. Our results show that ERK1/2 plays a role in the development of skeletal muscle pathology in LmnaH222/H222P mice. They further provide the first evidence that a small molecule drug may be beneficial for skeletal muscle in autosomal Emery-Dreifuss muscular dystrophy.
    Skeletal Muscle 07/2013; 3(1):17. DOI:10.1186/2044-5040-3-17
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    • "Several groups have investigated signaling disruptions in cells containing mutations in emerin or lamin A that are associated with EDMD. ERK1/2 is upregulated in emerin-null [10] and lamin A H222P mutant mouse [11] hearts. Importantly, downstream target genes were also misregulated showing that ERK signaling was disrupted in these mice [11]. "
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    ABSTRACT: Emerin is an integral membrane protein of the inner nuclear membrane. Mutations in emerin cause X-linked Emery-Dreifuss muscular dystrophy (EDMD), a disease characterized by skeletal muscle wasting and dilated cardiomyopathy. Current evidence suggests the muscle wasting phenotype of EDMD is caused by defective myogenic progenitor cell differentiation and impaired muscle regeneration. We obtained genome-wide expression data for both mRNA and micro-RNA (miRNA) in wildtype and emerin-null mouse myogenic progenitor cells. We report here that emerin-null myogenic progenitors exhibit differential expression of multiple signaling pathway components required for normal muscle development and regeneration. Components of the Wnt, IGF-1, TGF-β, and Notch signaling pathways are misexpressed in emerin-null myogenic progenitors at both the mRNA and protein levels. We also report significant perturbations in the expression and activation of p38/Mapk14 in emerin-null myogenic progenitors, showing that perturbed expression of Wnt, IGF-1, TGF-β, and Notch signaling components disrupts normal downstream myogenic signaling in these cells. Collectively, these data support the hypothesis that emerin is essential for proper myogenic signaling in myogenic progenitors, which is necessary for myogenic differentiation and muscle regeneration.
    PLoS ONE 05/2012; 7(5):e37262. DOI:10.1371/journal.pone.0037262 · 3.23 Impact Factor
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