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.
Highlights
The nucleus is the primary site of nucleic acid regulation, including DNA replication, RNA transcription, and the organization of active and repressed chromatin domains
The nucleus is separated from the cytosol by the nuclear envelope, which is composed of two lipid bilayers: the outer nuclear membrane (ONM), which is contiguous with the endoplasmic reticulum, and the inner nuclear membrane (INM)
H2K myogenic progenitors were used for this analysis because myogenic progenitors derived from emerin-null H2K mice are superior to the C2C12 myoblast-derived cell line in many ways
Summary
The nucleus is the primary site of nucleic acid regulation, including DNA replication, RNA transcription, and the organization of active and repressed chromatin domains. Proper regulation of these processes is essential for successful lineage specification and differentiation during embryonic development and for tissue repair after injury. Underlying the INM is a meshwork of type V intermediate filament proteins called lamins, which are the major scaffolding component of the nuclear lamina [1]. The INM proteins and lamins are referred to as the nuclear lamina. Lamins are required for proper localization of many INM proteins to the nuclear envelope [3]
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