Mutations in the gene encoding emerin cause Emery–Dreifuss muscular dystrophy (EDMD). Emerin is an integral inner nuclear membrane protein and a component of the nuclear lamina. EDMD is characterized by skeletal muscle wasting, cardiac conduction defects and tendon contractures. The failure to regenerate skeletal muscle is predicted to contribute to the skeletal muscle pathology of EDMD. We hypothesize that muscle regeneration defects are caused by impaired muscle stem cell differentiation. Myogenic progenitors derived from emerin-null mice were used to confirm their impaired differentiation and analyze selected myogenic molecular pathways. Emerin-null progenitors were delayed in their cell cycle exit, had decreased myosin heavy chain (MyHC) expression and formed fewer myotubes. Emerin binds to and activates histone deacetylase 3 (HDAC3). Here, we show that theophylline, an HDAC3-specific activator, improved myotube formation in emerin-null cells. Addition of the HDAC3-specific inhibitor RGFP966 blocked myotube formation and MyHC expression in wild-type and emerin-null myogenic progenitors, but did not affect cell cycle exit. Downregulation of emerin was previously shown to affect the p38 MAPK and ERK/MAPK pathways in C2C12 myoblast differentiation. Using a pure population of myogenic progenitors completely lacking emerin expression, we show that these pathways are also disrupted. ERK inhibition improved MyHC expression in emerin-null cells, but failed to rescue myotube formation or cell cycle exit. Inhibition of p38 MAPK prevented differentiation in both wild-type and emerin-null progenitors. These results show that each of these molecular pathways specifically regulates a particular stage of myogenic differentiation in an emerin-dependent manner. Thus, pharmacological targeting of multiple pathways acting at specific differentiation stages may be a better therapeutic approach in the future to rescue muscle regeneration in vivo.
Emerin is a highly conserved and ubiquitously expressed inner nuclear membrane protein of the nuclear envelope. Mutations in the gene encoding emerin cause X‐linked Emery–Dreifuss muscular dystrophy (EDMD), a tissue‐specific, progressive disease that selectively affects skeletal muscle, the cardiac conduction system and tendons. Emerin regulates a number of nuclear functions through interactions with many different binding partners. These emerin‐regulated cellular functions include regulating genomic architecture, maintaining nuclear structure and regulating gene transcription in response to mechanical and chemical signals. Emerin regulation of these activities is important for controlling the coordinated temporal expression of myogenic differentiation genes during skeletal muscle regeneration. This article focuses on the mechanisms by which emerin regulates chromatin architecture and gene transcription and how these mechanisms may function in the development of EDMD. Key Concepts Proteins of the nuclear lamina are important for chromatin architecture and regulation of gene transcription. Emerin is a nuclear lamina protein that plays key roles in regulating chromatin organisation and gene expression. Emerin regulates the coordinated temporal expression of myogenic differentiation genes. Emerin is required for proper myogenic differentiation. Loss of emerin causes Emery–Dreifuss muscular dystrophy.
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