Abstract
ABSTRACTMutations 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.
Highlights
The nuclear envelope is composed of two lipid bilayers and functionally separates the nucleoplasm from the cytoplasm
Myosin heavy chain was expressed in only 66.0% and 74.8% of differentiating emerin-null cells compared with 71.5% and 85.6% of differentiating wild-type progenitors at 48 h and 72 h, respectively (P
Multiple lines of evidence support the hypothesis that the skeletal muscle pathology of Emery–Dreifuss muscular dystrophy (EDMD) is caused, at least in part, by inefficient skeletal muscle regeneration
Summary
The nuclear envelope is composed of two lipid bilayers and functionally separates the nucleoplasm from the cytoplasm. The outer and inner nuclear membranes arise from a common membrane, they are functionally distinct membranes containing proteins localizing to either the outer or inner nuclear membrane. The inner nuclear membrane of the nuclear envelope contains a large number of integral inner nuclear membrane proteins (Gruenbaum and Foisner, 2015). There are more than 130 inner nuclear membrane proteins, specific cell types express only a subset of these inner nuclear membrane proteins (de Las Heras et al, 2013; Gonzalez et al, 2012; Korfali et al, 2010, 2012; Malik et al, 2010; Schirmer et al, 2003; Wilkie et al, 2011; Worman and Schirmer, 2015). The nuclear lamins are required for the localization of integral inner nuclear membrane proteins. The nuclear lamins and its associated inner nuclear membrane proteins define the nuclear lamina
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