MAPK signaling pathways and HDAC3 activity are disrupted during differentiation of emerin-null myogenic progenitor cells.
MAPK signaling pathways and HDAC3 activity are disrupted during differentiation of emerin-null myogenic progenitor cells.
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DOI：
10.1242/dmm.028787
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发表时间：
2017-04-01
影响因子：
4.3
通讯作者：
Holaska JM
中科院分区：
文献类型：
--
作者：
Collins CM;Ellis JA;Holaska JM
Emerin编码基因的突变会导致Emery-Dreifuss肌营养不良症(EDMD)。Emerin是一种完整的核内膜蛋白，也是核膜的组成部分。EDMD的特征是骨骼肌萎缩、心脏传导缺陷和肌腱痉挛。骨骼肌再生的失败被预测是EDMD骨骼肌病理的原因之一。我们假设肌肉再生缺陷是由肌肉干细胞分化受损引起的。来自Emerin缺失小鼠的成肌祖细胞被用来确认它们的分化受损，并分析选定的成肌分子通路。Emerin缺失的祖细胞在细胞周期退出时延迟，肌球蛋白重链(MyHC)表达减少，肌管形成减少。Emerin与组蛋白脱乙酰基酶3(HDAC3)结合并激活组蛋白脱乙酰酶3。在这里，我们展示了茶碱，一种HDAC3特异性激活剂，改善了Emerin零细胞中肌管的形成。加入HDAC3特异性抑制剂RGFP966可抑制野生型和Emerin缺失型肌祖细胞的肌管形成和MyHC表达，但不影响细胞周期退出。先前研究表明，在C2C12成肌细胞分化中，Emerin的下调影响p38MAPK和ERK/MAPK信号通路。使用完全缺乏Emerin表达的纯肌源性祖细胞群体，我们表明这些通路也被破坏。ERK抑制促进了Emerin缺失细胞中MyHC的表达，但不能挽救肌管形成或细胞周期退出。抑制p38MAPK可以阻止野生型和Emerin缺失祖细胞的分化。这些结果表明，这些分子通路中的每一个都以一种发生蛋白依赖的方式特异性地调节着肌细胞分化的特定阶段。因此，药物靶向作用于特定分化阶段的多个途径可能是未来挽救体内肌肉再生的更好的治疗方法。编辑选择：HDAC3、p38 MAPK和ERK信号在缺乏Emerin的肌源性前体细胞分化过程中发生变化；药物激活或抑制这些信号蛋白可以挽救肌源性分化的特定阶段。
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. Editors' choice: HDAC3, p38 MAPK and ERK signaling are altered during differentiation of myogenic progenitors lacking emerin; pharmacological activation or inhibition of these signaling proteins rescues specific stages of myogenic differentiation.