APOBEC2 negatively regulates myoblast differentiation in muscle regeneration
APOBEC2 negatively regulates myoblast differentiation in muscle regeneration
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APOBEC2 负向调节肌肉再生中的成肌细胞分化
DOI：
10.1016/j.biocel.2017.02.005
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发表时间：
2017
影响因子：
4
通讯作者：
Yoshihide Ikeuchi
中科院分区：
文献类型：
--
作者：
Hideaki Ohtsubo;Yusuke Sato;Takahiro Suzuki;Wataru Mizunoya;Mako Nakamura;Ryuichi Tatsumi;Yoshihide Ikeuchi
最近，我们发现APOBEC2 （apoB mRNA编辑酶的一员，催化多肽样家族）的缺乏会导致肌肉质量减少和肌纤维增加，其核位于中心位置，称为营养不良表型。APOBEC2的表达主要在骨骼肌和心肌中，并且只在野生型（WT）成肌细胞培养的早期分化阶段升高；然而，其生理意义尚不清楚。在这里，我们发现APOBEC2是肌肉再生中成肌细胞分化的关键负调节因子。apobec2敲除（A2KO）小鼠成肌细胞培养物表现出正常的原代肌管形态，融合指数较WT型成肌细胞更早增加，肌球蛋白重链（MyHC）、肌原素及其协同因子MEF2C表达水平更高。在分化期（非增殖期）转染特定siRNA的apobec2敲低培养的WT成肌细胞中也观察到类似的反应。重要的是，心脏毒素损伤的A2KO腓肠肌提供了活体证据，显示出新生儿MyHC和肌原素的较大上调，因此肌纤维结构的早期再生，横截面面积减少，纤维直径最小。因此，这些发现强调了APOBEC2在肌肉损伤早期分化阶段再生肌发生的正常进展中的有希望的作用。
Recently we found that the deficiency of APOBEC2, a member of apoB mRNA editing enzyme, catalytic polypeptide-like family, leads to a diminished muscle mass and increased myofiber with centrally-located nuclei known as dystrophic phenotypes. APOBEC2 expression is predominant in skeletal and cardiac muscles and elevated exclusively at the early-differentiation phase of wild-type (WT) myoblast cultures; however the physiological significance is still un-known. Here we show that APOBEC2 is a key negative regulator of myoblast differentiation in muscle regeneration. APOBEC2-knockout (A2KO) mice myoblast cultures displayed a normal morphology of primary myotubes along with earlier increase in fusion index and higher expression levels of myosin heavy chain (MyHC), myogenin and its cooperating factor MEF2C than WT myoblasts. Similar response was observable in APOBEC2-knockdown cultures of WT myoblasts that were transfected with the specific siRNA at the differentiation phase (not proliferation phase). Importantly, cardiotoxin-injured A2KO gastrocnemius muscle providedin vivoevidence by showing larger up-regulation of neonatal MyHC and myogenin and hence earlier regeneration of myofiber structures with diminished cross-sectional areas and minimal Feret diameters. Therefore, the findings highlight a promising role for APOBEC2 in normal progression of regenerative myogenesis at the early-differentiation phase upon muscle injury.