Deficiency of emerin contributes differently to the pathogenesis of skeletal and cardiac muscles in LmnaH222P/H222P mutant mice
Deficiency of emerin contributes differently to the pathogenesis of skeletal and cardiac muscles in LmnaH222P/H222P mutant mice
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DOI：
10.1371/journal.pone.0221512
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发表时间：
2019-08-20
期刊：
影响因子：
3.7
通讯作者：
Hayashi, Yukiko K.
中科院分区：
文献类型：
--
作者：
Wada, Eiji;Kato, Megumi;Hayashi, Yukiko K.
椎板病是组织选择性疾病，影响不同的器官系统。核膜、Emerin（Emd）和核纤层蛋白A/C（Lmna）基因中的突变引起临床上难以区分的肌病，称为Emery-Dreifuss肌营养不良症（EDMD）和肢带型肌营养不良症。已经产生了几种EDMD的鼠模型;然而，emerin-null（Emd）小鼠不显示明显的骨骼肌和心肌表型，并且Lmna（H222 P/H222 P）突变体（H222 P）小鼠在已经具有严重心肌病时仅显示骨骼肌中的轻度表型。因此，由于核异常导致肌肉受累的潜在分子机制仍不清楚。我们产生了双突变体（Emd（-/-）/Lmna（H222 P/H222 P）; EH）小鼠，以表征营养不良性变化并阐明骨骼肌和心肌中emerin和核纤层蛋白A/C之间的相互作用。EH小鼠与H222 P小鼠一样，生长正常，具有繁殖能力。与H222 P小鼠相比，EH小鼠表现出更大的肌肉受累，这与12周龄时的心脏异常无关。核异常、肌纤维尺寸减小和纤维化增加在EH小鼠中是突出的。以心肌毒素损伤为模型，研究了Emerin和Lamin A/C在卫星细胞功能和肌纤维再生中的作用。在H222 P和EH小鼠中均观察到myog和myh 3表达的延迟增加;然而，这些基因的表达水平与对照组相似，并且在损伤后第7天再生肌纤维大小没有差异。这些结果表明，EH小鼠是一个合适的模型，用于研究骨骼肌参与，独立于心脏功能，在laminopathies和emerin和lamin A/C之间的相互作用，在不同的组织。
Laminopathies are tissue-selective diseases that affect differently in organ systems. Mutations in nuclear envelopes, emerin (Emd) and lamin A/C (Lmna) genes, cause clinically indistinguishable myopathy called Emery-Dreifuss muscular dystrophy (EDMD) and limb-girdle muscular dystrophy. Several murine models for EDMD have been generated; however, emerin-null (Emd) mice do not show obvious skeletal and cardiac muscle phenotypes, and Lmna(H222P/H222P) mutant (H222P) mice show only a mild phenotype in skeletal muscle when they already have severe cardiomyopathy. Thus, the underlying molecular mechanism of muscle involvement due to nuclear abnormalities is still unclarified. We generated double mutant (Emd(-/-)/Lmna(H222P/H222P); EH) mice to characterize dystrophic changes and to elucidate interactions between emerin and lamin A/C in skeletal and cardiac muscles. As H222P mice, EH mice grow normally and have breeding productivity. EH mice showed severer muscle involvement compared with that of H222P mice which was an independent of cardiac abnormality at 12 weeks of age. Nuclear abnormalities, reduced muscle fiber size and increased fibrosis were prominent in EH mice. Roles of emerin and lamin A/C in satellite cells function and regeneration of muscle fiber were also evaluated by cardiotoxin-induced muscle injury. Delayed increases in myog and myh3 expression were seen in both H222P and EH mice; however, the expression levels of those genes were similar with control and regenerated muscle fiber size was not different at day 7 after injury. These results indicate that EH mouse is a suitable model for studying skeletal muscle involvement, independent of cardiac function, in laminopathies and an interaction between emerin and lamin A/C in different tissues.