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核纤层病是一类由编码核纤层蛋白laminA和laminC的LMNA基因突变引起的疾病 ,其发病机制不明。本文报道了laminA/C基因敲除 (Lmna / )小鼠表现出快速进行性的扩张型心肌病 (DCM ) ,其特征为左心室(LV)扩张及其收缩功能降低。分离出的Lmna / 小鼠心肌显示 ,正常基线水平和钙离子瞬变峰值时射血分数均降低。Lmna / 小鼠左心室心肌细胞核的形状和大小上均发生显著改变 ,并伴有异染色质的核中心转移及破裂。这些变化亦出现在左心房细胞核内 ,但是其程度要轻微的多。电子显微镜观察Lmna / 心肌细胞显示 ,desmin纤维结构被破坏 ,与核内膜表面分离 ,并伴随着胞浆骨架的desmin网进行性分裂。核骨架的改变与核功能的损伤密切相关 ,这为SREBP1入核减少、PPARg表达减少、肥厚基因活性缺失所证实。上述发现提出了一个模型 ,该模型认为lamin与横纹肌特异的desmin网络的相互作用障碍使力传导受损以及细胞骨架牵张力丧失是Lm na / 小鼠的主要病理学机制。尽管有严重的扩张型心肌病 ,但是核功能的缺陷阻止了Lmna / 心肌细胞发展为代偿性肥厚和病程的加速。
Laryngopathy is a group of diseases caused by mutations in the LMNA gene encoding lamin A and laminC, whose pathogenesis is unknown. This paper reports that laminA / C knockout (Lmna /) mice exhibit rapid progressive dilated cardiomyopathy (DCM) characterized by dilatation of the left ventricle (LV) and reduction of its systolic function. Isolated Lmna / mouse myocardium showed reduced ejection fraction at both normal baseline and peak calcium transient. Lmna / mouse left ventricular myocardial nucleus shape and size were significantly changed, accompanied by heterochromatin nuclear transfer and rupture. These changes also appear in the left atrial nucleus, but to a lesser extent. Electron microscopic observation of Lmna / cardiomyocytes showed that the desmin fiber structure was disrupted, separated from the surface of the intima, and progressively divided along the cytoplasmic backbone of the desmin network. Changes in the nuclear scaffold are closely related to impairment of nuclear function, as evidenced by decreased nuclear entry of SREBP1, reduced expression of PPARg, and loss of activity of hypertrophic genes. The above findings present a model that suggests that impairment of lamina interaction with striated muscle-specific desmin networks impairs both conduction and loss of cytoskeletal stretch and is a major pathological mechanism in Lm na / mice. Despite severe dilated cardiomyopathy, defects in nuclear function prevent the development of Lmna / cardiomyocytes to compensatory hypertrophy and accelerated course of disease.