Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload.
Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload.
复制标题
Myopalladin基因敲除小鼠出现心脏扩张，并对机械压力过载表现出适应不良反应。
DOI：
10.7554/elife.58313
复制
发表时间：
2021-09-24
期刊：
影响因子：
7.7
通讯作者：
Bang ML
中科院分区：
文献类型：
--
作者：
Filomena MC;Yamamoto DL;Carullo P;Medvedev R;Ghisleni A;Piroddi N;Scellini B;Crispino R;D'Autilia F;Zhang J;Felicetta A;Nemska S;Serio S;Tesi C;Catalucci D;Linke WA;Polishchuk R;Poggesi C;Gautel M;Bang ML
Myopalladin（MYPN）是一种横纹肌特异性免疫球蛋白结构域蛋白，位于肌节Z线和I带。MYPN基因突变是扩张型（DCM）、肥厚型和限制型心肌病的病因。在酵母双杂交筛选中，发现MYPN与Z-线中的肌联蛋白结合，这通过微量热电泳证实。MYPN基因敲除（MKO）小鼠的心脏分析显示，轻度心脏扩张和收缩功能障碍的发展，与肌原纤维等长张力产生减少和肌节长度较长时静息张力增加相关。MKO小鼠对经主动脉缩窄（TAC）表现出正常的肥大反应，但迅速发展为严重的心脏扩张和收缩功能障碍，与纤维化、胎儿基因表达增加、闰盘折叠幅度较高、钙螯合蛋白-2蛋白水平降低以及桥粒斑蛋白和SORBS 2蛋白水平增加相关。心肌细胞分析显示，在未应激的MKO小鼠中延迟的Ca 2+释放和再摄取以及TAC后降低的Ca 2+火花振幅，表明改变的Ca 2+处理可能有助于MKO小鼠中DCM的发展。
Myopalladin (MYPN) is a striated muscle-specific immunoglobulin domain-containing protein located in the sarcomeric Z-line and I-band. MYPN gene mutations are causative for dilated (DCM), hypertrophic, and restrictive cardiomyopathy. In a yeast two-hybrid screening, MYPN was found to bind to titin in the Z-line, which was confirmed by microscale thermophoresis. Cardiac analyses of MYPN knockout (MKO) mice showed the development of mild cardiac dilation and systolic dysfunction, associated with decreased myofibrillar isometric tension generation and increased resting tension at longer sarcomere lengths. MKO mice exhibited a normal hypertrophic response to transaortic constriction (TAC), but rapidly developed severe cardiac dilation and systolic dysfunction, associated with fibrosis, increased fetal gene expression, higher intercalated disc fold amplitude, decreased calsequestrin-2 protein levels, and increased desmoplakin and SORBS2 protein levels. Cardiomyocyte analyses showed delayed Ca2+ release and reuptake in unstressed MKO mice as well as reduced Ca2+ spark amplitude post-TAC, suggesting that altered Ca2+ handling may contribute to the development of DCM in MKO mice.