Knockout of Lmod2 results in shorter thin filaments followed by dilated cardiomyopathy and juvenile lethality
Knockout of Lmod2 results in shorter thin filaments followed by dilated cardiomyopathy and juvenile lethality
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DOI：
10.1073/pnas.1508273112
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发表时间：
2015-11-03
影响因子：
11.1
通讯作者：
Gregorio, Carol C.
中科院分区：
文献类型：
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作者：
Pappas, Christopher T.;Mayfield, Rachel M.;Gregorio, Carol C.
Leiomodin 2（Lmod 2）是一种肌动蛋白结合蛋白，其参与横纹肌细丝组装的调节;其生理功能尚未被研究。我们发现，敲除小鼠中的Lmod 2导致心脏中异常短的细丝。我们还发现Lmod 2通过促进肌动蛋白在细丝尖端的组装和动力学来延长细丝。Lmod 2-KO小鼠在幼年时死亡，心脏表现出收缩功能障碍和室腔扩大，与扩张型心肌病一致。当接种在微柱阵列上时，Lmod 2缺失的心肌细胞产生比野生型更少的收缩力。通过腺相关病毒转导引入GFP-Lmod 2延长了细丝并挽救了在Lmod 2-KO小鼠中观察到的结构和功能缺陷，将其寿命延长至成年。因此，据我们所知，Lmod 2是第一个被鉴定的哺乳动物蛋白，其功能是延长心脏中的肌动蛋白丝;它对于心脏细丝达到成熟长度是必不可少的，并且是发育期间有效收缩力和适当心脏功能所必需的。
Leiomodin 2 (Lmod2) is an actin-binding protein that has been implicated in the regulation of striated muscle thin filament assembly; its physiological function has yet to be studied. We found that knockout of Lmod2 in mice results in abnormally short thin filaments in the heart. We also discovered that Lmod2 functions to elongate thin filaments by promoting actin assembly and dynamics at thin filament pointed ends. Lmod2-KO mice die as juveniles with hearts displaying contractile dysfunction and ventricular chamber enlargement consistent with dilated cardiomyopathy. Lmod2-null cardiomyocytes produce less contractile force than wild type when plated on micropillar arrays. Introduction of GFP-Lmod2 via adeno-associated viral transduction elongates thin filaments and rescues structural and functional defects observed in Lmod2-KO mice, extending their lifespan to adulthood. Thus, to our knowledge, Lmod2 is the first identified mammalian protein that functions to elongate actin filaments in the heart; it is essential for cardiac thin filaments to reach a mature length and is required for efficient contractile force and proper heart function during development.