Conditional expression of mutant M-line titins results in cardiomyopathy with altered sarcomere structure
Conditional expression of mutant M-line titins results in cardiomyopathy with altered sarcomere structure
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DOI：
10.1074/jbc.m211723200
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发表时间：
2003-02-21
影响因子：
4.8
通讯作者：
Herz, J
中科院分区：
文献类型：
--
作者：
Gotthardt, M;Hammer, RE;Herz, J
肌联蛋白是一种负责肌肉弹性的巨大蛋白质，并为几种肌节蛋白提供支架，包括新型肌联蛋白结合蛋白MURF-1，其结合在肌联蛋白M线区域附近。肌联蛋白的另一个独特的特征是在肌节的M线区域的边缘处存在丝氨酸/苏氨酸激酶样结构域，尚未显示出其生理催化功能。为了研究肌联蛋白M线片段的作用，我们在胚胎发育的不同阶段有条件地删除了外显子MEx 1和MEx 2（编码激酶结构域和Ranking序列）。我们的数据表明，MEx 1和MEx 2在早期心脏发育（胚胎致死）以及出生后M线肌联蛋白破坏导致肌无力和5周龄左右死亡中起重要作用。肌病变化包括缺乏MURF-1的苍白M线和逐渐的肌节解体。这里提出的动物模型表明肌联蛋白的M线区域在维持肌节结构完整性中的关键作用。
Titin is a giant protein responsible for muscle elasticity and provides a scaffold for several sarcomeric proteins, including the novel titin-binding protein MURF-1, which binds near the titin M-line region. Another unique feature of titin is the presence of a serine/threonine kinase-like domain at the edge of the M-line region of the sarcomere, for which no physiological catalytic function has yet been shown. To investigate the role(s) of the titin M-line segment, we have conditionally deleted the exons MEx1 and MEx2 (encoding the kinase domain plus Ranking sequences) at different stages of embryonic development. Our data demonstrate an important role for MEx1 and MEx2 in early cardiac development (embryonic lethality) as well as postnatally when disruption of M-line titin leads to muscle weakness and death at similar to5 weeks of age. Myopathic changes include pale M-lines devoid of MURF-1, and gradual sarcomeric disassembly. The animal model presented here indicates a critical role for the M-line region of titin in maintaining the structural integrity of the sarcomere.