Orai1 deficiency leads to heart failure and skeletal myopathy in zebrafish
Orai1 deficiency leads to heart failure and skeletal myopathy in zebrafish
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DOI：
10.1242/jcs.090464
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发表时间：
2012-01
影响因子：
4
通讯作者：
M. Völkers;Nima Dolatabadi;N. Gude;P. Most;Mark A Sussman;D. Hassel
中科院分区：
文献类型：
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作者：
M. Völkers;Nima Dolatabadi;N. Gude;P. Most;Mark A Sussman;D. Hassel
据报道，钙库操纵的钙离子进入孔蛋白ORAI1的突变会引起人类患者的肌病，但涉及的机制尚不清楚。心肌细胞表达ORAI1，但其在心脏功能中的作用也是未知的。在斑马鱼中使用反向遗传学，我们证明了高度保守的斑马鱼orai 1直系同源物的失活导致严重的心力衰竭，心室收缩功能降低，心动过缓和骨骼肌无力。Orai1缺陷型肌细胞的电子显微镜检查显示骨骼肌进行性不稳定，骨骼肌和心肌中的肌纤维完整性丧失，Z盘超微结构异常。分离的Orai1缺陷型心肌细胞表现出钙调神经磷酸酶相关蛋白calsarcin从z盘的损失。此外，我们发现机械信号转导在Orai1缺失的心脏中受到影响，这表明Orai1在z盘建立心脏信号转导机制中起着重要作用。我们的研究结果确定了ORAI1作为心脏和骨骼肌功能的重要调节因子，并提供了将ORAI1介导的钙信号传导与肌节完整性和心肌细胞功能联系起来的证据。
Mutations in the store-operated Ca2+ entry pore protein ORAI1 have been reported to cause myopathies in human patients but the mechanism involved is not known. Cardiomyocytes express ORAI1 but its role in heart function is also unknown. Using reverse genetics in zebrafish, we demonstrated that inactivation of the highly conserved zebrafish orthologue of ORAI1 resulted in severe heart failure, reduced ventricular systolic function, bradycardia and skeletal muscle weakness. Electron microscopy of Orai1-deficient myocytes revealed progressive skeletal muscle instability with loss of myofiber integrity and ultrastructural abnormalities of the z-disc in both skeletal and cardiac muscle. Isolated Orai1-deficient cardiomyocytes showed loss of the calcineurin-associated protein calsarcin from the z-discs. Furthermore, we found mechanosignal transduction was affected in Orai1-depleted hearts, indicating an essential role for ORAI1 in establishing the cardiac signaling transduction machinery at the z-disc. Our findings identify ORAI1 as an important regulator of cardiac and skeletal muscle function and provide evidence linking ORAI1-mediated calcium signaling to sarcomere integrity and cardiomyocyte function.