Atrogin-1 Deficiency Leads to Myopathy and Heart Failure in Zebrafish
Atrogin-1 Deficiency Leads to Myopathy and Heart Failure in Zebrafish
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DOI：
10.3390/ijms17020187
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发表时间：
2016-02-01
影响因子：
5.6
通讯作者：
Just, Steffen
中科院分区：
文献类型：
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作者：
Buehler, Anja;Kustermann, Monika;Just, Steffen
蛋白质的合成和降解是正常细胞功能的基础。在肌肉中，蛋白质稳态的损害通常导致严重的细胞缺陷，最终干扰收缩功能。在这里，我们第一次分析Atrogin-1的作用，肌肉特异性E3泛素连接酶已知参与蛋白质降解的调节通过泛素蛋白酶体和自噬/溶酶体系统，在体内模型系统斑马鱼（斑马鱼）。我们发现，斑马鱼Atrogin-1的靶向失活导致心脏和骨骼肌功能的进行性损害和肌肉结构的破坏，而不影响早期心脏发生和骨骼肌发育。Atrogin-1缺陷的斑马鱼胚胎自噬严重受损，导致心肌细胞和骨骼肌细胞的细胞结构紊乱。这些观察结果与Atrogin-1敲除小鼠的分子和超微结构结果一致，并证明斑马鱼是研究Atrogin-1介导的自噬性肌肉病理学的分子机制和在高通量体内小化合物筛选（SCS）中筛选新型治疗活性物质的合适脊椎动物模型。
Orchestrated protein synthesis and degradation is fundamental for proper cell function. In muscle, impairment of proteostasis often leads to severe cellular defects finally interfering with contractile function. Here, we analyze for the first time the role of Atrogin-1, a muscle-specific E3 ubiquitin ligase known to be involved in the regulation of protein degradation via the ubiquitin proteasome and the autophagy/lysosome systems, in the in vivo model system zebrafish (Danio rerio). We found that targeted inactivation of zebrafish Atrogin-1 leads to progressive impairment of heart and skeletal muscle function and disruption of muscle structure without affecting early cardiogenesis and skeletal muscle development. Autophagy is severely impaired in Atrogin-1-deficient zebrafish embryos resulting in the disturbance of the cytoarchitecture of cardiomyocytes and skeletal muscle cells. These observations are consistent with molecular and ultrastructural findings in an Atrogin-1 knockout mouse and demonstrate that the zebrafish is a suitable vertebrate model to study the molecular mechanisms of Atrogin-1-mediated autophagic muscle pathologies and to screen for novel therapeutically active substances in high-throughput in vivo small compound screens (SCS).