Pathophysiological defects and transcriptional profiling in the RBM20-/- rat model.
Pathophysiological defects and transcriptional profiling in the RBM20-/- rat model.
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DOI：
10.1371/journal.pone.0084281
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Greaser ML
中科院分区：
文献类型：
--
作者：
Guo W;Pleitner JM;Saupe KW;Greaser ML
我们最近的研究表明，RNA结合基序20（Rbm 20）改变肌联蛋白和其他基因的剪接。目前的目标是了解Rbm 20-/-大鼠如何与导致心力衰竭的生理，结构和分子变化相关。采用真实的RT-PCR和SDS琼脂糖凝胶电泳对Rbm 20-/-和野生型大鼠肌联蛋白亚型的表达进行了定量和定性比较。亚型的变化与转录的改变有关，而不是肌联蛋白信息的翻译。基因敲除大鼠跑步至力竭的时间减少也表明最大心输出量降低或骨骼肌性能下降。基因敲除动物左心室的电子显微镜观察显示异常肌原纤维排列、Z线流和脂褐素沉积。突变体骨骼肌超微结构正常。结果表明，Rbm 20-/-大鼠的剪接改变导致生理和心脏超微结构的病理变化。在许多基因的信息水平上观察到次级变化，这些基因的剪接没有受到直接影响。基因和蛋白表达数据表明，病理生理和肌肉应力激活途径的激活。这些数据为Rbm 20功能及其功能障碍如何导致心肌病提供了新的见解。
Our recent study indicated that RNA binding motif 20 (Rbm20) alters splicing of titin and other genes. The current goals were to understand how the Rbm20-/- rat is related to physiological, structural, and molecular changes leading to heart failure. We quantitatively and qualitatively compared the expression of titin isoforms between Rbm20-/- and wild type rats by real time RT-PCR and SDS agarose electrophoresis. Isoform changes were linked to alterations in transcription as opposed to translation of titin messages. Reduced time to exhaustion with running in knockout rats also suggested a lower maximal cardiac output or decreased skeletal muscle performance. Electron microscopic observations of the left ventricle from knockout animals showed abnormal myofibril arrangement, Z line streaming, and lipofuscin deposits. Mutant skeletal muscle ultrastructure appeared normal. The results suggest that splicing alterations in Rbm20-/- rats resulted in pathogenic changes in physiology and cardiac ultrastructure. Secondary changes were observed in message levels for many genes whose splicing was not directly affected. Gene and protein expression data indicated the activation of pathophysiological and muscle stress-activated pathways. These data provide new insights on Rbm20 function and how its malfunction leads to cardiomyopathy.
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