Musashi-2通过破坏Cluh和Smyd1mRNA的稳定而诱导线粒体功能障碍,从而导致心肌肥大和心力衰竭。

IF 7.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Basic Research in Cardiology Pub Date : 2023-11-03 DOI:10.1007/s00395-023-01016-y
Sandhya Singh, Aakash Gaur, Rakesh Kumar Sharma, Renu Kumari, Shakti Prakash, Sunaina Kumari, Ayushi Devendrasingh Chaudhary, Pankaj Prasun, Priyanka Pant, Hannah Hunkler, Thomas Thum, Kumaravelu Jagavelu, Pragya Bharati, Kashif Hanif, Pragya Chitkara, Shailesh Kumar, Kalyan Mitra, Shashi Kumar Gupta
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引用次数: 0

摘要

RNA结合蛋白(RBPs)对RNA稳定性和翻译的调节是改变基因表达的关键过程。已知包含Msi1和Msi2的RBPs的Musashi家族控制RNA的稳定性和翻译。然而,尽管MSI2在心脏中存在,但其功能在很大程度上仍然未知。在这里,我们旨在探索MSI2的心脏功能。我们证实了MSI2在成年小鼠、大鼠心脏和新生大鼠心肌细胞中的存在。此外,Msi2在心脏心肌细胞部分中显著富集。接下来,使用RNA-seq数据和亚型特异性PCR引物,我们鉴定了Msi2亚型1、4和5,以及两种新的推定亚型,标记为Msi2 6和7,将在心脏中表达。Msi2亚型的过度表达导致培养的心肌细胞中的心肌肥大。此外,Msi2在心脏肥大的压力超负荷模型中表现出显著增加。我们选择了同种型4和7,以验证由于其独特的选择性剪接模式而产生的肥大效应。AAV9介导的Msi2亚型4和7在小鼠心脏中的过表达导致心脏肥大、扩张、心力衰竭,并最终导致早期死亡,证实了Msi2的病理功能。使用全球蛋白质组学、基因本体论、透射电子显微镜、海马和跨膜电位测量分析,发现MSI2增加会导致心脏线粒体功能障碍。从机制上讲,我们确定Cluh和Smyd1是Msi2的直接下游目标。Cluh和Smyd1的过表达抑制了Msi2诱导的心脏功能障碍和线粒体功能障碍。总之,我们发现Msi2诱导肥大、线粒体功能障碍和心力衰竭。
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Musashi-2 causes cardiac hypertrophy and heart failure by inducing mitochondrial dysfunction through destabilizing Cluh and Smyd1 mRNA.

Regulation of RNA stability and translation by RNA-binding proteins (RBPs) is a crucial process altering gene expression. Musashi family of RBPs comprising Msi1 and Msi2 is known to control RNA stability and translation. However, despite the presence of MSI2 in the heart, its function remains largely unknown. Here, we aim to explore the cardiac functions of MSI2. We confirmed the presence of MSI2 in the adult mouse, rat heart, and neonatal rat cardiomyocytes. Furthermore, Msi2 was significantly enriched in the heart cardiomyocyte fraction. Next, using RNA-seq data and isoform-specific PCR primers, we identified Msi2 isoforms 1, 4, and 5, and two novel putative isoforms labeled as Msi2 6 and 7 to be expressed in the heart. Overexpression of Msi2 isoforms led to cardiac hypertrophy in cultured cardiomyocytes. Additionally, Msi2 exhibited a significant increase in a pressure-overload model of cardiac hypertrophy. We selected isoforms 4 and 7 to validate the hypertrophic effects due to their unique alternative splicing patterns. AAV9-mediated overexpression of Msi2 isoforms 4 and 7 in murine hearts led to cardiac hypertrophy, dilation, heart failure, and eventually early death, confirming a pathological function for Msi2. Using global proteomics, gene ontology, transmission electron microscopy, seahorse, and transmembrane potential measurement assays, increased MSI2 was found to cause mitochondrial dysfunction in the heart. Mechanistically, we identified Cluh and Smyd1 as direct downstream targets of Msi2. Overexpression of Cluh and Smyd1 inhibited Msi2-induced cardiac malfunction and mitochondrial dysfunction. Collectively, we show that Msi2 induces hypertrophy, mitochondrial dysfunction, and heart failure.

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来源期刊
Basic Research in Cardiology
Basic Research in Cardiology 医学-心血管系统
CiteScore
16.30
自引率
5.30%
发文量
54
审稿时长
6-12 weeks
期刊介绍: Basic Research in Cardiology is an international journal for cardiovascular research. It provides a forum for original and review articles related to experimental cardiology that meet its stringent scientific standards. Basic Research in Cardiology regularly receives articles from the fields of - Molecular and Cellular Biology - Biochemistry - Biophysics - Pharmacology - Physiology and Pathology - Clinical Cardiology
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