Global alternative splicing landscape of skeletal muscle atrophy induced by hindlimb unloading.
Global alternative splicing landscape of skeletal muscle atrophy induced by hindlimb unloading.
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后肢卸载引起的骨骼肌萎缩的全局选择性剪接景观
DOI：
10.21037/atm-20-5388
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发表时间：
2021-04
影响因子：
--
通讯作者：
Sun H
中科院分区：
文献类型：
--
作者：
Sun J;Yang H;Yang X;Chen X;Xu H;Shen Y;Ding F;Gu X;Zhu J;Sun H
长期暴露在微重力环境中会导致骨骼肌萎缩，这会对太空旅行中的宇航员造成严重伤害。因此，深入研究骨骼肌萎缩的分子机制，对预防和治疗骨骼肌萎缩具有重要意义。然而，作为骨骼肌生理学的重要调节途径，选择性剪接在骨骼肌萎缩，特别是废用性骨骼肌萎缩中的作用尚不清楚。我们建立了大鼠后肢去负荷模型，并对去负荷过程中严重萎缩的比目鱼肌进行了RNA测序。多种生物信息学方法被用来鉴定选择性剪接事件并确定其基因功能。许多选择性剪接事件被发现发生在后肢卸载后的不同时间点（12小时，24小时，36小时，3天，和7天）。这些差异选择性剪接事件主要发生在基因的编码区序列区域，59%的选择性剪接事件引起开放阅读移码。生物信息学分析结果表明，具有不同选择性剪接事件的基因在与肌肉萎缩相关的多个通路中富集，包括胰岛素信号通路、内吞作用、线粒体自噬和泛素-蛋白酶体通路。此外，选择性剪接的几个去泛素化酶基因持续在骨骼肌萎缩引起的卸载。另外，我们还鉴定了10个在骨骼肌萎缩过程中差异表达的RNA结合蛋白，主要包括Xpo 4、Eif 4 e2、P4 ha 1、Lrrfip 1、Zc 3 h14、Emg 1、Hnrnp h1、Mbnl 2、RBfox 1和Mbnl 1。Hnrnp h1和Mbnl 2在去负荷引起的骨骼肌萎缩过程中显著下调，RBfox 1和Mbnl 1在去负荷引起的骨骼肌萎缩过程中显著上调。据我们所知，本研究是第一个提出与废用性肌肉萎缩相关的选择性剪接改变，强调选择性剪接是肌肉萎缩发生的一个新的关注焦点。
Long-term exposure to microgravity will cause skeletal muscle atrophy, which can cause serious harm to astronauts in space travel. Therefore, it is important to explore skeletal muscle atrophy’s molecular mechanism for its prevention and treatment. However, as an important regulatory approach of skeletal muscle physiology, the role of alternative splicing in skeletal muscle atrophy, especially skeletal muscle atrophy caused by disuse, is unclear. We established a rat hindlimb unloading model and performed RNA sequencing on soleus muscle, which was seriously atrophied during unloading. Several bioinformatics methods were used to identify alternative splicing events and determine their gene functions. Many alternative splicing events were found to occur at different time points (12 h, 24 h, 36 h, 3 days, and 7 days) after hindlimb unloading. These differential alternative splicing events mainly occurred in the gene's coding domain sequence region, and 59% of the alternative splicing events caused open reading frameshift. Bioinformatics analysis results showed that genes with different alternative splicing events were enriched in multiple pathways related to muscle atrophy, including the insulin signaling pathway, endocytosis, mitophagy, and ubiquitin-proteasome pathway. Moreover, alternative splicing of several deubiquitinase genes persisted during skeletal muscle atrophy induced by unloading. Additionally, we identified 10 differentially expressed RNA binding proteins during skeletal muscle atrophy induced by unloading, mainly containing Xpo4, Eif4e2, P4ha1, Lrrfip1, Zc3h14, Emg1, Hnrnp h1, Mbnl2, RBfox1, and Mbnl1. Hnrnp h1 and Mbnl2 were significantly downregulated, and RBfox1 and Mbnl1 were significantly upregulated during skeletal muscle atrophy caused by unloading. To the best of our knowledge, the present study is the first to propose alternative splicing alterations related to disuse-induced muscle atrophy, emphasizing that alternative splicing is a new focus of attention in the occurrence of muscle atrophy.
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