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Rbm24 modulates adult skeletal muscle regeneration via regulation of alternative splicing
Theranostics ( IF 12.4 ) Pub Date : 2020-9-11 , DOI: 10.7150/thno.44389
Mengkai Zhang , Yue Han , Jing Liu , Lefeng Liu , Longqing Zheng , Yongxiong Chen , Rongmu Xia , Dongbo Yao , Xuemin Cai , Xiuqin Xu

Rationale: The adult skeletal muscle can self-repair efficiently following mechanical or pathological damage due to its remarkable regenerative capacity. However, regulatory mechanisms underlying muscle regeneration are complicated and have not been fully elucidated. Alternative splicing (AS) is a major mechanism responsible for post-transcriptional regulation. Many aberrant AS events have been identified in patients with muscular dystrophy which is accompanied by abnormal muscle regeneration. However, little is known about the correlation between AS and muscle regeneration. It has been reported that RNA binding motif protein 24 (Rbm24), a tissue-specific splicing factor, is involved in embryo myogenesis while the role of Rbm24 in adult myogenesis (also called muscle regeneration) is poorly understood./nMethods: To investigate the role of Rbm24 in adult skeletal muscle, we generated Rbm24 conditional knockout mice and satellite cell-specific knockout mice. Furthermore, a cardiotoxin (CTX)-induced injury model was utilized to assess the effects of Rbm24 on skeletal muscle regeneration. Genome-wide RNA-Seq was performed to identify the changes in AS following loss of Rbm24./nResults: Rbm24 knockout mice displayed abnormal regeneration 4 months after tamoxifen treatment. Using RNA-Seq, we found that Rbm24 regulated a complex network of AS events involved in multiple biological processes, including myogenesis, muscle regeneration and muscle hypertrophy. Moreover, using a CTX-induced injury model, we showed that loss of Rbm24 in skeletal muscle resulted in myogenic fusion and differentiation defects and significantly delayed muscle regeneration. Furthermore, satellite cell-specific Rbm24 knockout mice recapitulated the defects in regeneration seen in the global Rbm24 knockout mice. Importantly, we demonstrated that Rbm24 regulated AS of Mef2d, Naca, Rock2 and Lrrfip1 which are essential for myogenic differentiation and muscle regeneration./nConclusions: The present study demonstrated that Rbm24 regulates dynamic changes in AS and is essential for adult skeletal muscle regeneration.

中文翻译:

Rbm24通过调节选择性剪接调节成年骨骼肌再生

基本原理:由于其显着的再生能力,成年骨骼肌在受到机械或病理损伤后可以有效地自我修复。但是,肌肉再生的调控机制很复杂,尚未完全阐明。选择性剪接(AS)是负责转录后调控的主要机制。在患有肌营养不良症并伴有异常肌肉再生的患者中发现了许多异常的AS事件。但是,关于AS与肌肉再生之间的相关性知之甚少。据报道,RNA结合基序蛋白24(Rbm24)是一种组织特异性的剪接因子,参与胚胎的肌发生,而对Rbm24在成年肌发生(也称为肌肉再生)中的作用知之甚少。方法:为了研究Rbm24在成年骨骼肌中的作用,我们产生了Rbm24条件性基因敲除小鼠和卫星细胞特异性基因敲除小鼠。此外,心脏毒素(CTX)诱导的损伤模型被用来评估Rbm24对骨骼肌再生的影响。全基因组RNA测序以鉴定以下Rbm24./n的损失在AS的变化结果:他莫昔芬治疗4个月后,Rbm24基因敲除小鼠显示异常再生。使用RNA-Seq,我们发现Rbm24调节了AS事件的复杂网络,该事件涉及多个生物过程,包括肌发生,肌肉再生和肌肉肥大。此外,使用CTX诱导的损伤模型,我们显示骨骼肌中Rbm24的丢失导致肌源性融合和分化缺陷,并显着延迟了肌肉的再生。此外,卫星细胞特异性Rbm24基因敲除小鼠概括了在全球Rbm24基因敲除小鼠中看到的再生缺陷。重要的是,我们证明了Rbm24调节了Mef2d,Naca,Rock2和Lrrfip1的AS,这对于成肌分化和肌肉再生至关重要。/n结论: 本研究表明,Rbm24调节AS的动态变化,并且对于成人骨骼肌再生至关重要。
更新日期:2020-09-14
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