Rbm24 modulates adult skeletal muscle regeneration via regulation of alternative splicing

被引:28
作者
Zhang, Mengkai [1 ]
Han, Yue [1 ]
Liu, Jing [1 ,2 ]
Liu, Lefeng [3 ]
Zheng, Longqing [1 ]
Chen, Yongxiong [4 ]
Xia, Rongmu [1 ]
Yao, Dongbo [1 ]
Cai, Xuemin [1 ]
Xu, Xiuqin [1 ]
机构
[1] Xiamen Univ, Sch Med, Inst Stem Cell & Regenerat Med, Chengzhi Bldg,Xiangan Campus, Xiamen 361100, Fujian, Peoples R China
[2] Xiamen Univ, Shenzhen Res Inst, Shenzhen 518000, Guangdong, Peoples R China
[3] Fujian Heze Biol Technol Co Ltd, Xiamen, Fujian, Peoples R China
[4] Xiamen Univ, Eye Inst, Fujian Prov Key Lab Ophthalmol & Visual Sci, Xiamen, Fujian, Peoples R China
来源
THERANOSTICS | 2020年 / 10卷 / 24期
基金
国家重点研发计划; 中国国家自然科学基金;
关键词
RNA binding motif protein 24; muscle injury; muscle regeneration; alternative splicing; myogenic differentiation; BINDING PROTEIN RBM24; MYOBLAST FUSION; SATELLITE CELLS; TRANSCRIPTION FACTOR; MUSCULAR-DYSTROPHY; RNA; EXPRESSION; DIFFERENTIATION; GENE; MECHANISMS;
D O I
10.7150/thno.44389
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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. Methods: 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. Results: 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. Conclusions: The present study demonstrated that Rbm24 regulates dynamic changes in AS and is essential for adult skeletal muscle regeneration.
引用
收藏
页码:11159 / 11177
页数:19
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