CircTmeff1 Promotes Muscle Atrophy by Interacting with TDP-43 and Encoding A Novel TMEFF1-339aa Protein

被引:19
作者
Chen, Rui [1 ,2 ]
Yang, Tingting [1 ,2 ]
Jin, Bing [1 ,2 ]
Xu, Wanru [1 ,2 ]
Yan, Yuwei [1 ,2 ]
Wood, Nathanael [3 ]
Lehmann, H. Immo [4 ,5 ]
Wang, Siqi [1 ,2 ]
Zhu, Xiaolan [1 ,2 ]
Yuan, Weilin [1 ,2 ]
Chen, Hongjian [1 ,2 ]
Liu, Zhengyu [1 ,2 ]
Li, Guoping [4 ,5 ]
Bowen, T. Scott [3 ]
Li, Jin [1 ,2 ]
Xiao, Junjie [1 ,2 ]
机构
[1] Shanghai Univ, Affiliated Nantong Hosp, Sch Med, Peoples Hosp Nantong 6,Inst Geriatr, Nantong 226011, Peoples R China
[2] Shanghai Univ, Inst Cardiovasc Sci, Shanghai Engn Res Ctr Organ Repair, Sch Life Sci,Cardiac Regenerat & Ageing Lab, Shanghai 200444, Peoples R China
[3] Univ Leeds, Fac Biol Sci, Sch Biomed Sci, Leeds LS2 9JT, England
[4] Massachusetts Gen Hosp, Cardiovasc Div, Boston, MA 02114 USA
[5] Harvard Med Sch, Boston, MA 02114 USA
基金
国家重点研发计划; 英国医学研究理事会; 中国国家自然科学基金;
关键词
circular RNA; muscle atrophy; TDP-43; translation; CIRCULAR RNAS DRIVEN; SKELETAL-MUSCLE; MITOCHONDRIAL DAMAGE; EMERGING ROLE; DIFFERENTIATION; PROLIFERATION; TRANSLATION; ACTIVATION; PYROPTOSIS; PATHOLOGY;
D O I
10.1002/advs.202206732
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Skeletal muscle atrophy is a common clinical feature of many acute and chronic conditions. Circular RNAs (circRNAs) are covalently closed RNA transcripts that are involved in various physiological and pathological processes, but their role in muscle atrophy remains unknown. Global circRNA expression profiling indicated that circRNAs are involved in the pathophysiological processes of muscle atrophy. circTmeff1 is identified as a potential circRNA candidate that influences muscle atrophy. It is further identified that circTmeff1 is highly expressed in multiple types of muscle atrophy in vivo and in vitro. Moreover, the overexpression of circTmeff1 triggers muscle atrophy in vitro and in vivo, while the knockdown of circTmeff1 expression rescues muscle atrophy in vitro and in vivo. In particular, the knockdown of circTmeff1 expression partially rescues muscle mass in mice during established atrophic settings. Mechanistically, circTmeff1 directly interacts with TAR DNA-binding protein 43 (TDP-43) and promotes aggregation of TDP-43 in mitochondria, which triggers the release of mitochondrial DNA (mtDNA) into cytosol and activation of the cyclic GMP-AMP synthase (cGAS)/ stimulator of interferon genes (STING) pathway. Unexpectedly, TMEFF1-339aa is identified as a novel protein encoded by circTmeff1 that mediates its pro-atrophic effects. Collectively, the inhibition of circTmeff1 represents a novel therapeutic approach for multiple types of skeletal muscle atrophy.
引用
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页数:19
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