CircTmeff1 Promotes Muscle Atrophy by Interacting with TDP-43 and Encoding A Novel TMEFF1-339aa Protein.
CircTmeff1 Promotes Muscle Atrophy by Interacting with TDP-43 and Encoding A Novel TMEFF1-339aa Protein.
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DOI：
10.1002/advs.202206732
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发表时间：
2023-06
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影响因子：
--
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中科院分区：
文献类型：
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骨骼肌萎缩是许多急慢性疾病的共同临床特征。环状RNA(CircRNAs)是参与多种生理和病理过程的共价闭合RNA转录本，但它们在肌肉萎缩中的作用尚不清楚。全球CircRNA表达谱显示，CircRNA参与了肌肉萎缩的病理生理过程。CircTmeff1被认为是影响肌肉萎缩的潜在CircRNA候选基因。进一步证实，在体内和体外的多种类型的肌肉萎缩中，CircTmeff1都有高表达。此外，CircTmeff1的过表达在体外和体内都会引发肌肉萎缩，而CircTmeff1的表达下调则在体外和体内挽救了肌肉萎缩。特别是，在已经建立的萎缩环境中，CircTmeff1表达的下调部分挽救了小鼠的肌肉群。在机制上，CircTmeff1与TAR DNA结合蛋白43(TDP-43)直接相互作用，促进TDP-43在线粒体聚集，从而触发线粒体DNA(MtDNA)释放到胞浆中，激活环状GMP-AMP合成酶(CGAS)/干扰素基因刺激物(STING)途径。出乎意料的是，TMEFF1-339aa被鉴定为CircTmeff1编码的一种新的蛋白质，它介导了Tmeff1的促萎缩作用。总的来说，CircTmeff1的抑制代表了多种类型骨骼肌萎缩的一种新的治疗方法。CircTmeff1在各种类型的肌肉萎缩模型中均升高。过度表达CircTmeff1会促进肌肉萎缩，而该基因的敲除则在动物和细胞水平上挽救肌肉萎缩。CircTmeff1通过直接与TDP-43相互作用并编码TMEFF1-339aa蛋白来促进肌肉萎缩。总的来说，抑制CircTmeff1代表了一种治疗多种类型骨骼肌萎缩的新方法。
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. circTmeff1 is elevated in various types of muscle atrophy models. Overexpressing circTmeff1 promotes muscle atrophy, while the knockdown of that rescues the muscle atrophy at both animal and cellular levels. circTmeff1 promotes muscle atrophy by directly interacting with TDP‐43 and encoding a protein TMEFF1‐339aa. Collectively, inhibiting circTmeff1 represents a novel therapeutic approach for multiple types of skeletal muscle atrophy.
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DOI：
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发表时间：
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期刊：
Molecular therapy. Nucleic acids
影响因子：
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