长非编码 RNA SMUL 通过无义介导的 mRNA 衰减抑制 SMURF2 产生介导的肌肉萎缩,Molecular Therapy - Nucleic Acids

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长非编码 RNA SMUL 通过无义介导的 mRNA 衰减抑制 SMURF2 产生介导的肌肉萎缩
Molecular Therapy - Nucleic Acids ( IF 6.5 ) Pub Date : 2020-12-10 , DOI: 10.1016/j.omtn.2020.12.003
Bolin Cai , Zhenhui Li , Manting Ma , Jing Zhang , Shaofen Kong , Bahareldin Ali Abdalla , Haiping Xu , Endashaw Jebessa , Xiquan Zhang , Raman Akinyanju Lawal , Qinghua Nie

随着世界人口的增长，导致肌肉萎缩的肌肉萎缩可能成为更大的风险。已知长非编码 RNA (lncRNA) 在肌肉生长和肌肉萎缩中发挥重要作用。与此同时，最近发现许多假定的小开放阅读框（sORF）隐藏在lncRNA中；然而，它们的翻译能力和功能仍不清楚。在这项研究中，我们通过整合转录组和蛋白质组分析，发现了 104 个肌源性相关的 lncRNA，至少在一个小肽中被翻译。此外，构建了上游ORF（uORF）调控网络，并鉴定了一种新型肌肉萎缩相关lncRNA，命名为（Smad泛素调节因子2[]上游lncRNA）。在骨骼肌中高表达，在成肌细胞分化过程中表达水平下调。促进成肌细胞增殖并抑制分化。，诱导骨骼肌萎缩并促进从慢肌纤维向快肌纤维的转变。与此同时，sORF 的翻译破坏了 mRNA 的稳定性。从机制上讲，通过无义介导的mRNA衰减（NMD）抑制生产，参与转化生长因子β（TGF-β）/SMAD途径的调节，并进一步调节肌生成和肌肉萎缩。综上所述，这些结果表明这可能是肌肉萎缩的新治疗靶点。

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Long noncoding RNA SMUL suppresses SMURF2 production-mediated muscle atrophy via nonsense-mediated mRNA decay

As the world population grows, muscle atrophy leading to muscle wasting could become a bigger risk. Long noncoding RNAs (lncRNAs) are known to play important roles in muscle growth and muscle atrophy. Meanwhile, it has recently come to light that many putative small open reading frames (sORFs) are hidden in lncRNAs; however, their translational capabilities and functions remain unclear. In this study, we uncovered 104 myogenic-associated lncRNAs translated, in at least a small peptide, by integrated transcriptome and proteomic analyses. Furthermore, an upstream ORF (uORF) regulatory network was constructed, and a novel muscle atrophy-associated lncRNA named (Smad ubiquitin regulatory factor 2 [] upstream lncRNA) was identified. was highly expressed in skeletal muscle, and its expression level was downregulated during myoblast differentiation. promoted myoblast proliferation and suppressed differentiation . , induced skeletal muscle atrophy and promoted a switch from slow-twitch to fast-twitch fibers. In the meantime, translation of the sORF disrupted the stability of mRNA. Mechanistically, restrained production via nonsense-mediated mRNA decay (NMD), participating in the regulation of the transforming growth factor β (TGF-β)/SMAD pathway and further regulating myogenesis and muscle atrophy. Taken together, these results suggest that could be a novel therapeutic target for muscle atrophy.

更新日期：2020-12-10

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