Decreased miR-497-5p Suppresses IL-6 Induced Atrophy in Muscle Cells.
Decreased miR-497-5p Suppresses IL-6 Induced Atrophy in Muscle Cells.
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DOI：
10.3390/cells10123527
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发表时间：
2021-12-14
期刊：
影响因子：
6
通讯作者：
Carvalho RF
中科院分区：
文献类型：
--
作者：
Freire PP;Cury SS;Lopes LO;Fernandez GJ;Liu J;de Moraes LN;de Oliveira G;Oliveira JS;de Moraes D;Cabral-Marques O;Dal-Pai-Silva M;Hu X;Wang DZ;Carvalho RF
白细胞介素 - 6（IL - 6）是一种促炎细胞因子，与癌症恶病质中的骨骼肌萎缩有关。微小核糖核酸（miRNAs）对肌肉萎缩中基因表达的调控涉及数千种靶转录本的调节。然而，与IL - 6诱导的肌肉萎缩相关的miRNA - 靶标网络仍有待阐明。在此，我们表明IL - 6促进C2C12肌管萎缩，并改变20种miRNAs的表达（5种上调，15种下调）。对预测的miRNAs靶标的基因本体分析揭示了参与细胞分化、凋亡、迁移和分解代谢过程的基因的转录后调控。接下来，我们对已发表的miRNA数据进行了荟萃分析，确定了miR - 497 - 5p，一种由IL - 6诱导下调的miRNA，在其他肌肉萎缩状况下也下调。我们使用miR - 497 - 5p模拟物和抑制剂来探究miR - 497 - 5p在C2C12成肌细胞和肌管中的功能。我们发现miR - 497 - 5p能够调节细胞周期基因CcnD2和CcnE1的表达，而不影响成肌细胞的增殖速率。值得注意的是，miR - 497 - 5p模拟物诱导肌管萎缩并降低Insr表达。用miR - 497 - 5p抑制剂处理不会改变肌管的直径，但会增加其靶基因Insr和Igf1r的表达。已知这些基因通过胰岛素样生长因子途径调节骨骼肌再生和肥大，并且在恶病质肌肉样本中上调。我们的miRNA调控网络分析揭示了miR - 497 - 5p在IL - 6诱导的肌肉细胞萎缩过程中的潜在作用，并表明miR - 497 - 5p可能参与了对IL - 6作出反应的肌肉萎缩的代偿机制。
Interleukin-6 (IL-6) is a pro-inflammatory cytokine associated with skeletal muscle wasting in cancer cachexia. The control of gene expression by microRNAs (miRNAs) in muscle wasting involves the regulation of thousands of target transcripts. However, the miRNA-target networks associated with IL6-induced muscle atrophy remain to be characterized. Here, we show that IL-6 promotes the atrophy of C2C12 myotubes and changes the expression of 20 miRNAs (5 up-regulated and 15 down-regulated). Gene Ontology analysis of predicted miRNAs targets revealed post-transcriptional regulation of genes involved in cell differentiation, apoptosis, migration, and catabolic processes. Next, we performed a meta-analysis of miRNA-published data that identified miR-497-5p, a down-regulated miRNAs induced by IL-6, also down-regulated in other muscle-wasting conditions. We used miR-497-5p mimics and inhibitors to explore the function of miR-497-5p in C2C12 myoblasts and myotubes. We found that miR-497-5p can regulate the expression of the cell cycle genes CcnD2 and CcnE1 without affecting the rate of myoblast cellular proliferation. Notably, miR-497-5p mimics induced myotube atrophy and reduced Insr expression. Treatment with miR-497-5p inhibitors did not change the diameter of the myotubes but increased the expression of its target genes Insr and Igf1r. These genes are known to regulate skeletal muscle regeneration and hypertrophy via insulin-like growth factor pathway and were up-regulated in cachectic muscle samples. Our miRNA-regulated network analysis revealed a potential role for miR-497-5p during IL6-induced muscle cell atrophy and suggests that miR-497-5p is likely involved in a compensatory mechanism of muscle atrophy in response to IL-6.
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影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
影响因子：
3.7
作者：
Ando K;Takahashi F;Kato M;Kaneko N;Doi T;Ohe Y;Koizumi F;Nishio K;Takahashi K
通讯作者：
Takahashi K
影响因子：
3.3
作者：
Haddad, F;Zaldivar, F;Adams, GR
通讯作者：
Adams, GR
DOI：
10.1158/1541-7786.mcr-13-0189
发表时间：
2013-09
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Laine A;Iyengar P;Pandita TK
通讯作者：
Pandita TK
影响因子：
11.5
作者：
Gallagher, Iain J.;Stephens, Nathan A.;Fearon, Kenneth C. H.
通讯作者：
Fearon, Kenneth C. H.