Dynamic transcriptome profile in db/db skeletal muscle reveal critical roles for long noncoding RNA regulator.
Dynamic transcriptome profile in db/db skeletal muscle reveal critical roles for long noncoding RNA regulator.
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DOI：
10.1016/j.biocel.2018.08.013
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发表时间：
2018-11
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影响因子：
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通讯作者：
N. Zhang;Yahui Zhou;Qingxin Yuan;Yao Gao;Yan Wang;Xingyun Wang;X. Cui;P. Xu;C. Ji;Xirong Guo;L. You;Nan Gu;Yu Zeng
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文献类型：
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作者：
N. Zhang;Yahui Zhou;Qingxin Yuan;Yao Gao;Yan Wang;Xingyun Wang;X. Cui;P. Xu;C. Ji;Xirong Guo;L. You;Nan Gu;Yu Zeng
T2 DM是一个严重降低生活质量的全球性健康问题，胰岛素抵抗在T2 DM的病理生理过程中起着重要作用。长非编码RNA(LncRNAs)是糖脂代谢的重要调节因子。然而，对indb/db小鼠骨骼肌中的lncRNAs及其在骨骼肌胰岛素抵抗(IR)中的潜在作用的全面分析仍然缺乏特征。在这里，我们鉴定了331个lncRNAs，其中172个上调，159个下调(|折叠式变化|>；2，q<；0.05)，差异表达的inb/db小鼠骨骼肌。基因本体论分析、通路分析和网络基因表达的基因集浓缩分析表明，异常表达的lncRNAs的潜在功能可能涉及骨骼肌功能、脂肪酸代谢和PPAR信号通路。此外，在广为人知的IR小鼠模型(db/dbandob/ob)的骨骼肌中，证实了差异表达的lncRNAs。进一步验证暴露于不同浓度棕榈酸酯的C2C12肌管中的lncRNAs发现，lncRNAs对高浓度棕榈酸酯(0.5 mM和0.75 mM)的暴露有反应。共表达分析揭示了关键的lncRNA-mRNA相互作用，并表明lncRNAs具有潜在的调节作用。此外，我们还对两个候选LncRNAs Gm15441和3110045C21Rik进行了基因组背景分析，并通过Spearman相关分析验证了它们与邻近基因(TXNIP和DDR2)的表达。总之，这些发现提高了我们对介导糖尿病骨骼肌胰岛素抵抗的lncRNAs的理解，并代表了改善胰岛素敏感性和相关代谢性疾病的潜在分子治疗靶点。
T2DM is a global health problem that seriously lowers the quality of life and insulin resistance makes a considerable contribution to the pathophysiology of T2DM. Long noncoding RNAs (lncRNAs) have emerged as important regulators in glucose and lipid metabolism. However, comprehensive analysis of lncRNAs indb/dbmice skeletal muscle and their potential roles involved in skeletal muscle insulin resistance (IR) remains poorly characterized. Here, we identified 331 lncRNAs, 172 upregulated and 159 downregulated (|fold change|>2, q<0.05), differentially expressed indb/dbmice skeletal muscle. Gene Ontology analysis, Pathway analysis and Gene Set Enrichment Analysis of network gene expression revealed the potential functions of dysregulated lncRNAs may involve skeletal muscle function, fatty acid metabolism and the PPAR signaling pathway. In addition, differentially expressed lncRNAs were verified in skeletal muscle from the widely known IR mouse models (db/dbandob/obmice). Further validation of lncRNAs in C2C12 myotubes exposed with various concentrations of palmitate uncovered that lncRNAs were responsive to palmitate exposure at the high concentrations (0.5mM and 0.75mM). Coexpression analysis revealed the key lncRNA-mRNA interactions and indicated a potential regulatory role of lncRNAs. Moreover, we characterized two candidate lncRNAs Gm15441 and 3110045C21Rik by a comprehensive examination of their genomic context and validated their expression with neighboring genes (Txnip and Ddr2) by the Spearman correlation analysis. Collectively, these findings improve our understanding of lncRNAs that mediate skeletal muscle insulin resistance in diabetes and represent potential molecular therapeutic targets to improve insulin sensitivity and associated metabolic diseases.