Resveratrol Alleviates Skeletal Muscle Insulin Resistance by Downregulating Long Noncoding RNA

Abstract

Long noncoding RNA (lncRNA) is a crucial factor in the progression of insulin resistance (IR). Resveratrol (RSV) exhibits promising therapeutic potential for IR. However, there are few studies on whether RSV improves IR through lncRNA. This study aimed to determine whether RSV could influence the expression of lncRNA and to elucidate the underlying mechanism. Mice were divided into three groups: control group, high-fat diet (HFD) group, and HFD + RSV group. We conducted a high-throughput sequencing analysis to detect lncRNA and mRNA expression signatures and the ceRNA-network in the skeletal muscles of mice that were fed an HFD to induce IR. Hierarchical clustering, gene enrichment, and gene ceRNA-network analyses were subsequently conducted. Differentially expressed lncRNAs were selected and validated via reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The biological functions of the selected lncRNAs were investigated by silencing the target genes via lentivirus transfection of C2C12 mouse myotube cells. RSV treatment reversed the expression of 338 mRNAs and 629 lncRNAs in the skeletal muscles of mice with HFD-induced IR. The results of the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes database analyses indicated that the differentially expressed mRNAs modulated type II diabetes mellitus. After validating randomly selected lncRNAs via RT-qPCR, we identified a novel lncRNA, NONMMUT044897.2, which was upregulated in the HFD group and reversed with RSV treatment. Additionally, NONMMUT044897.2 was proven to function as a ceRNA of microRNA- (miR-) 7051-5p. Suppressor of Cytokine Signaling 1 (SOCS1) was confirmed as a target of miR-7051-5p. We further performed lentivirus transfection to knock down NONMMUT044897.2 in vitro and found that NONMMUT044897.2 silenced SOCS1 and potentiated the insulin signaling pathway. Hence, RSV mimicked the silencing effect of lentivirus transfection on NONMMUT044897.2. Our study revealed that RSV reduced IR in mouse skeletal muscles via the regulation of NONMMUT044897.2.

Integrated analysis of lncRNA and mRNA for the apoptosis of porcine ovarian granulosa cells after polyphenol resveratrol treatment

“…It was reported that RES inhibited cancer cell survival, while the knockdown of lncRNA H19 resulted in increased sensitivity to RES therapy ( 38 ). Liu et al ( 20 ) showed that RES could promote skeletal muscle insulin resistance via a competitive endogenous RNA (lncRNA NONMMUT044897.2/miR-7051-5p/SOCS1 pathway). In addition, RES inhibits cell apoptosis by suppressing lncRNA XLOC_014869 in lung injury rats ( 21 ).…”

“…In recent years, there are a substantial number of literature about RES, including a few studies that have involved the differential effects of polyphenols such as RES on lncRNA expression. Interestingly, a study established that RES alleviates skeletal muscle insulin resistance by downregulating lncRNA ( 20 ), and inhibits cell apoptosis by suppressing lncRNA in rats' lungs ( 21 ). However, the effects of different RES concentrations on apoptosis-related lncRNA and mRNA functions in POGCs have not been elucidated.…”

Identification of HDAC9 and ARRDC4 as potential biomarkers and targets for treatment of type 2 diabetes

“…The control mice were fed a routine diet, while the IR mice were fed a 60% high-fat diet (HFD) for 8 weeks to induce IR. The IR model was validated by determining the area under the curve in accordance with the protocol presented in our previously published study 26 . Insulin resistance was estimated using the quantitative insulin sensitivity check index (QUICKI).The mice were anesthetized, and their hepatic tissues were removed.…”

Non-coding RNAs in diabetes mellitus and diabetic cardiovascular disease

“…LncRNA PTGS2 can impair pancreatic β-cell function by regulating miR-146a-5p and upregulating RBP4, an effect that is reversible ( 118 ). And reversal of abnormal lncRNAs can also reverse skeletal muscle IR, such as in the case of lncRNA NONMMUT044897.2 ( 119 ). These evidences demonstrated that lncRNAs are located upstream of miRNAs in the regulation of many types of DM and that their use as biomarkers for clinical diagnosis of DM or as potential therapeutic targets is valid and feasible ( Table 2 ).…”