MicroRNA‑106b regulates skeletal muscle insulin sensitivity and glucose homeostasis by targeting mitofusion‑2

Zhang,Ying; He,Wei; Gao,Yuan‑Fu; Fan,Zhong‑Min; Gao,Chun‑Lin; Xia,Zheng‑Kun

doi:10.3892/mmr.2017.7439

MicroRNA‑106b regulates skeletal muscle insulin sensitivity and glucose homeostasis by targeting mitofusion‑2

Authors:
- Ying Zhang
- Wei He
- Yuan‑Fu Gao
- Zhong‑Min Fan
- Chun‑Lin Gao
- Zheng‑Kun Xia
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Affiliations: Department of Pediatrics, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, P.R. China
Published online on: September 8, 2017 https://doi.org/10.3892/mmr.2017.7439
Pages: 6858-6863

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Abstract

MicroRNA‑106b (miR‑106b) is reported to be closely associated with skeletal muscle insulin resistance. The present study further investigated the role of miR‑106b in skeletal muscle insulin sensitivity and glucose homeostasis in vivo. Mice were randomly divided into 4 groups and infected with lentivirus expressing miR‑106b (miR‑106b mice), miR‑106b sponge (miR‑106b inhibition mice) or the corresponding empty vectors. Mitofusion‑2 (Mfn2) protein expression levels and glucose transporter (Glut)‑4 protein translocation were significantly reduced in the muscle of miR‑106b mice, whereas they were unaffected in miR‑106b inhibition mice. miR‑106b mice had significantly increased blood glucose levels following 12 h of fasting and impaired glucose tolerance, whereas miR‑106b inhibition mice had no significant alterations in fasting blood glucose levels and glucose tolerance. In vitro, the suppressive effect of miR‑106b on glucose uptake and Glut4 translocation was completely inhibited in C2C12 myotubes infected with Mfn2 plasmids. Following treatment of C2C12 myotubes with Mfn2 small interfering RNA, miR‑106b inhibition consistently increased Mfn2 protein levels and improved glucose uptake and Glut4 translocation. These results indicated that miR‑106b targeted Mfn2 and regulated skeletal muscle insulin sensitivity and glucose tolerance. Therefore, increased miR‑106b expression may be a potential mechanism underlying insulin resistance and type 2 diabetes.

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1	International Diabetes Federation: Diabetes Atlas. 3rd edition. International Diabetes Federation; Brussels, Belgium: 2006
2	Guo H, Ingolia NT, Weissman JS and Bartel DP: Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature. 466:835–840. 2010. View Article : Google Scholar : PubMed/NCBI
3	Xiao F, Yu J, Liu B, Guo Y, Li K, Deng J, Zhang J, Wang C, Chen S, Du Y, et al: A novel function of microRNA 130a-3p in hepatic insulin sensitivity and liver steatosis. Diabetes. 63:2631–2642. 2014. View Article : Google Scholar : PubMed/NCBI
4	Zhou B, Li C, Qi W, Zhang Y, Zhang F, Wu JX, Hu YN, Wu DM, Liu Y, Yan TT, et al: Downregulation of miR-181a upregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity. Diabetologia. 55:2032–2043. 2012. View Article : Google Scholar : PubMed/NCBI
5	Ferland-McCollough D, Ozanne SE, Siddle K, Willis AE and Bushell M: The involvement of microRNAs in Type 2 diabetes. Biochem Soc Trans. 38:1565–1570. 2010. View Article : Google Scholar : PubMed/NCBI
6	Gallagher IJ, Scheele C, Keller P, Nielsen AR, Remenyi J, Fischer CP, Roder K, Babraj J, Wahlestedt C, Hutvagner G, et al: Integration of microRNA changes in vivo identifies novel molecular features of muscle insulin resistance in type 2 diabetes. Genome Med. 2:92010. View Article : Google Scholar : PubMed/NCBI
7	Chen GQ, Lian WJ, Wang GM, Wang S, Yang YQ and Zhao ZW: Altered microRNA expression in skeletal muscle results from high-fat diet-induced insulin resistance in mice. Mol Med Rep. 5:1362–1368. 2012.PubMed/NCBI
8	Zhang Y, Yang L, Gao YF, Fan ZM, Cai XY, Liu MY, Guo XR, Gao CL and Xia ZK: MicroRNA-106b induces mitochondrial dysfunction and insulin resistance in C2C12 myotubes by targeting mitofusin-2. Mol Cell Endocrinol. 381:230–240. 2013. View Article : Google Scholar : PubMed/NCBI
9	Zhang Y, Zhao YP, Gao YF, Fan ZM, Liu MY, Cai XY, Xia ZK and Gao CL: Silencing miR-106b improves palmitic acid-induced mitochondrial dysfunction and insulin resistance in skeletal myocytes. Mol Med Rep. 11:3834–3841. 2015. View Article : Google Scholar : PubMed/NCBI
10	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
11	Liesa M, Palacin M and Zorzano A: Mitochondrial dynamics in mammalian health and disease. Physiol Rev. 89:799–845. 2009. View Article : Google Scholar : PubMed/NCBI
12	de Brito OM and Scorrano L: Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature. 456:605–610. 2008. View Article : Google Scholar : PubMed/NCBI
13	Zorzano A: Regulation of mitofusin-2 expression in skeletal muscle. Appl Physiol Nutr Metab. 34:433–449. 2009. View Article : Google Scholar : PubMed/NCBI
14	Bach D, Naon D, Pich S, Soriano FX, Vega N, Rieusset J, Laville M, Guillet C, Boirie Y, Wallberg-Henriksson H, et al: Expression of Mfn2, the Charcot-Marie-Tooth neuropathy type 2A gene, in human skeletal muscle: Effects of type 2 diabetes, obesity, weight loss, and the regulatory role of tumor necrosis factor alpha and interleukin-6. Diabetes. 54:2685–2693. 2005. View Article : Google Scholar : PubMed/NCBI
15	Cartoni R, Léger B, Hock MB, Praz M, Crettenand A, Pich S, Ziltener JL, Luthi F, Dériaz O, Zorzano A, et al: Mitofusins 1/2 and ERRalpha expression are increased in human skeletal muscle after physical exercise. J Physiol. 567:349–358. 2005. View Article : Google Scholar : PubMed/NCBI
16	Nie Q, Wang C, Song G, Ma H, Kong D, Zhang X, Gan K and Tang Y: Mitofusin 2 deficiency leads to oxidative stress that contributes to insulin resistance in rat skeletal muscle cells. Mol Biol Rep. 41:6975–6983. 2014. View Article : Google Scholar : PubMed/NCBI
17	Zhang X, Wang C, Song G, Gan K, Kong D, Nie Q and Ren L: Mitofusion-2-mediated alleviation of insulin resistance in rats through reduction in lipid intermediate accumulation in skeletal muscle. J Biomed Sci. 20:452013. View Article : Google Scholar : PubMed/NCBI
18	Borengasser SJ, Faske J, Kang P, Blackburn ML, Badger TM and Shankar K: In utero exposure to prepregnancy maternal obesity and postweaning high-fat diet impair regulators of mitochondrial dynamics in rat placenta and offspring. Physiol Genomics. 46:841–850. 2014. View Article : Google Scholar : PubMed/NCBI