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MicroRNA-194 Modulates Glucose Metabolism and Its Skeletal Muscle Expression Is Reduced in Diabetes.

ABSTRACT: BACKGROUND:The regulation of microRNAs (miRNAs) at different stages of the progression of type 2 diabetes mellitus (T2DM) and their role in glucose homeostasis was investigated. METHODS:Microarrays were used to assess miRNA expression in skeletal muscle biopsies taken from healthy individuals and patients with pre-diabetes or T2DM, and insulin resistant offspring of rat dams fed a high fat diet during pregnancy. RESULTS:Twenty-three miRNAs were differentially expressed in patients with T2DM, and 7 in the insulin resistant rat offspring compared to their controls. Among these, only one miRNA was similarly regulated: miR-194 expression was significantly reduced by 25 to 50% in both the rat model and in human with pre-diabetes and established diabetes. Knockdown of miR-194 in L6 skeletal muscle cells induced an increase in basal and insulin-stimulated glucose uptake and glycogen synthesis. This occurred in conjunction with an increased glycolysis, indicated by elevated lactate production. Moreover, oxidative capacity was also increased as we found an enhanced glucose oxidation in presence of the mitochondrial uncoupler FCCP. When miR-194 was down-regulated in vitro, western blot analysis showed an increased phosphorylation of AKT and GSK3? in response to insulin, and an increase in expression of proteins controlling mitochondrial oxidative phosphorylation. CONCLUSIONS:Type 2 diabetes mellitus is associated with regulation of several miRNAs in skeletal muscle. Interestingly, miR-194 was a unique miRNA that appeared regulated across different stages of the disease progression, from the early stages of insulin resistance to the development of T2DM. We have shown miR-194 is involved in multiple aspects of skeletal muscle glucose metabolism from uptake, through to glycolysis, glycogenesis and glucose oxidation, potentially via mechanisms involving AKT, GSK3 and oxidative phosphorylation. MiR-194 could be down-regulated in patients with early features of diabetes as an adaptive response to facilitate tissue glucose uptake and metabolism in the face of insulin resistance.

SUBMITTER: Latouche C

PROVIDER: S-EPMC4862646 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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MicroRNA-194 Modulates Glucose Metabolism and Its Skeletal Muscle Expression Is Reduced in Diabetes.

Latouche Celine C Natoli Alaina A Reddy-Luthmoodoo Medini M Heywood Sarah E SE Armitage James A JA Kingwell Bronwyn A BA

PloS one 20160510 5

<h4>Background</h4>The regulation of microRNAs (miRNAs) at different stages of the progression of type 2 diabetes mellitus (T2DM) and their role in glucose homeostasis was investigated.<h4>Methods</h4>Microarrays were used to assess miRNA expression in skeletal muscle biopsies taken from healthy individuals and patients with pre-diabetes or T2DM, and insulin resistant offspring of rat dams fed a high fat diet during pregnancy.<h4>Results</h4>Twenty-three miRNAs were differentially expressed in p ...[more]

PMID: 27163678

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Project description:Background: Exercise mimetics is a proposed class of therapeutics that specifically mimics or enhances the therapeutic effects of exercise. Muscle glycogen and lactate extrusion are critical for physical performance. The mechanism by which glycogen and lactate metabolism are manipulated during exercise remains unclear. This study aimed to assess the effect of miR-92b on the upregulation of exercise training-induced physical performance. Methods: Adeno-associated virus (AAV)-mediated skeletal muscle miR-92b overexpression in C57BLKS/J mice, and global knockout of miR-92b mice were used to explore the function of miR-92b in glycogen and lactate metabolism in skeletal muscle. AAV-mediated UGP2 or MCT4 knockdown in WT or miR-92 knockout mice was used to confirm whether miR-92b regulates glycogen and lactate metabolism in skeletal muscle through UGP2 and MCT4. Body weight, muscle weight, grip strength, running time and distance to exhaustion, and muscle histology were assessed. The expression levels of muscle mass-related and functionrelated proteins were analysed by immunoblotting or immunostaining. Results: Global knockout of miR-92b resulted in normal body weight and insulin sensitivity, but higher glycogen content before exercise exhaustion (0.8538 ± 0.0417 vs 1.043 ± 0.040, **P=0.0087), lower lactate levels after exercise exhaustion (4.133 ± 0.2589 vs 3.207 ± 0.2511, *P=0.0279), and better exercise capacity (running distance to exhaustion, 3616 ± 86.71 vs 4231 ± 90.29, ***P=0.0006; running time to exhaustion, 186.8 ± 8.027 vs 220.8 ± 3.156, **P=0.0028), as compared to those observed in the control mice. Mice skeletal muscle overexpressing miR-92b (both miR-92b-3p and miR-92b-5p) displayed lower glycogen content before exercise exhaustion (0.6318 ± 0.0231 vs 0.535 ± 0.0194, **P=0.0094), and higher lactate accumulation after exercise exhaustion (4.5 ± 0.2394 vs 5.467 ± 0.1892, *P=0.01), and poorer exercise capacity (running distance to exhaustion, 4005 ± 81.65 vs 3228 ± 149.8, ***P＜0.0001; running time to exhaustion, 225.5 ± 7.689 vs 163 ± 6.476, **P=0.001). Mechanistic analysis revealed that miR-92b-3p targets UDP-glucose pyrophosphorylase 2 (UGP2) expression to inhibit glycogen synthesis, while miR-92b-5p represses lactate extrusion by directly target monocarboxylate transporter 4 (MCT4). Knockdown of UGP2 and MCT4 reversed the effects observed in the absence of miR-92b in vivo. Conclusions: This study revealed regulatory pathways, including miR-92b-3p/UGP2/glycogen synthesis and miR-92b-5p/MCT4/lactate extrusion, which could be targeted to control exercise capacity.

Dataset Information

MicroRNA-194 Modulates Glucose Metabolism and Its Skeletal Muscle Expression Is Reduced in Diabetes.

Publications

MicroRNA-194 Modulates Glucose Metabolism and Its Skeletal Muscle Expression Is Reduced in Diabetes.

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