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Exercise promotes peripheral glycolysis through miR-204 induction in skeletal muscle

ABSTRACT: Mechanisms underlying exercise induced insulin sensitization are of interest as exercise is a clinically critical option as a lifestyle intervention for diabetic patients. Some of microRNAs (miRNAs), which can be secreted from skeletal muscle after exercise, regulate insulin sensitivity and are used for diagnostic marker for diabetic patients. MiR-204 is well-known for its involvement in development, cancer, and metabolism. However, it is still unknown whether miR-204 associates with exerciseinduced glycemic control. In preliminary data, we found that endurance exercise of mice increases miR-204 expression levels in skeletal muscle. In chronic exercise mice model, miR-204 expression levels were increased with glycolytic enzymes in skeletal muscle. When hypoxia induced hypoxia inducible factor 1 alpha (HIF1α), miR-204 expression levels were increased. HIF1α overexpression also increased miR-204 expression levels. To corroborate the causality between miR-204 and glycolysis, miR-204 mimic was introduced to myoblast cell line, C2C12 myoblast cell line. After exposure to miR-204 mimic, C2C12 cells could increase the glycolysis rate measured by extracellular acidification rate. miR-204 mimics also increased mRNA expression levels of glycolytic enzymes. In vivo intravenous miR-204 administration to mice also increased the glucose clearance rate after refeeding of mice. MiR-204 increased blood glucose surge on earlier point of refeeding but promoted the blood glucose lowering on later point of refeeding. Skeletal muscle glycolytic enzymes were increased in mRNA expression levels by miR-204 injection. This finding suggests the novel physiological role of miR-204 in skeletal muscle glycolysis where insulin action is limited.

ORGANISM(S): Mus musculus

PROVIDER: GSE276372 | GEO | 2024/09/04

REPOSITORIES: GEO

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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.

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Exercise promotes peripheral glycolysis through miR-204 induction in skeletal muscle

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