miR-182 Regulates Metabolic Homeostasis by Modulating Glucose Utilization in Muscle

•miR-182 is enriched in fast muscle, and its level correlates with blood glucose level•Loss of miR-182 leads to muscle fiber-type switching and impaired glucose metabolism•miR-182 regulates glucose utilization by modulating PDHC activity via FoxO1/PDK4•Restoration of miR-182 expression improves glucose metabolism in mice fed a high-fat diet-fed

SummaryUnderstanding the fiber-type specification and metabolic switch in skeletal muscle provides insights into energy metabolism in physiology and diseases. Here, we show that miR-182 is highly expressed in fast-twitch muscle and negatively correlates with blood glucose level. miR-182 knockout mice display muscle loss, fast-to-slow fiber-type switching, and impaired glucose metabolism. Mechanistic studies reveal that miR-182 modulates glucose utilization in muscle by targeting FoxO1 and PDK4, which control fuel selection via the pyruvate dehydrogenase complex (PDHC). Short-term high-fat diet (HFD) feeding reduces muscle miR-182 levels by tumor necrosis factor α (TNFα), which contributes to the upregulation of FoxO1/PDK4. Restoration of miR-182 expression in HFD-fed mice induces a faster muscle phenotype, decreases muscle FoxO1/PDK4 levels, and improves glucose metabolism. Together, our work establishes miR-182 as a critical regulator that confers robust and precise controls on fuel usage and glucose homeostasis. Our study suggests that a metabolic shift toward a faster and more glycolytic phenotype is beneficial for glucose control.

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