Journal
CELL REPORTS
Volume 16, Issue 3, Pages 757-768Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.06.040
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Funding
- National Key Basic Research Program [2013CB967502]
- National Natural Science Foundation of China [31525012, 31371189, 31500959, 81570768, 31070679, 31100550, 81201476, 81172009, 81372168, 81302820, 81522014, 81371059, 81402209]
- Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences [SIBS2012004]
- CAS/SAFEA International Partnership Program for Creative Research Teams
- Shanghai Charity Foundation (The Special Fund for DMD)
- Xuhui Central Hospital (Shanghai, China)
- Zhejiang Provincial Natural Science Foundation of China [LR13H120001]
- NHFPC [201472911]
- Wenzhou Science and Technology Innovation Team Project [C20150004]
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Understanding 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 alpha (TNF alpha), 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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