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Aerobic Glycolysis Induced by mTOR/HIF-1α Promotes Early Brain Injury After Subarachnoid Hemorrhage via Activating M1 Microglia

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Abstract

M1 microglial activation is crucial for the pathogenesis of early brain injury (EBI) following subarachnoid hemorrhage (SAH), and there is growing evidence that glucose metabolism is frequently involved in microglial activation. However, the molecular mechanism of glycolysis and its role in M1 microglial activation in the context of EBI are not yet fully understood. In this study, firstly, the relationship between aerobic glycolysis and M1 microglial activation as well as SAH-induced EBI was researched in vivo. Then, intervention on mammalian target of rapamycin (mTOR) was performed to investigate the effects on glycolysis-dependent M1 microglial activation and EBI and its relationship with hypoxia-inducible factor-1α (HIF-1α) in vivo. Next, Hif-1α was inhibited to analyze its role in aerobic glycolysis, M1 microglial activation, and EBI in vivo. Lastly, both in vivo and in vitro, mTOR inhibition and Hif-1α enhancement were administered simultaneously, and the combined effects were further confirmed again. The results showed that aerobic glycolysis and M1 microglial polarization were increased after SAH, and glycolytic inhibition could attenuate M1 microglial activation and EBI. Inhibition of mTOR reduced glycolysis-dependent M1 microglial polarization and EBI severity by down-regulating HIF-1α expression, while enhancement had the opposite effects. Blockading HIF-1α had the similar effects as suppressing mTOR, while HIF-1α agonist worked against mTOR antagonist when administered simultaneously. In conclusion, the present study showed new evidence that aerobic glycolysis induced by mTOR/HIF-1α might promote EBI after SAH by activating M1 microglia. This finding provided new insights for the treatment of EBI.

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Data Availability

The authors confirm that the findings of this study are supported by the data therein. The data are available from the corresponding author.

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Acknowledgements

We would like to thank the following projects for funding this research: Shanxi Province’s Great Research Project, Shanxi Health Committee’s Project, and Shanxi Province’s Basic Research Plan.

Funding

This study was supported by Shanxi Province’s Great Research Project (201903D321044), Shanxi Health Committee’s Project (2019045), and Shanxi Province’s Basic Research Plan (20210302123264).

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  1. Xin-Gang Sun and Xue-Hong Chu contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, The Second Hospital Affiliated to Shanxi Medical University, Taiyuan, 030000, Shanxi, China

    Xin-Gang Sun

  2. Shanxi Medical University, Taiyuan, 030000, Shanxi, China

    Xue-Hong Chu, Ivan Steve Godje Godje, Shao-Yu Liu, Hui-Yu Hu, Yi-Bo Zhang, Li-Juan Zhu, Hai Wang, Chen Sui, Juan Huang & Ying-Jie Shen

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Contributions

Xin-Gang Sun and Xue-Hong Chu designed the study and drafted the manuscript for content, including medical writing for content; Shao-Yu Liu, Yi-Bo Zhang, Li-Juan Zhu, Juan Huang, and Hai Wang had done experiments and obtained data; Ivan Steve Godje Godje, Hui-Yu Hu, Chen Sui, and Ying-Jie Shen analyzed and organized data. All authors reviewed the manuscript.

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Correspondence to Xin-Gang Sun.

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This study was conducted in accordance with the ARRIVE guidelines and approved by the Animal and Ethics Review Committee of the Second Hospital Affiliated to Shanxi Medical University of China. All experimental procedures were conducted according to the ARRIVE guidelines. The protocols for the animal experiments were performed according to the Animal and Ethics Review Committee of our institution.

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Sun, XG., Chu, XH., Godje Godje, I.S. et al. Aerobic Glycolysis Induced by mTOR/HIF-1α Promotes Early Brain Injury After Subarachnoid Hemorrhage via Activating M1 Microglia. Transl. Stroke Res. 15, 1–15 (2024). https://doi.org/10.1007/s12975-022-01105-5

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