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Aerobic Glycolysis Induced by mTOR/HIF-1α Promotes Early Brain Injury After Subarachnoid Hemorrhage via Activating M1
Xin-Gang Sun1, Xue-Hong Chu2, Ivan Steve Godje Godje2
1Department of Neurology, The Second Hospital Affiliated to Shanxi Medical University, Taiyuan, 030000, Shanxi, China. sunyanxia820701@163.com.
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.
Insights
Aerobic glycolysis fuels M1 microglial activation and early brain injury (EBI) after subarachnoid hemorrhage (SAH). Targeting the mTOR/HIF-1α pathway offers a potential therapeutic strategy for EBI treatment.
Area of Science:
- Neuroscience
- Immunology
- Metabolism
Background:
- M1 microglial activation is key in early brain injury (EBI) after subarachnoid hemorrhage (SAH).
- The role of glucose metabolism, specifically aerobic glycolysis, in M1 microglial activation and EBI is not fully understood.
Purpose of the Study:
- To investigate the molecular mechanisms linking aerobic glycolysis, M1 microglial activation, and EBI following SAH.
- To explore the involvement of the mammalian target of rapamycin (mTOR) and hypoxia-inducible factor-1α (HIF-1α) pathways in this process.
Main Methods:
- In vivo and in vitro studies were conducted to examine the relationship between aerobic glycolysis, M1 microglial activation, and SAH-induced EBI.
- Interventions included modulating mTOR and HIF-1α pathways, as well as inhibiting glycolysis.
Main Results:
- SAH increased aerobic glycolysis and M1 microglial polarization, contributing to EBI.
- Inhibition of mTOR reduced glycolysis-dependent M1 microglial activation and EBI by down-regulating HIF-1α.
- HIF-1α blockade mimicked the effects of mTOR suppression, while HIF-1α activation counteracted mTOR inhibition.
Conclusions:
- Aerobic glycolysis, regulated by the mTOR/HIF-1α pathway, promotes EBI after SAH by activating M1 microglia.
- Targeting this pathway presents a novel therapeutic approach for mitigating EBI following SAH.
