Preconditioning Exercise Inhibits Neuron Ferroptosis and Ameliorates Brain Ischemia Damage by Skeletal Muscle–Derived Exosomes via Regulating miR-484/ACSL4 Axis

作者：Mudan Huang, Shimei Cheng, Ziwen Li, Jinshuo Chen, Chuangjia Wang, Jun Li, Haiqing Zheng · 发表于：Antioxidants and Redox Signaling · 年份：2024 · DOI：10.1089/ars.2023.0492 · 被引用次数：38 · 研究领域：Extracellular vesicles in disease、MicroRNA in disease regulation、Circular RNAs in diseases

Aims: Although there is evidence that patients with stroke who exercise regularly before stroke have a better prognosis than those who do not exercise, the detailed mechanism remains unclear. Moreover, neuronal death plays a central role in neurological dysfunction caused by ischemic stroke. Thus, we investigated whether exercise could reduce stroke-induced neuronal death and its associated mediators in the current study. Results: Ferroptosis was the most dominant form of programmed cell death in neurons. Preconditioning exercise before stroke improved the neurological function and decreased the infarct area in rats with ischemic stroke. Preconditioning exercise attenuated stroke-induced ferroptosis by reducing lipid peroxidation (LPO) production, upregulating glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), and downregulating acyl-CoA synthetase long-chain family member 4 (ACSL4). High-throughput sequencing and dual luciferase reporter assays revealed that exercise-induced exosomal miR-484 inhibits Acsl4 expression. Moreover, we showed that exercise-induced exosomal miR-484 is mainly derived from skeletal muscle, and the neuroprotective effect of preconditioning exercise is suppressed by inhibiting miR-484 production in skeletal muscle. Innovation: This study suggested that neuronal ferroptosis is the most dominant form of programmed cell death in a hypoxic environment. Moreover, we showed that the ferroptosis pathway is a potential therapeuti...