Exercise training alleviates neuronal apoptosis and re-establishes mitochondrial quality control after cerebral ischemia by increasing SIRT3 expression
Wenwen Wu, Zengyu Wei, Zhiyun Wu, Jianmin Chen, Ji Liu, Manli Chen, Jinjin Yuan, Zhijian Zheng, Zijun Zhao, Qiang Lin, Nan Liu, Hongbin Chen
Abstract
Existing evidence indicates that exercise training can enhance neural function by regulating mitochondrial quality control (MQC), which can be impaired by cerebral ischemia, and that sirtuin-3 (SIRT3), a protein localized in mitochondria, is crucial in maintaining mitochondrial functions. However, the relationship among exercise training, SIRT3, and MQC after cerebral ischemia remains obscure. This study attempted to elucidate the relationship among exercise training, SIRT3 and MQC after cerebral ischemia in rats. Male adult SD rats received tMCAO after the transfection of adeno-associated virus encoding either sirtuin-3 (AAV-SIRT3) or SIRT3 knockdown (AAV-sh-SIRT3) into the ipsilateral striata and cortex. Subsequently, the animals were randomly selected for exercise training. The index changes were measured by transmission electron microscopy, Western blot analysis, nuclear magnetic resonance imaging, TUNEL staining, and immunofluorescence staining, etc. The results revealed that after cerebral ischemia, exercise training increased SIRT3 expression, significantly improved neural function, alleviated infarct volume and neuronal apoptosis, maintained the mitochondrial structural integrity, and re-established MQC. The latter promoted mitochondrial biogenesis, balanced mitochondrial fission/fusion, and enhanced mitophagy. These favorable benefits were reversed after SIRT3 interference. In addition, a cellular OGD/R model showed that the increased SIRT3 expression alleviates neuronal apoptosis and re-establishes mitochondrial quality control by activating the β-catenin pathway. These findings suggest that exercise training may optimize mitochondrial quality control by increasing the expression of SIRT3, thereby improving neural functions after cerebral ischemia, which illuminates the mechanism underlying the exercise training-conferred neural benefits and indicates SIRT3 as a therapeutic strategy for brain ischemia. 1. The expression of SIRT3 decreases after cerebral ischemia in rats, while exercise training can increase SIRT3 levels in ischemic rats. 2. Exercise training alleviates neuronal apoptosis and re-establishes mitochondrial quality control (MQC) after cerebral ischemia by increasing SIRT3 expression, thereby promoting neurological function recovery. 3. SIRT3 overexpression reduces neuronal apoptosis and re-establishes MQC by activating the β-catenin pathway.