Aerobic Exercise Enhances Neurological Recovery after Ischemic Stroke via α-Tubulin Lactylation

Background Ischemic stroke causes severe neurological disability, with some patients still presenting with residual neurological dysfunction. Aerobic exercise shows potential for post-stroke recovery. However, the mechanism behind its beneficial effects on the brain remains to be further explored. This study aimed to explore aerobic exercise’s role in the neurological recovery of ischemic stroke mice and to clarify the specific protective mechanisms involved. Methods A mouse model of ischemic stroke was employed in this study. Mice were subjected to aerobic exercise intervention, with additional exogenous lactate administration and RNA-sequencing (RNA-seq) analysis conducted to explore the molecular mechanisms. Results Results demonstrated that aerobic exercise significantly elevated protein lactylation levels in ischemic stroke mice and facilitated neurological recovery. In addition, aerobic exercise attenuated neuroinflammation in the ischemic penumbra and promoted neural cell proliferation in the subventricular zone. Mechanistically, aerobic exercise induced lactylation of α-tubulin, which enhanced microtubule dynamics and thereby contributed to neural repair. Exogenous lactate intervention was found to augment α-tubulin lactylation, promote hippocampal neurogenesis, and increase dendritic spine density as well as synaptic plasticity in both the ischemic penumbra and hippocampus. Consistent with these findings, exogenous lactate administration improved neurological function in ischemic stroke mice. RNA-seq analysis further revealed that elevated lactate levels exerted a promotive effect on neural repair. Conclusion Aerobic exercise promotes post-ischemic stroke neurological recovery via elevating protein lactylation (α-tubulin lactylation), attenuating neuroinflammation, and enhancing neural repair. These findings highlight the potential of targeting lactate metabolism and protein lactylation as therapeutic strategies for facilitating neural repair and improving neurological outcomes following ischemic stroke.