Lactate Mediates the Effects of Exercise on Learning and Memory through SIRT1-Dependent Activation of Hippocampal Brain-Derived Neurotrophic Factor (BDNF)
Lactate Mediates the Effects of Exercise on Learning and Memory through SIRT1-Dependent Activation of Hippocampal Brain-Derived Neurotrophic Factor (BDNF)
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DOI：
10.1523/jneurosci.1661-18.2019
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发表时间：
2019-03-27
影响因子：
5.3
通讯作者：
Sleiman, Sama F.
中科院分区：
文献类型：
--
作者：
El Hayek, Lauretta;Khalifeh, Mohamad;Sleiman, Sama F.
锻炼能促进学习和记忆的形成。这些效应依赖于海马区BDNF的增加，这是一种与认知改善和缓解抑郁症状有关的生长因子。识别在运动过程中产生并调节海马区BDNF表达的分子将使我们能够利用运动的治疗潜力。在这里，我们报告了在运动中产生的一种内源性分子诱导小鼠肌肉BDNF基因，并促进学习和记忆的形成。肌肉在运动过程中释放的代谢物乳酸穿过血脑屏障，在海马区诱导BDNF表达和TrkB信号转导。事实上，我们发现脑源性神经营养因子中乳酸依赖的增加与改善空间学习和记忆保持有关。乳酸的作用依赖于Sirtuin1脱乙酰基酶的激活。SIRT1增加转录辅助激活因子PGC1a和分泌分子FNDC5的水平，已知FNDC5介导BDNF的表达。这些结果揭示了一种内源性机制，可以解释运动是如何导致BDNF的诱导，并确定乳酸是一种潜在的内源性分子，可能对BDNF信号转导中断的中枢神经系统疾病具有治疗价值。
Exercise promotes learning and memory formation. These effects depend on increases in hippocampal BDNF, a growth factor associated with cognitive improvement and the alleviation of depression symptoms. Identifying molecules that are produced during exercise and that mediate hippocampal Bdnf expression will allow us to harness the therapeutic potential of exercise. Here, we report that an endogenous molecule produced during exercise in male mice induces the Mus musculus Bdnf gene and promotes learning and memory formation. The metabolite lactate, which is released during exercise by the muscles, crosses the blood-brain barrier and induces Bdnf expression and TRKB signaling in the hippocampus. Indeed, we find that lactate-dependent increases in BDNF are associated with improved spatial learning and memory retention. The action of lactate is dependent on the activation of the Sirtuin1 deacetylase. SIRT1 increases the levels of the transcriptional coactivator PGC1a and the secreted molecule FNDC5, known to mediate Bdnf expression. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF, and identify lactate as a potential endogenous molecule that may have therapeutic value for CNS diseases in which BDNF signaling is disrupted.