运动通过 AMPK-SIRT1-TFEB 通路激活大脑中的溶酶体功能。

Exercise activates lysosomal function in the brain through AMPK-SIRT1-TFEB pathway.

机构信息

Department of Pharmacology, Laboratory of Aging and Nervous Diseases (SZS0703), Soochow University School of Pharmaceutical Science, Su Zhou, China.

Suzhou Vocation Health college, SuZhou, China.

出版信息

CNS Neurosci Ther. 2019 Jun;25(6):796-807. doi: 10.1111/cns.13114. Epub 2019 Mar 12.

AIM

To study the effects of exercise on lysosomal functions.

METHODS

Mouse exercise model was established and wheel running was scheduled as 18 rpm (14:00-17:00), 5 d/wk, for 8 weeks. Mice were injected EX527 to inhibit SIRT1 activity. The protein level was assayed with Western blot and immunofluorescence histochemistry. The transmission electron microscopic examination was used to show the structure of lysosome and mitochondria.

RESULTS

Exercise promoted the nuclear translocation of TFEB in the cortex which upregulated the transcription of genes associated with autophagy and lysosome. Exercise directly activated autophagy/lysosome system via up-regulating of AMPK-SIRT1 signaling. The SIRT1 inhibitor EX527 decreased TFEB regulated gene transcription but had little effect on the nuclear translocation of TFEB. In addition, long-term exercise showed more significant effects on activation of lysosomes biogenesis compared with the short-term exercise and trehalose, a classical autophagy activator in the mTOR-independent pathway.

CONCLUSION

Running exercise activates lysosomal function in the brain through AMPK-SIRT1-TFEB pathway.

目的

研究运动对溶酶体功能的影响。

方法

建立小鼠运动模型，设定滚轮转速为 18rpm（14:00-17:00），每周 5 天，持续 8 周。用 EX527 抑制 SIRT1 活性。采用 Western blot 和免疫荧光组织化学法检测蛋白水平。透射电镜观察溶酶体和线粒体的结构。

结果

运动促进皮质中 TFEB 的核易位，上调与自噬和溶酶体相关的基因转录。运动通过上调 AMPK-SIRT1 信号直接激活自噬/溶酶体系统。SIRT1 抑制剂 EX527 降低 TFEB 调节基因的转录，但对 TFEB 的核易位影响不大。此外，与短期运动相比，长期运动对溶酶体生物发生的激活作用更为显著，而海藻糖是 mTOR 非依赖性途径中的一种经典自噬激活剂。