L-leucine promotes axonal outgrowth and regeneration via mTOR activation
L-leucine promotes axonal outgrowth and regeneration via mTOR activation
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DOI：
10.1096/fj.202001798rr
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发表时间：
2021-05-01
期刊：
影响因子：
4.8
通讯作者：
Liu, Mei
中科院分区：
文献类型：
--
作者：
Ma, Chao;Teng, Long;Liu, Mei
发现安全有效的促进神经元再生的药物是中枢神经系统损伤恢复的重要策略。在这项研究中，我们发现l -亮氨酸，一种从补充剂和食物来源中获得的必需氨基酸，可以显著促进轴突的生长和再生。首先，通过细胞凋亡、存活和死亡实验来评估l -亮氨酸对神经元的影响，结果显示治疗后这些过程没有变化。通过活细胞成像，发现l -亮氨酸显著增加了轴突切开后的轴突长度和生长速度。我们还通过mTOR抑制剂雷帕霉素测试，证实l -亮氨酸增强了神经元中p-mTOR/p-S6K的激活。随后，我们在体内研究了l -亮氨酸对脊髓损伤的影响。建立小鼠脊髓半断模型，尾静脉注射l -亮氨酸。Basso小鼠尺度值显示l -亮氨酸可以促进损伤后的功能恢复。l -亮氨酸处理促进了硫酸软骨素蛋白多糖（CSPG）区域轴突的生长。此外，我们使用CSPGs作为抑制环境线索，并澄清了l -亮氨酸通过促进p-mTOR和p-S6K的激活显著增强轴突的生长和再生。因此，我们的研究首次报道了l -亮氨酸在体外和体内促进轴突再生，可能是轴突再生和神经功能恢复的候选药物。
Discovering safe and effective drugs that promote neuron regeneration is an essential strategy for the recovery of central nervous system injuries. In this study, we found that L-leucine, an essential amino acid obtained from both supplements and food sources, could dramatically boost axonal outgrowth and regeneration. First, the effects of L-leucine on neurons were evaluated by cell apoptosis, survival, and death assays, and the results showed no changes in these processes after treatment. By live cell imaging, L-leucine was found to remarkably increase axonal length and growth velocity after axotomy. We also verified that L-leucine enhanced p-mTOR/p-S6K activation in neurons by testing with an mTOR inhibitor, rapamycin. Thereafter, we investigated the effects of L-leucine on the spinal cord injury in vivo. A mouse model of spinal cord hemi-section was established, and L-leucine was administered by tail intravenous injection. Basso mouse scale values revealed that L-leucine could improve functional recovery after injury. It was also notable that L-leucine treatment promoted axon growth across chondroitin sulfate proteoglycan (CSPG) areas. Furthermore, we used CSPGs as inhibitory environmental cues and clarified that L-leucine significantly enhanced axonal outgrowth and regeneration by promoting p-mTOR and p-S6K activation. Therefore, our study is the first to report that L-leucine promotes axonal regeneration in vitro and in vivo and could be candidate drug for axonal re-growth and nervous functional recovery.