β-Hydroxy-β-Methylbutyrate (HMB) Promotes Neurite Outgrowth in Neuro2a Cells.
β-Hydroxy-β-Methylbutyrate (HMB) Promotes Neurite Outgrowth in Neuro2a Cells.
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DOI：
10.1371/journal.pone.0135614
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
López-Pedrosa JM
中科院分区：
文献类型：
--
作者：
Salto R;Vílchez JD;Girón MD;Cabrera E;Campos N;Manzano M;Rueda R;López-Pedrosa JM
β-羟基-β-甲基丁酸酯（HMB）已被证明可以增强细胞存活、分化和蛋白质在肌肉中的转换，主要激活磷酸肌醇-3-激酶/蛋白激酶B （PI3K/Akt）和丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）信号通路。由于这两条通路都与神经元的存活和分化有关，因此在本研究中，我们研究了HMB对小鼠神经母细胞瘤Neuro2a细胞的神经营养作用。在Neuro2a细胞中，HMB促进分化为神经突而不受任何增殖影响。这些作用是通过PI3K/Akt和细胞外信号调节激酶（ERK1/2）信号的激活介导的，这两种途径的特异性抑制剂的使用证明了这一点。由于肌细胞增强因子2 （myocyte-enhancer factor 2, MEF2）家族转录因子参与神经元的存活和可塑性，我们还对MEF2的转录活性和蛋白水平进行了评估。HMB通过激活Akt和ERK1/2通路促进mef2依赖性转录活性。此外，HMB增加了脑葡萄糖转运蛋白1 （GLUT1）和3 （GLUT3）的表达，以及mTOR磷酸化，这在Neuro2a细胞中转化为更高的蛋白质合成。此外，Torin1和雷帕霉素对MEF2转录活性和HMB依赖性神经突生长的影响支持HMB通过mTORC2起作用。总之，这些发现为支持HMB在神经突起生长中的重要作用提供了明确的证据。
β-Hydroxy-β-methylbutyrate (HMB) has been shown to enhance cell survival, differentiation and protein turnover in muscle, mainly activating phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) and mitogen-activated protein kinases/ extracellular-signal-regulated kinases (MAPK/ERK) signaling pathways. Since these two pathways are related to neuronal survival and differentiation, in this study, we have investigated the neurotrophic effects of HMB in mouse neuroblastoma Neuro2a cells. In Neuro2a cells, HMB promotes differentiation to neurites independent from any effects on proliferation. These effects are mediated by activation of both the PI3K/Akt and the extracellular-signal-regulated kinases (ERK1/2) signaling as demonstrated by the use of specific inhibitors of these two pathways. As myocyte-enhancer factor 2 (MEF2) family of transcription factors are involved in neuronal survival and plasticity, the transcriptional activity and protein levels of MEF2 were also evaluated. HMB promoted MEF2-dependent transcriptional activity mediated by the activation of Akt and ERK1/2 pathways. Furthermore, HMB increases the expression of brain glucose transporters 1 (GLUT1) and 3 (GLUT3), and mTOR phosphorylation, which translates in a higher protein synthesis in Neuro2a cells. Furthermore, Torin1 and rapamycin effects on MEF2 transcriptional activity and HMB-dependent neurite outgrowth support that HMB acts through mTORC2. Together, these findings provide clear evidence to support an important role of HMB in neurite outgrowth.