β-Hydroxy-β-Methylbutyrate (HMB) Promotes Neurite Outgrowth in Neuro2a Cells

被引:51
|
作者
Salto, Rafael [1 ]
Vilchez, Jose D. [1 ]
Giron, Maria D. [1 ]
Cabrera, Elena [1 ]
Campos, Nefertiti [2 ]
Manzano, Manuel [2 ]
Rueda, Ricardo [2 ]
Lopez-Pedrosa, Jose M. [2 ]
机构
[1] Univ Granada, Sch Pharm, Dept Biochem & Mol Biol 2, Granada, Spain
[2] Abbott Nutr R&D, Granada, Spain
来源
PLOS ONE | 2015年 / 10卷 / 08期
关键词
MEF2 TRANSCRIPTION FACTORS; MYOCYTE-ENHANCER FACTOR-2; NEUROPROTECTIVE ACTIVITY; SIGNALING PATHWAY; CORTICAL-NEURONS; DIFFERENTIATION; BRAIN; GROWTH; ACETYLCHOLINESTERASE; PROLIFERATION;
D O I
10.1371/journal.pone.0135614
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
beta-Hydroxy-beta-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.
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页数:13
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