Abstract
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.
Highlights
Neurite outgrowth is a requisite for an accurate functional network of neurons during development [1]
Among the transcription factors regulated by these signaling pathways that are involved in neuronal differentiation and survival stands out the Myocyte-enhancer factor 2 family (MEF2)
We have shown for the first time that HMB promoted neurite outgrowth through PI3K/Akt and ERK1/2 signaling pathways in Neuro2a cells
Summary
Neurite outgrowth is a requisite for an accurate functional network of neurons during development [1]. Activation of the extracellular-signal-regulated kinases (ERK1/2) [4, 5] and the phosphoinositide3-kinase/protein kinase B (PI3K/PKB) [1, 6, 7] signaling pathways has been reported to regulate neuronal differentiation and survival and several aspects of neurite outgrowth, PLOS ONE | DOI:10.1371/journal.pone.0135614. Among the transcription factors regulated by these signaling pathways that are involved in neuronal differentiation and survival stands out the Myocyte-enhancer factor 2 family (MEF2). This family of transcriptional regulators was first described in muscle development [8]. PI3k/ Akt pathway is involved in the regulation of MEF2 activity upon either insulin-like growth factor-1 (IGF-I) stimulation or membrane depolarization [13]
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