β-Hydroxy-β-Methylbutyrate (HMB) Promotes Neurite Outgrowth in Neuro2a Cells.
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.
Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, Granada, Spain.
Rafael
R
Salto
Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, Granada, Spain.
Jose D
JD
Vílchez
Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, Granada, Spain.
María D
MD
Girón
Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, Granada, Spain.
Elena
E
Cabrera
Abbott Nutrition R&D, Granada, Spain.
Nefertiti
N
Campos
Abbott Nutrition R&D, Granada, Spain.
Manuel
M
Manzano
Abbott Nutrition R&D, Granada, Spain.
Ricardo
R
Rueda
Abbott Nutrition R&D, Granada, Spain.
Jose M
JM
López-Pedrosa
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051274:Glucose Transporter Type 3 / Q000378:metabolism; D064326:MEF2 Transcription Factors / Q000378:metabolism; D051379:Mice; D009287:Naphthyridines / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014631:Valerates / Q000494:pharmacology*
C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; D064326:MEF2 Transcription Factors; D009287:Naphthyridines; D014631:Valerates; C004961:beta-hydroxyisovaleric acid; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus