Neuregulin-1 triggers GLUT4 translocation and enhances glucose uptake independently of insulin receptor substrate and ErbB3 in neonatal rat cardiomyocytes

Neuregulin-1 triggers GLUT4 translocation and enhances glucose uptake independently of insulin receptor substrate and ErbB3 in neonatal rat cardiomyocytes

During stress conditions such as pressure overload and acute ischemia, the myocardial endothelium releases neuregulin-1β (NRG-1), which acts as a cardioprotective factor and supports recovery of the heart. Recently, we demonstrated that recombinant human (rh)NRG-1 enhances glucose uptake in neonatal...

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Published in:Biochimica et biophysica acta. Molecular cell research Vol. 1867; no. 3; p. 118562
Main Authors: Heim, Philippe, Morandi, Christian, Brouwer, Gian R., Xu, Lifen, Montessuit, Christophe, Brink, Marijke
Format: Journal Article
Language:English
Published: Netherlands Elsevier B.V 01-03-2020
Subjects:
AS160
Cardiomyocyte
ErbB
HER2
Metabolism
Neuregulin
Neuregulin
AS160
ErbB
HER2
Metabolism
Cardiomyocyte
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Summary:During stress conditions such as pressure overload and acute ischemia, the myocardial endothelium releases neuregulin-1β (NRG-1), which acts as a cardioprotective factor and supports recovery of the heart. Recently, we demonstrated that recombinant human (rh)NRG-1 enhances glucose uptake in neonatal rat ventricular myocytes via the ErbB2/ErbB4 heterodimer and PI3Kα. The present study aimed to further elucidate the mechanism whereby rhNRG-1 activates glucose uptake in comparison to the well-established insulin and to extend the findings to adult models. Combinations of rhNRG-1 with increasing doses of insulin did not yield any additive effect on glucose uptake measured as 3H-deoxy-d-glucose incorporation, indicating that the mechanisms of the two stimuli are similar. In c-Myc-GLUT4-mCherry-transfected neonatal rat cardiomyocytes, rhNRG-1 increased sarcolemmal GLUT4 by 16-fold, similar to insulin. In contrast to insulin, rhNRG-1 did not phosphorylate IRS-1 at Tyr612, indicating that IRS-1 is not implicated in the signal transmission. Treatment of neonatal rats with rhNRG-1 induced a signaling response comparable with that observed in vitro, including increased ErbB4-pTyr1284, Akt-pThr308 and Erk1/2-pThr202/Tyr204. In contrast, in adult cardiomyocytes rhNRG-1 only increased the phosphorylation of Erk1/2 without having any significant effect on Akt and AS160 phosphorylation and glucose uptake, suggesting that rhNRG-1 function in neonatal cardiomyocytes differs from that in adult cardiomyocytes. In conclusion, our results show that similar to insulin, rhNRG-1 can induce glucose uptake by activating the PI3Kα-Akt-AS160 pathway and GLUT4 translocation. Unlike insulin, the rhNRG-1-induced effect is not mediated by IRS proteins and is observed in neonatal, but not in adult rat cardiomyocytes. [Display omitted] •Recombinant human NRG-1 induces glucose uptake in neonatal but not in adult cardiomyocytes.•rhNRG-1 triggers GLUT4 translocation in neonatal rat cardiomyocytes.•rhNRG-1 activates Akt/AS160 signaling via ErbB4/ErbB2 in cardiomyocytes.•In contrast, skeletal muscle and cancer cells have been reported to utilize ErbB3/ErbB2.
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ISSN:0167-4889
1879-2596
DOI:10.1016/j.bbamcr.2019.118562