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

• 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
• DOI: 10.1016/j.bbamcr.2019.118562
• EISSN: 1879-2596
• ISSN: 0167-4889

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.
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•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.