title: Neuregulin-1β promotes glucose uptake via PI3K/Akt in neonatal rat cardiomyocytes.
abstract: Nrg1β is critically involved in cardiac development and also maintains function of the adult heart. Studies conducted in animal models showed that it improves cardiac performance under a range of pathological conditions, which led to its introduction in clinical trials to treat heart failure. Recent work also implicated Nrg1β in the regenerative potential of neonatal and adult hearts. The molecular mechanisms whereby Nrg1β acts in cardiac cells are still poorly understood. In the present study, we analyzed the effects of Nrg1β on glucose uptake in neonatal rat ventricular myocytes and investigated to what extent mTOR/Akt signaling pathways are implicated. We show that Nrg1β enhances glucose uptake in cardiomyocytes as efficiently as IGF-I and insulin. Nrg1β causes phosphorylation of ErbB2 and ErbB4 and rapidly induces the phosphorylation of FAK (Tyr(861)), Akt (Thr(308) and Ser(473)), and its effector AS160 (Thr(642)). Knockdown of ErbB2 or ErbB4 reduces Akt phosphorylation and blocks the glucose uptake. The Akt inhibitor VIII and the PI3K inhibitors LY-294002 and Byl-719 abolish Nrg1β-induced phosphorylation and glucose uptake. Finally, specific mTORC2 inactivation after knockdown of rictor blocks the Nrg1β-induced increases in Akt-p-Ser(473) but does not modify AS160-p-Thr(642) or the glucose uptake responses to Nrg1β. In conclusion, our study demonstrates that Nrg1β enhances glucose uptake in cardiomyocytes via ErbB2/ErbB4 heterodimers, PI3Kα, and Akt. Furthermore, although Nrg1β activates mTORC2, the resulting Akt-Ser(473) phosphorylation is not essential for glucose uptake induction. These new insights into pathways whereby Nrg1β regulates glucose uptake in cardiomyocytes may contribute to the understanding of its regenerative capacity and protective function in heart failure.
authors.affiliation: Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
authors.forename: Laura
authors.initials: L
authors.lastname: Pentassuglia
authors.affiliation: Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Heim
authors.affiliation: Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
authors.forename: Sonia
authors.initials: S
authors.lastname: Lebboukh
authors.affiliation: Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Morandi
authors.affiliation: Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
authors.forename: Lifen
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland marijke.brink@unibas.ch.
authors.forename: Marijke
authors.initials: M
authors.lastname: Brink
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism*; D006352:Heart Ventricles / Q000166:cytology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D047468:Immunoprecipitation; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D020890:Neuregulin-1 / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects* / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D066247:Receptor, ErbB-4 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D005947:Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; D058570:TOR Serine-Threonine Kinases; C117467:neuregulin beta; C483804:Erbb2 protein, rat; C587691:Erbb4 protein, rat
keywords: ErbB; metabolism; phosphatidylinositol 3-kinase; protein synthesis; signaling; tyrosine kinase