title: Role of ERK1/2 activation in microtubule stabilization and glucose transport in cardiomyocytes.
abstract: We previously demonstrated that microtubule disruption impairs stimulation of glucose uptake in cardiomyocytes and that 9-cis retinoic acid (9cRA) treatment preserved both microtubule integrity and stimulated glucose transport. Herein we investigated whether 1) activation of the extracellular signal-regulated kinases (ERK1/2) is responsible for microtubule destabilization and 2) ERK1/2 inactivation may explain the positive effects of 9cRA on glucose uptake and microtubule stabilization. Adult rat cardiomyocytes in primary culture showed increased basal ERK1/2 phosphorylation. Cardiomyocytes exposed to inhibitors of the ERK1/2 kinase mitogen/extracellular signal-regulated kinase (MEK) 1/2 had preserved microtubular scaffold, including microtubule-organizing centers (MTOC), together with increased insulin and metabolic stress-stimulated glucose transport as well as signaling, thus replicating the effects of 9cRA treatment. Although 9cRA treatment did not significantly reduce global ERK1/2 activation, it markedly reduced perinuclear-activated ERK1/2 at the location of MTOC. 9cRA also triggered relocation of the ERK1/2 phosphatase mitogen-activated protein kinase phosphatase-3 from the cytosol to the nucleus. These results indicate that, in cardiomyocytes, microtubule destabilization, leading to impaired stimulation of glucose transport, is mediated by ERK1/2 activation, impacting on the MTOC. 9cRA acid restores stimulated glucose transport indirectly through compartmentalized inactivation of ERK1/2.
authors.affiliation: Division of Cardiology, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Asrih
authors.forename: Corinne
authors.initials: C
authors.lastname: Pellieux
authors.forename: Irène
authors.initials: I
authors.lastname: Papageorgiou
authors.forename: René
authors.initials: R
authors.lastname: Lerch
authors.forename: Christophe
authors.initials: C
authors.lastname: Montessuit
mesh_terms: D000077556:Alitretinoin; D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D061251:Primary Cell Culture; D055503:Protein Multimerization / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D007328:Insulin; D000077556:Alitretinoin; D014212:Tretinoin; D048052:Mitogen-Activated Protein Kinase 3; D005947:Glucose