Role of ERK1/2 activation in microtubule stabilization and glucose transport in cardiomyocytes

• Published in: American journal of physiology: endocrinology and metabolism 2011-11, Vol.301 (5), p.E836-E843
• Main Authors: Asrih, Mohamed, Pellieux, Corinne, Papageorgiou, Irène, Lerch, René, Montessuit, Christophe
• Format: Article
• Language: English
• Subjects: Animals; Biological Transport - drug effects; Biological Transport - physiology; Cardiomyocytes; Cells, Cultured; Enzyme Activation - drug effects; Enzyme Activation - physiology; Glucose; Glucose - metabolism; Insulin - pharmacology; Kinases; Male; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Microtubules - drug effects; Microtubules - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - physiology; Primary Cell Culture; Protein Multimerization - drug effects; Protein Stability - drug effects; Rats; Rats, Sprague-Dawley; Rodents; Signal transduction; Stress, Physiological - physiology; Tretinoin - pharmacology
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00160.2011

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.