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Dual effect of the heart-targeting cytokine cardiotrophin-1 on glucose transport in cardiomyocytes

Published in Journal of Molecular and Cellular Cardiology. 2013, vol. 56, p. 106-115
Abstract Cardiotrophin-1 (CT-1) is a heart-targeting cytokine that is increased in the metabolic syndrome due to overexpression in the adipocytes. The effects of CT-1 on cardiomyocyte substrate metabolism remain unknown. We therefore determined the effects of CT-1 on basal and stimulated glucose transport in cardiomyocytes exposed to a low dose (1nM) or a high dose (10nM). Dose-response curves for insulin showed that 1nM CT-1 reduced insulin responsiveness, while 10nM CT-1 increased insulin responsiveness. In either condition insulin sensitivity was unaffected. Similarly 1nM CT-1 reduced the stimulation of glucose transport in response to metabolic stress, induced by the mitochondrial poison oligomycin, while 10nM CT-1 increased this response. Reduction of stimulated glucose transport by 1nM CT-1 was associated with overexpression of SOCS-3, a protein known to hinder proximal insulin signaling, and increased phosphorylation of STAT5. In cardiomyocytes exposed to 1nM CT-1 there was also reduced phosphorylation of Akt and AS160 in response to insulin, and of AMPK in response to oligomycin. Insulin-stimulated glucose transport and signaling were restored by inhibition of STAT5 activity. On the other hand in cardiomyocytes exposed to 10nM CT-1 there was increased phosphorylation of the AS160 and Akt in response to insulin. Most importantly, basal and oligomycin-stimulated phosphorylation of AMPK was markedly increased in cardiomyocytes exposed to 10nM CT-1. The enhancement of basal and stimulated-glucose transport was abolished in cardiomyocytes treated with the calmodulin-dependent kinase II (CaMKII) inhibitor KN93, and so was AMPK phosphorylation. This suggests that activation of CaMKII mediates activation of AMPK by a high dose of CT-1 independently of metabolic stress. Our results point to a role for CT-1 in the regulation of myocardial glucose metabolism and implicate entirely separate mechanisms in the inhibitory or stimulatory effects of CT-1 on glucose transport at low or high concentrations respectively.
Keywords AnimalsBiological TransportCell HypoxiaCells, CulturedCytokines/physiologyGlucose/metabolismGlucose Transporter Type 1/metabolismGlucose Transporter Type 4/metabolismInsulin/physiologyMaleMyocytes, Cardiac/metabolismOligomycins/pharmacologyPhosphorylationProtein Processing, Post-TranslationalPyruvate Dehydrogenase (Lipoamide)/metabolismRatsRats, Sprague-DawleySTAT5 Transcription Factor/antagonists & inhibitors/metabolismSignal TransductionStress, Physiological
PMID: 23277190
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Research group Ophtalmologie expérimentale (925)
Swiss National Science Foundation: 310000-122001
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ASRIH, Mohamed et al. Dual effect of the heart-targeting cytokine cardiotrophin-1 on glucose transport in cardiomyocytes. In: Journal of Molecular and Cellular Cardiology, 2013, vol. 56, p. 106-115. doi: 10.1016/j.yjmcc.2012.12.015 https://archive-ouverte.unige.ch/unige:88469

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Deposited on : 2016-10-28

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