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Scientific article
English

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

Published inJournal of Molecular and Cellular Cardiology, vol. 56, p. 106-115
Publication date2013
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
  • Animals
  • Biological Transport
  • Cell Hypoxia
  • Cells, Cultured
  • Cytokines/physiology
  • Glucose/metabolism
  • Glucose Transporter Type 1/metabolism
  • Glucose Transporter Type 4/metabolism
  • Insulin/physiology
  • Male
  • Myocytes, Cardiac/metabolism
  • Oligomycins/pharmacology
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Pyruvate Dehydrogenase (Lipoamide)/metabolism
  • Rats
  • Rats, Sprague-Dawley
  • STAT5 Transcription Factor/antagonists & inhibitors/metabolism
  • Signal Transduction
  • Stress, Physiological
Funding
  • Swiss National Science Foundation - 310000-122001
Citation (ISO format)
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
Main files (1)
Article (Published version)
accessLevelRestricted
Identifiers
ISSN of the journal0022-2828
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