Journal
CARDIOVASCULAR RESEARCH
Volume 76, Issue 1, Pages 71-80Publisher
OXFORD UNIV PRESS
DOI: 10.1016/j.cardiores.2007.05.004
Keywords
amino acids; glucose; growth substances; insulin; metabolism
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Funding
- NHLBI NIH HHS [T32 HL007591, R01 HL043133, 5T32 HL 07591, R01 HL043133-12, R01 HL 43133, T32 HL007591-15, R01 HL061483] Funding Source: Medline
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Objective: Insulin regulates both glucose uptake and postnatal cardiac growth. The anabolic effects of insulin are mediated by the mammalian target of rapamycin (mTOR), an evolutionarily conserved kinase which is also a convergence point between nutrient sensing and cell growth. We postulated that mTOR signalling in the heart requires the metabolism of glucose. Methods: We interrogated the insulin-mediated mTOR signalling pathway in response to different metabolic interventions regulating substrate metabolism in the isolated working rat heart and in isolated cardiomyocytes. Results: Although insulin enhanced Akt activity, phosphorylation of mTOR and its downstream targets (p70S6K and 4EBP1) required the addition of glucose. Glucose-dependent p70S6K phosphorylation was independent of the hexosamine biosynthetic pathway, the AMP kinase pathway, and the pentose phosphate pathway. However, inhibition of glycolysis downstream of hexokinase markedly enhanced p70S6K phosphorylation. Furthermore, 2-deoxyglucose activated p70S6K suggesting that phosphorylation of glucose is required for carbohydrate-mediated mTOR signalling in the heart. Lastly, we also found enhanced p70S6K phosphorylation in the hearts of diabetic rats. Conclusion: Phosphorylation of glucose is necessary for insulin-dependent mTOR activity in the heart, suggesting a link between intermediary metabolism and cardiac growth. (C) 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
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