Current Hypertension Reports

, Volume 5, Issue 6, pp 459–465

The role of AMP-activated protein kinase in fuel selection by the stressed heart

  • Raymond RussellIII


The heart responds to energetic stress with both acute and chronic changes in substrate metabolism. Recent work has demonstrated that the metabolic stress kinase AMP-activated protein kinase (AMPK) plays an important role in the acute regulation of carbohydrate and fatty acid metabolism in the setting of acute energetic stressors, such as ischemia/reperfusion, or increased workload, through covalent and noncovalent regulation of enzymes involved in intermediary metabolism. In addition, chronic activation of AMPK has been shown to affect the expression of key proteins regulating carbohydrate and fatty acid metabolism. Characterizing the effects of AMPK will provide important insights into its function in the normal heart and might provide new metabolic therapies for ischemic heart disease and heart failure.


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References and Recommended Reading

  1. 1.
    Woods A, Salt I, Scott J, et al.: The a1 and a2 isoforms of the AMP-activated protein kinase have similar activities in rat liver but exhibit differences in substrate specificity in vitro. FEBS Lett 1996, 397:347–351.PubMedCrossRefGoogle Scholar
  2. 2.
    Salt I, Celler J, Hawley S, et al.: AMP-activated protein kinase: greater AMP dependence, and preferential nuclear localization, of complexes containing the a2 isoform. Biochem J 1998, 334:177–187.PubMedGoogle Scholar
  3. 3.
    Cheung PC, Salt IP, Davies SP, et al.: Characterization of AMPactivated protein kinase gamma-subunit isoforms and their role in AMP binding. Biochem J 2000, 346:659–669.PubMedCrossRefGoogle Scholar
  4. 4.
    Hardie D, Carling D: The AMP-activated protein kinase: fuel gauge of the mammalian cell? Eur J Biochem 1997, 246:259–273.PubMedCrossRefGoogle Scholar
  5. 5.
    Marsin AS, Bertrand L, Rider MH, et al.: Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Curr Biol 2000, 10:1247–1255.PubMedCrossRefGoogle Scholar
  6. 6.
    Stein SC, Woods A, Jones NA, et al.: The regulation of AMPactivated protein kinase by phosphorylation. Biochem J 2000, 345:437–443.PubMedCrossRefGoogle Scholar
  7. 7.
    Davies S, Helps N, Cohen P, Hardie D: 5’-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. FEBS Lett 1995, 377:421–425.PubMedCrossRefGoogle Scholar
  8. 8.
    Frederich M, Balschi JA: The relationship between AMPactivated protein kinase activity and AMP concentration in the isolated perfused rat heart. J Biol Chem 2002, 277:1928–1932.PubMedCrossRefGoogle Scholar
  9. 9.
    Choi SL, Kim SJ, Lee KT, et al.: The regulation of AMP-activated protein kinase by H2O2. Biochem Biophys Res Commun 2001, 287:92–97.PubMedCrossRefGoogle Scholar
  10. 10.
    Yamauchi T, Kamon J, Minokoshi Y, et al.: Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 2002, 8:1288–1295.PubMedCrossRefGoogle Scholar
  11. 11.
    Minokoshi Y, Kim YB, Peroni OD, et al.: Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 2002, 415:339–343.PubMedCrossRefGoogle Scholar
  12. 12.
    Fryer LG, Parbu-Patel A, Carling D: The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J Biol Chem 2002, 277:25226–25232.PubMedCrossRefGoogle Scholar
  13. 13.
    Bergeron R, Previs SF, Cline GW, et al.: Effect of 5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside infusion on in vivo glucose and lipid metabolism in lean and obese Zucker rats. Diabetes 2001, 50:1076–1082. This study demonstrated that acute activation of AMPK can increase whole-body glucose uptake in the setting of insulin resistance, leading to other studies of the effect of chronic AMPK activation on insulin resistance and non-insulin-dependent diabetes mellitus.PubMedCrossRefGoogle Scholar
  14. 14.
    Buhl ES, Jessen N, Pold R, et al.: Long-term AICAR administration reduces metabolic disturbances and lowers blood pressure in rats displaying features of the insulin resistance syndrome. Diabetes 2002, 51:2199–2206. This study demonstrated that chronic AMPK activation might improve both the insulin resistance and hemodynamic abnormalities of the metabolic syndrome, an entity with significant associated cardiovascular morbidity.PubMedCrossRefGoogle Scholar
  15. 15.
    Carling D, Zammit V, Hardie DG: A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis. FEBS Lett 1987, 223:217–222.PubMedCrossRefGoogle Scholar
  16. 16.
    Russell R, Renfu Y, Caplan M, et al.: Additive effects of hyperinsulinemia and ischemia on myocardial GLUT1 and GLUT4 translocation in vivo. Circulation 1998, 98:2180–2186.PubMedGoogle Scholar
  17. 17.
    Young L, Renfu Y, Russell R, et al.: Low-flow ischemia leads to translocation of canine heart GLUT-4 and GLUT-1 glucose transporters to the sarcolemma in vivo. Circulation 1997, 95:415–422.PubMedGoogle Scholar
  18. 18.
    Russell R, Bergeron R, Shulman G, Young L: Translocation of myocardial GLUT4 and increased glucose uptake through activation of AMP-activated protein kinase by AICAR. Am J Physiol 1999, 277:H643-H649.PubMedGoogle Scholar
  19. 19.
    Mu J, Brozinick JT Jr, Valladares O, et al.: A role for AMPactivated protein kinase in contraction- and hypoxiaregulated glucose transport in skeletal muscle. Mol Cell 2001, 7:1085–1094.PubMedCrossRefGoogle Scholar
  20. 20.
    Depré C, Rider M, Veitch K, Hue L: Role of fructose 2,6-bisphosphate in the control of heart glycolysis. J Biol Chem 1993, 268:13274–13279.PubMedGoogle Scholar
  21. 21.
    Ido Y, Carling D, Ruderman N: Hyperglycemia-induced apoptosis in human umbilical vein endothelial cells: inhibition by the AMP-activated protein kinase activation. Diabetes 2002, 51:159–167. The results of this study build on earlier studies demonstrating that AMPK can regulate intermediary metabolism in endothelial cells and support the role of AMPK in protecting against the complications of insulin resistance and diabetes. Furthermore, the role of AMPK in preventing apoptosis is demonstrated.PubMedCrossRefGoogle Scholar
  22. 22.
    Kudo N, Barr A, Barr R, et al.: High rates of fatty acid oxidation during reperfusion of ischemic hearts are associated with a decrease in malonyl-CoA levels due to an increase in 5’-AMPactivated protein kinase inhibition of acetyl-CoA carboxylase. J Biol Chem 1995, 270:17513–17520.PubMedCrossRefGoogle Scholar
  23. 23.
    Park H, Kaushik VK, Constant S, et al.: Coordinate regulation of malonyl-CoA decarboxylase, sn-glycerol-3-phosphate acyltransferase, and acetyl-CoA carboxylase by AMP-activated protein kinase in rat tissues in response to exercise. J Biol Chem 2002, 277:32571–32577.PubMedCrossRefGoogle Scholar
  24. 24.
    Lopaschuk G, Wambolt R, Barr R: An imbalance between glycolysis and glucose oxidation is a possible explanation for the detrimental effects of high levels of fatty acids during aerobic reperfusion of ischemic hearts. J Pharmacol Exp Ther 1993, 264:135–144.PubMedGoogle Scholar
  25. 25.
    McCormack J, Barr R, Wolff A, Lopaschuk G: Ranolazine stimulates glucose oxidation in normoxic, ischemic, and reperfused ischemic rat hearts. Circulation 1996, 93:135–142.PubMedGoogle Scholar
  26. 26.
    Goodwin G, Ahmad F, Taegtmeyer H: Preferential oxidation of glycogen in isolated working rat heart. J Clin Invest 1996, 97:1409–1416.PubMedCrossRefGoogle Scholar
  27. 27.
    Zaninetti D, Greco-Perotto R, Jeanrenaud B: Heart glucose transport and transporters in rat heart: regulation by insulin, workload and glucose. Diabetologia 1988, 31:108–113.PubMedCrossRefGoogle Scholar
  28. 28.
    Coven DL, Hu X, Cong L, et al.: Physiologic role of AMP-activated protein kinase (AMPK) in the heart: graded activation during exercise. Am J Physiol 2003, In press. This study emphasizes the importance of AMPK in the regulation of metabolic responses to physiologic stimuli in the heart (ie, exercise) rather than in response to pathologic changes in the heart (ie, ischemia, chronic pressure overload).Google Scholar
  29. 29.
    Ingwall JS: Is creatine kinase a target for AMP-activated protein kinase in the heart? J Mol Cell Cardiol 2002, 34:1111–1120.PubMedCrossRefGoogle Scholar
  30. 30.
    Dagher Z, Ruderman N, Tornheim K, Ido Y: Acute regulation of fatty acid oxidation and AMP-activated protein kinase in human umbilical vein endothelial cells. Circ Res 2001, 88:1276–1282. This study demonstrates that endothelial cell metabolism can respond to AMPK stimulation and suggests that metabolic stress might regulate endothelial cell metabolism.PubMedGoogle Scholar
  31. 31.
    Chen Z, Mitchelhill K, Michell B, et al.: AMP-activated protein kinase phosphorylation of endothelial NO synthase. FEBS Lett 1999, 443:285–289.PubMedCrossRefGoogle Scholar
  32. 32.
    McGee SL, Howlett KF, Starkie RL, et al.: Exercise increases nuclear AMPK a2 in human skeletal muscle. Diabetes 2003, 52:926–928.PubMedCrossRefGoogle Scholar
  33. 33.
    Yang W, Hong YH, Shen X-Q, et al.: Regulation of transcription by AMP-activated protein kinase. J Biol Chem 2001, 276:38341–38344.PubMedCrossRefGoogle Scholar
  34. 34.
    Holmes BF, Kurth-Kraczek EJ, Winder WW: Chronic activation of 5’-AMP-activated protein kinase increases GLUT-4, hexokinase, and glycogen in muscle. J Appl Physiol 1999, 87:1990–1995.PubMedGoogle Scholar
  35. 35.
    Winder WW, Holmes BF, Rubink DS, et al.: Activation of AMPactivated protein kinase increases mitochondrial enzymes in skeletal muscle. J Appl Physiol 2000, 88:2219–2226.PubMedGoogle Scholar
  36. 36.
    Stoppani J, Hildebrandt AL, Sakamoto K, et al.: AMP-activated protein kinase activates transcription of the UCP3 and HKII genes in rat skeletal muscle. Am J Physiol 2002, 283:E1239-E1248.Google Scholar
  37. 37.
    Pedersen SB, Lund S, Buhl ES, Richelsen B: Insulin and contraction directly stimulate UCP2 and UCP3 mRNA expression in rat skeletal muscle in vitro. Biochem Biophys Res Commun 2001, 283:19–25.PubMedCrossRefGoogle Scholar
  38. 38.
    Bergeron R, Ren JM, Cadman KS, et al.: Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. Am J Physiol 2001, 281:E1340-E1346.Google Scholar
  39. 39.
    Zong H, Ren JM, Young LH, et al.: AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci U S A 2002, 99:15983–15987.PubMedCrossRefGoogle Scholar
  40. 40.
    Tian R, Musi N, D’Agostino J, et al.: Increased adenosine monophosphate-activated protein kinase activity in rat hearts with pressure-overload hypertrophy. Circulation 2001, 104:1664–1669. This study was the first to demonstrate that chronic metabolic stress in the heart increases AMPK activation.PubMedGoogle Scholar
  41. 41.
    Razeghi P, Young ME, Alcorn JL, et al.: Metabolic gene expression in fetal and failing human heart. Circulation 2001, 104:2923–2931.PubMedGoogle Scholar
  42. 42.
    Davila-Roman VG, Vedala G, Herrero P, et al.: Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy. J Am Coll Cardiol 2002, 40:271–277.PubMedCrossRefGoogle Scholar
  43. 43.
    Neubauer S, Horn M, Cramer M, et al.: Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation 1997, 96:2190–2196.PubMedGoogle Scholar
  44. 44.
    Makinde A, Gamble J, Lopaschuk G: Upregulation of 5’-AMPactivated protein kinase is responsible for the increase in myocardial fatty acid oxidation rates following birth in the newborn rabbit. Circ Res 1997, 80:482–489.PubMedGoogle Scholar
  45. 45.
    Ponticos M, Lu Q, Morgan J, et al.: Dual regulation of the AMP-activated protein kinase provides a novel mechanism for the control of creatine kinase in skeletal muscle. EMBO J 1998, 17:1688–1699.PubMedCrossRefGoogle Scholar
  46. 46.
    Gollob MH, Green MS, Tang AS, et al.: Identification of a gene responsible for familial Wolff-Parkinson-White syndrome. N Engl J Med 2001, 344:1823–1831. This study was the first reporting that mutations in the γ subunit of AMPK could lead to a cardiac phenotype in patients with evidence of hypertrophy and preexcitation.PubMedCrossRefGoogle Scholar
  47. 47.
    Arad M, Benson DW, Perez-Atayde AR, et al.: Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. J Clin Invest 2002, 109:357–362. This study demonstrated that the γ subunit mutation of AMPK associated with the development of hypertrophic cardiomyopathy also causes excessive glycogen deposition in cardiac myocytes.PubMedCrossRefGoogle Scholar
  48. 48.
    Arad M, Moskowitz IP, Patel VV, et al.: Transgenic mice overexpressing mutant PRKAG2 define the cause of Wolff-Parkinson-White syndrome in glycogen storage cardiomyopathy. Circulation 2003, 107:2850–2856. This study demonstrated that the accumulation of glycogen in cardiac myocytes overexpressing the γ subunit mutation most likely causes preexcitation by disrupting the annulus fibrosis.PubMedCrossRefGoogle Scholar
  49. 49.
    Light PE, Wallace CHR, Dyck JRB: Constitutively active adenosine monophosphate-activated protein kinase regulates voltagegated sodium channels in ventricular myocytes. Circulation 2003, 107:1962–1965.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2003

Authors and Affiliations

  • Raymond RussellIII
    • 1
  1. 1.Section of Cardiovascular MedicineYale University School of MedicineNew HavenUSA

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