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

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Abstract

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. 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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  4. Hardie D, Carling D: The AMP-activated protein kinase: fuel gauge of the mammalian cell? Eur J Biochem 1997, 246:259–273.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  6. Stein SC, Woods A, Jones NA, et al.: The regulation of AMPactivated protein kinase by phosphorylation. Biochem J 2000, 345:437–443.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  26. Goodwin G, Ahmad F, Taegtmeyer H: Preferential oxidation of glycogen in isolated working rat heart. J Clin Invest 1996, 97:1409–1416.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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).

  29. Ingwall JS: Is creatine kinase a target for AMP-activated protein kinase in the heart? J Mol Cell Cardiol 2002, 34:1111–1120.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  31. Chen Z, Mitchelhill K, Michell B, et al.: AMP-activated protein kinase phosphorylation of endothelial NO synthase. FEBS Lett 1999, 443:285–289.

    Article  PubMed  CAS  Google Scholar 

  32. McGee SL, Howlett KF, Starkie RL, et al.: Exercise increases nuclear AMPK a2 in human skeletal muscle. Diabetes 2003, 52:926–928.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  41. Razeghi P, Young ME, Alcorn JL, et al.: Metabolic gene expression in fetal and failing human heart. Circulation 2001, 104:2923–2931.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

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Russell, R. The role of AMP-activated protein kinase in fuel selection by the stressed heart. Current Science Inc 5, 459–465 (2003). https://doi.org/10.1007/s11906-003-0053-6

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