Abstract
The stress-signaling protein, adenosine monophosphate-activated protein kinase (AMPK), regulates a variety of pathways in cells that 1) increase the provision and utilization of energy-providing substrates such as glucose and fatty acids, 2) inhibit energy-requiring pathways such as cholesterol biosynthesis and protein synthesis, and 3) increase the transcription of genes involved in energy metabolism and mitochondrial biogenesis. In the heart, AMPK therefore becomes very important in protecting against ischemia-reperfusion injury and regulating substrate metabolism in the face of changes in workload. This review summarizes the regulation of AMPK activity in the heart and discusses the effects of AMPK activation.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References and Recommended Reading
Carling D, Clarke PR, Zammit VA, Hardie DG: Purification and characterization of the AMP-activated protein kinase. Copurification of acetyl-CoA carboxylase kinase and 3-hydroxy-3-methylglutaryl-CoA reductase kinase activities. Eur J Biochem 1989, 186:129–136.
Bolster DR, Crozier SJ, Kimball SR, Jefferson LS: AMPactivated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling. J Biol Chem 2002, 277:23977–23980.
Horman S, Beauloye C, Vertommen D, et al.: Myocardial ischemia and increased heart work modulate the phosphorylation state of eukaryotic elongation factor-2. J Biol Chem 2003, 278:41970–41976.
Russell RR III, Bergeron R, Shulman GI, Young LH: Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR. Am J Physiol 1999, 277:H643-H649.
Russell RR III, Li J, Coven DL, et al.: AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Invest 2004, 114:465–468. In this study, transgenic mice expressing a dominant negative form of AMPK were used to demonstrate that loss of AMPK function blocks the ischemia-mediated increase in glycolysis in the heart. The inability to increase glucose uptake in response to ischemia resulted in greater myocyte damage and cell death and greater postischemic contractile dysfunction.
Hayashi T, Hirshman MF, Kurth EJ, et al.: Evidence for 5’ AMP-activated protein kinase mediation of the effect of muscle contraction on glucose transport. Diabetes 1998, 47:1369–1373.
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.
Kudo N, Barr AJ, Barr RL, 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’-AMP-activated protein kinase inhibition of acetyl-CoA carboxylase. J Biol Chem 1995, 270:17513–17520.
Kudo N, Gillespie JG, Kung L, et al.: Characterization of 5’AMP-activated protein kinase activity in the heart and its role in inhibiting acetyl-CoA carboxylase during reperfusion following ischemia. Biochim Biophys Acta 1996, 1301:67–75.
Hardie DG, Carling D: The AMP-activated protein kinase—fuel gauge of the mammalian cell? Eur J Biochem 1997, 246:259–273.
Winder WW, Hardie DG: AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am J Physiol 1999, 277:E1-E10.
Cheung PC, Salt IP, Davies SP, et al.: Characterization of AMP-activated protein kinase gamma-subunit isoforms and their role in AMP binding. Biochem J 2000, 346:659–669.
Woods A, Salt I, Scott J, et al.: The alpha1 and alpha2 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.
Salt I, Celler JW, Hawley SA, et al.: AMP-activated protein kinase: greater AMP dependence, and preferential nuclear localization, of complexes containing the alpha2 isoform. Biochem J 1998, 334:177–187.
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.
Winder WW, Holmes BF, Rubink DS, et al.: Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle. J Appl Physiol 2000, 88:2219–2226.
Bergeron R, Ren JM, Cadman KS, et al.: Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. Am J Physiol Endocrinol Metab 2001, 281:E1340-E1346.
Putman CT, Kiricsi M, Pearcey J, et al.: AMPK activation increases uncoupling protein-3 expression and mitochondrial enzyme activities in rat muscle without fibre type transitions. J Physiol 2003, 551:169–178.
Bamford JA, Lopaschuk GD, MacLean IM, et al.: Effects of chronic AICAR administration on the metabolic and contractile phenotypes of rat slow- and fast-twitch skeletal muscles. Can J Physiol Pharmacol 2003, 81:1072–1082.
Chabowski A, Momken I, Coort SL, et al.: Prolonged AMPK activation increases the expression of fatty acid transporters in cardiac myocytes and perfused hearts. Mol Cell Biochem 2006, 288:210–212.
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.
Halseth AE, Ensor NJ, White TA, et al.: Acute and chronic treatment of ob/ob and db/db mice with AICAR decreases blood glucose concentrations. Biochem Biophys Res Commun 2002, 294:798–805.
Zou L, Shen M, Arad M, et al.: N488I mutation of the gamma2-subunit results in bidirectional changes in AMPactivated protein kinase activity. Circ Res 2005, 97:323–328.
Ahmad F, Arad M, Musi N, et al.: Increased alpha2 subunit-associated AMPK activity and PRKAG2 cardiomyopathy. Circulation 2005, 112:3140–3148.
Hawley S, Boudeau J, Reid J, et al.: Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2003, 2:28. This study identified the first of several upstream kinases of AMPK. These kinases, collectively known as AMPK kinases, are responsible for the phosphorylation and activation of AMPK.
Shaw RJ, Kosmatka M, Bardeesy N, et al.: The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci U S A 2004, 101:3329–3335.
Woods A, Dickerson K, Heath R, et al.: Ca2+/calmodulindependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab 2005, 2:21–33.
Hawley SA, Pan DA, Mustard KJ, et al.: Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab 2005, 2:9–19.
Sakamoto K, Zarrinpashneh E, Budas GR, et al.: Deficiency of LKB1 in heart prevents ischemia-mediated activation of AMPKalpha2 but not AMPKalpha1. Am J Physiol Endocrinol Metab 2006, 290:E780-E788.
Davies SP, Helps NR, Cohen PT, Hardie DG: 5’-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2C alpha and native bovine protein phosphatase-2AC. FEBS Lett 1995, 377:421–425.
Coven DL, Hu X, Cong L, et al.: Physiological role of AMP-activated protein kinase in the heart: graded activation during exercise. Am J Physiol Endocrinol Metab 2003, 285:E629-E636.
Wojtaszewski JF, Nielsen P, Hansen BF, et al.: Isoformspecific and exercise intensity-dependent activation of 5’-AMP-activated protein kinase in human skeletal muscle. J Physiol 2000, 528:221–226.
Choi SL, Kim SJ, Lee KT, et al.: The regulation of AMPactivated protein kinase by H2O2. Biochem Biophys Res Commun 2001, 287:92–97.
Leon H, Atkinson LL, Sawicka J, et al.: Pyruvate prevents cardiac dysfunction and AMP-activated protein kinase activation by hydrogen peroxide in isolated rat hearts. Can J Physiol Pharmacol 2004, 82:409–416.
Barnes K, Ingram JC, Porras OH, et al.: Activation of GLUT1 by metabolic and osmotic stress: potential involvement of AMP-activated protein kinase (AMPK). J Cell Sci 2002, 115(Pt 11):2433–2442.
Corton JM, Gillespie JG, Hawley SA, Hardie DG: 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? Eur J Biochem 1995, 229:558–565.
Zhang L, Frederich M, He H, Balschi JA: Relationship between 5-aminoimidazole-4-carboxamide-ribotide and AMP-activated protein kinase activity in the perfused mouse heart. Am J Physiol Heart Circ Physiol 2006, 290:H1235-H1243.
Zhou G, Myers R, Li Y, et al.: Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001, 108:1167–1174.
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.
Fryer LG, Hajduch E, Rencurel F, et al.: Activation of glucose transport by AMP-activated protein kinase via stimulation of nitric oxide synthase. Diabetes 2000, 49:1978–1985.
Chen ZP, Mitchelhill KI, Michell BJ, et al.: AMP-activated protein kinase phosphorylation of endothelial NO synthase. FEBS Lett 1999, 443:285–289.
Li J, Hu X, Selvakumar P, et al.: Role of the nitric oxide pathway in AMPK-mediated glucose uptake and GLUT4 translocation in heart muscle. Am J Physiol Endocrinol Metab 2004, 287:E834–841. This study identified nitric oxide synthesis by eNOS as one of the downstream signals of AMPK-mediated increases in glucose uptake.
Minokoshi Y, Kim YB, Peroni OD, et al.: Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 2002, 415:339–343.
Steinberg GR, Rush JW, Dyck DJ: AMPK expression and phosphorylation are increased in rodent muscle after chronic leptin treatment. Am J Physiol Endocrinol Metab 2003, 284:E648-E654.
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.
Shibata R, Sato K, Pimentel DR, et al.: Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanisms. Nat Med 2005, 11:1096–1103.
Atkinson LL, Fischer MA, Lopaschuk GD: Leptin activates cardiac fatty acid oxidation independent of changes in the AMP-activated protein kinase-acetyl-CoA carboxylasemalonyl-CoA axis. J Biol Chem 2002, 277:29424–29430.
Baron SJ, Li J, Russell RR III, et al.: Dual mechanisms regulating AMPK kinase action in the ischemic heart. Circ Res 2005, 96:337–345. This study demonstrated the rapid time course of activation of AMPK and its upstream kinase, AMPKK, in response to myocardial ischemia. The study also demonstrated that, in contrast to AMPK, the activity of AMPKK is not affected by AMP concentrations.
Xing Y, Musi N, Fujii N, et al.: Glucose metabolism and energy homeostasis in mouse hearts overexpressing dominant negative alpha2 subunit of AMP-activated protein kinase. J Biol Chem 2003, 278:28372–28377.
Williamson JR: Glycolytic control mechanisms. II. Kinetics of intermediate changes during the aerobicanoxic transition in perfused rat heart. J Biol Chem 1966, 241:5026–5036.
Altarejos JY, Taniguchi M, Clanachan AS, Lopaschuk GD: Myocardial ischemia differentially regulates LKB1 and an alternate 5’-AMP-activated protein kinase kinase. J Biol Chem 2005, 280:183–190.
Li J, Miller EJ, Ninomiya-Tsuji J, et al.: AMP-activated protein kinase activates p38 mitogen-activated protein kinase by increasing recruitment of p38 MAPK to TAB1 in the ischemic heart. Circ Res 2005, 97:872–879. This study demonstrated that, in addition to increased NO production, AMPK activation increases p38 MAPK activity as part of the pathway that enhances glucose uptake.
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.
Kantor PF, Robertson MA, Coe JY, Lopaschuk GD: Volume overload hypertrophy of the newborn heart slows the maturation of enzymes involved in the regulation of fatty acid metabolism. J Am Coll Cardiol 1999, 33:1724–1734.
Hickson-Bick DL, Buja ML, McMillin JB: Palmitatemediated alterations in the fatty acid metabolism of rat neonatal cardiac myocytes. J Mol Cell Cardiol 2000, 32:511–519.
Clark H, Carling D, Saggerson D: Covalent activation of heart AMP-activated protein kinase in response to physiological concentrations of long-chain fatty acids. Eur J Biochem 2004, 271:2215–2224.
Gonzalez AA, Kumar R, Mulligan JD, et al.: Metabolic adaptations to fasting and chronic caloric restriction in heart, muscle, and liver do not include changes in AMPK activity. Am J Physiol Endocrinol Metab 2004, 287:E1032-E1037.
Atkinson LL, Kozak R, Kelly SE, et al.: Potential mechanisms and consequences of cardiac triacylglycerol accumulation in insulin-resistant rats. Am J Physiol Endocrinol Metab 2003, 284:E923-E930.
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.
Dagher Z, Ruderman N, Tornheim K, Ido Y: The effect of AMP-activated protein kinase and its activator AICAR on the metabolism of human umbilical vein endothelial cells. Biochem Biophys Res Commun 1999, 265:112–115.
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.
Kukidome D, Nishikawa T, Sonoda K, et al.: Activation of AMP-activated protein kinase reduces hyperglycemiainduced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. Diabetes 2006, 55:120–127.
Nagata D, Mogi M, Walsh K: AMP-activated protein kinase (AMPK) signaling in endothelial cells is essential for angiogenesis in response to hypoxic stress. J Biol Chem 2003, 278:31000–31006.
Ouchi N, Shibata R, Walsh K: AMP-activated protein kinase signaling stimulates VEGF expression and angiogenesis in skeletal muscle. Circ Res 2005, 96:838–846.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Russell, R. Stress signaling in the heart by AMP-activated protein kinase. Current Science Inc 8, 446–450 (2006). https://doi.org/10.1007/s11906-006-0021-z
Issue Date:
DOI: https://doi.org/10.1007/s11906-006-0021-z