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AMP-Activated Protein Kinase: A Metabolic Stress Sensor in the Heart

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Cardiac Cytoarchitecture

Abstract

AMP-activated protein kinase (AMPK) is a central cellular signaling hub that senses and responds to different kinds of stress, mainly those triggered by impaired cellular energy homeostasis. Since this is of major importance for the heart, the kinase plays important roles for cardiovascular function in human health and disease. Here, we review recent progress on the molecular structure and role of AMPK and summarize regulation and biological actions of the AMPK pathway, in particular those relevant for the heart. Activation of the kinase is involved in the myocardial response to ischemia, pressure overload, and heart failure. Pharmacological activation of AMPK may prove to be a useful therapeutic strategy in the treatment of these pathologies.

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References

  • Abbott Laboratories (2005) Preparation of substituted thieno[2,3-b]pyridones as activators for AMP-activated kinase for the treatment of diabetes and obesity. US20050038068

    Google Scholar 

  • Allard MF, Parsons HL, Saeedi R, Wambolt RB, Brownsey R (2007) AMPK and metabolic adaptation by the heart to pressure overload. Am J Physiol Heart Circ Physiol 292:H140–H148

    CAS  PubMed  Google Scholar 

  • Amodeo GA, Rudolph MJ, Tong L (2007) Crystal structure of the heterotrimer core of Saccharomyces cerevisiae AMPK homologue SNF1. Nature 449:492–495

    CAS  PubMed  Google Scholar 

  • Andersen MN, Rasmussen HB (2012) AMPK: a regulator of ion channels. Commun Integr Biol 5:480–484

    PubMed Central  CAS  PubMed  Google Scholar 

  • Arad M, Seidman CE, Seidman JG (2007) AMP-activated protein kinase in the heart: role during health and disease. Circ Res 100:474–488

    CAS  PubMed  Google Scholar 

  • Atkinson DE (1968) The energy charge of the adenylate pool as a regulatory parameter. Interaction with feedback modifiers. Biochemistry (Mosc) 7:4030–4034

    CAS  Google Scholar 

  • Ballantyne CM, Davidson MH, Macdougall DE, Bays HE, Dicarlo LA, Rosenberg NL, Margulies J, Newton RS (2013) Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. J Am Coll Cardiol 62:1154–1162

    CAS  PubMed  Google Scholar 

  • Banerjee RR, Rangwala SM, Shapiro JS, Rich AS, Rhoades B, Qi Y, Wang J, Rajala MW, Pocai A, Scherer PE et al (2004) Regulation of fasted blood glucose by resistin. Science 303:1195–1198

    CAS  PubMed  Google Scholar 

  • Barazzoni R, Bosutti A, Stebel M, Cattin MR, Roder E, Visintin L, Cattin L, Biolo G, Zanetti M, Guarnieri G (2005) Ghrelin regulates mitochondrial-lipid metabolism gene expression and tissue fat distribution in liver and skeletal muscle. Am J Physiol Endocrinol Metab 288:E228–E235

    CAS  PubMed  Google Scholar 

  • Barnes K, Ingram JC, Porras OH, Barros LF, Hudson ER, Fryer LGD, Foufelle F, Carling D, Hardie DG, Baldwin SA (2002) Activation of GLUT1 by metabolic and osmotic stress: potential involvement of AMP-activated protein kinase (AMPK). J Cell Sci 115:2433–2442

    CAS  PubMed  Google Scholar 

  • Bar-Peled L, Sabatini DM (2014) Regulation of mTORC1 by amino acids. Trends Cell Biol 24:400–406

    CAS  PubMed  Google Scholar 

  • Baskin KK, Taegtmeyer H (2011) An expanded role for AMP-activated protein kinase: regulator of myocardial protein degradation. Trends Cardiovasc Med 21:124–127

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bateman A (1997) The structure of a domain common to archaebacteria and the homocystinuria disease protein. Trends Biochem Sci 22:12–13

    CAS  PubMed  Google Scholar 

  • Beg ZH, Stonik JA, Brewer HB (1980) In vitro and in vivo phosphorylation of rat liver 3-hydroxy-3-methylglutaryl coenzyme A reductase and its modulation by glucagon. J Biol Chem 255:8541–8545

    CAS  PubMed  Google Scholar 

  • Behrends C, Sowa ME, Gygi SP, Harper JW (2010) Network organization of the human autophagy system. Nature 466:68–76

    PubMed Central  CAS  PubMed  Google Scholar 

  • Benziane B, Björnholm M, Lantier L, Viollet B, Zierath JR, Chibalin AV (2009) AMP-activated protein kinase activator A-769662 is an inhibitor of the Na(+)-K(+)-ATPase. Am J Physiol Cell Physiol 297:C1554–C1566

    CAS  PubMed  Google Scholar 

  • Bouhidel O, Pons S, Souktani R, Zini R, Berdeaux A, Ghaleh B (2008) Myocardial ischemic postconditioning against ischemia-reperfusion is impaired in ob/ob mice. Am J Physiol Heart Circ Physiol 295:H1580–H1586

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bultot L, Guigas B, Von Wilamowitz‑Moellendorff A, Maisin L, Vertommen D, Hussain N, Beullens M, Guinovart JJ, Foretz M, Viollet B et al (2012) AMP-activated protein kinase phosphorylates and inactivates liver glycogen synthase. Biochem J 443:193–203

    CAS  PubMed  Google Scholar 

  • Burwinkel B, Scott JW, Bührer C, van Landeghem FKH, Cox GF, Wilson CJ, Grahame Hardie D, Kilimann MW (2005) Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the gamma 2-subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency. Am J Hum Genet 76:1034–1049

    PubMed Central  CAS  PubMed  Google Scholar 

  • Cai XJ, Chen L, Li L, Feng M, Li X, Zhang K, Rong YY, Hu XB, Zhang MX, Zhang Y et al (2010) Adiponectin inhibits lipopolysaccharide-induced adventitial fibroblast migration and transition to myofibroblasts via AdipoR1-AMPK-iNOS pathway. Mol Endocrinol 24:218–228

    CAS  PubMed  Google Scholar 

  • Calabrese MF, Rajamohan F, Harris MS, Caspers NL, Magyar R, Withka JM, Wang H, Borzilleri KA, Sahasrabudhe PV, Hoth LR et al (2014) Structural basis for AMPK activation: natural and synthetic ligands regulate kinase activity from opposite poles by different molecular mechanisms. Structure 1993(22):1161–1172

    Google Scholar 

  • Calvert JW, Gundewar S, Jha S, Greer JJ, Bestermann WH, Tian R, Lefer DJ (2008) Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS-mediated signaling. Diabetes 57:696–705

    CAS  PubMed  Google Scholar 

  • Carey AL, Steinberg GR, Macaulay SL, Thomas WG, Holmes AG, Ramm G, Prelovsek O, Hohnen-Behrens C, Watt MJ, James DE et al (2006) Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 55:2688–2697

    CAS  PubMed  Google Scholar 

  • Carling D (2004) The AMP-activated protein kinase cascade–a unifying system for energy control. Trends Biochem Sci 29:18–24

    CAS  PubMed  Google Scholar 

  • Chen Z-P, Stephens TJ, Murthy S, Canny BJ, Hargreaves M, Witters LA, Kemp BE, McConell GK (2003) Effect of exercise intensity on skeletal muscle AMPK signaling in humans. Diabetes 52:2205–2212

    CAS  PubMed  Google Scholar 

  • Chen L, Jiao Z-H, Zheng L-S, Zhang Y-Y, Xie S-T, Wang Z-X, Wu J-W (2009) Structural insight into the autoinhibition mechanism of AMP-activated protein kinase. Nature 459:1146–1149

    CAS  PubMed  Google Scholar 

  • Chen L, Wang J, Zhang Y-Y, Yan SF, Neumann D, Schlattner U, Wang Z-X, Wu J-W (2012) AMP-activated protein kinase undergoes nucleotide-dependent conformational changes. Nat Struct Mol Biol 19:716–718

    CAS  PubMed  Google Scholar 

  • Chen L, Xin F-J, Wang J, Hu J, Zhang Y-Y, Wan S, Cao L-S, Lu C, Li P, Yan SF et al (2013) Conserved regulatory elements in AMPK. Nature 498:E8–E10

    CAS  PubMed  Google Scholar 

  • Clark H, Carling D, Saggerson D (2004) Covalent activation of heart AMP-activated protein kinase in response to physiological concentrations of long-chain fatty acids. Eur J Biochem 271:2215–2224

    CAS  PubMed  Google Scholar 

  • Cool B, Zinker B, Chiou W, Kifle L, Cao N, Perham M, Dickinson R, Adler A, Gagne G, Iyengar R et al (2006) Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab 3:403–416

    CAS  PubMed  Google Scholar 

  • Coven DL, Hu X, Cong L, Bergeron R, Shulman GI, Hardie DG, Young LH (2003) Physiological role of AMP-activated protein kinase in the heart: graded activation during exercise. Am J Physiol Endocrinol Metab 285:E629–E636

    CAS  PubMed  Google Scholar 

  • Crute BE, Seefeld K, Gamble J, Kemp BE, Witters LA (1998) Functional domains of the alpha1 catalytic subunit of the AMP-activated protein kinase. J Biol Chem 273:35347–35354

    CAS  PubMed  Google Scholar 

  • Curigliano G, Cardinale D, Suter T, Plataniotis G, de Azambuja E, Sandri MT, Criscitiello C, Goldhirsch A, Cipolla C, Roila F et al (2012) Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol 23(7):vii155–vii166

    PubMed  Google Scholar 

  • Davies SP, Helps NR, Cohen PT, Hardie DG (1995) 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 377:421–425

    CAS  PubMed  Google Scholar 

  • Davies JK, Wells DJ, Liu K, Whitrow HR, Daniel TD, Grignani R, Lygate CA, Schneider JE, Noel G, Watkins H et al (2006) Characterization of the role of gamma2 R531G mutation in AMP-activated protein kinase in cardiac hypertrophy and Wolff-Parkinson-White syndrome. Am J Physiol Heart Circ Physiol 290:H1942–H1951

    CAS  PubMed  Google Scholar 

  • D’Eon TM, Souza SC, Aronovitz M, Obin MS, Fried SK, Greenberg AS (2005) Estrogen regulation of adiposity and fuel partitioning. Evidence of genomic and non-genomic regulation of lipogenic and oxidative pathways. J Biol Chem 280:35983–35991

    PubMed  Google Scholar 

  • Djouder N, Tuerk RD, Suter M, Salvioni P, Thali RF, Scholz R, Vaahtomeri K, Auchli Y, Rechsteiner H, Brunisholz RA et al (2010) PKA phosphorylates and inactivates AMPKalpha to promote efficient lipolysis. EMBO J 29:469–481

    PubMed Central  CAS  PubMed  Google Scholar 

  • Dolinsky VW, Chan AY, Robillard Frayne I, Light PE, Des Rosiers C, Dyck JR (2009) Resveratrol prevents the prohypertrophic effects of oxidative stress on LKB1. Circulation 119:1643–1652

    CAS  PubMed  Google Scholar 

  • Du J, Guan T, Zhang H, Xia Y, Liu F, Zhang Y (2008) Inhibitory crosstalk between ERK and AMPK in the growth and proliferation of cardiac fibroblasts. Biochem Biophys Res Commun 368:402–407

    CAS  PubMed  Google Scholar 

  • Ducommun S, Ford RJ, Bultot L, Deak M, Bertrand L, Kemp BE, Steinberg GR, Sakamoto K (2014) Enhanced activation of cellular AMPK by dual-small molecule treatment: AICAR and A769662. Am J Physiol Endocrinol Metab 306:E688–E696

    PubMed Central  CAS  PubMed  Google Scholar 

  • Dyck JR, Lopaschuk GD (2006) AMPK alterations in cardiac physiology and pathology: enemy or ally? J Physiol 574:95–112

    PubMed Central  CAS  PubMed  Google Scholar 

  • El-Mir MY, Nogueira V, Fontaine E, Avéret N, Rigoulet M, Leverve X (2000) Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 275:223–228

    CAS  PubMed  Google Scholar 

  • Eschenhagen T, Force T, Ewer MS, de Keulenaer GW, Suter TM, Anker SD, Avkiran M, de Azambuja E, Balligand J-L, Brutsaert DL et al (2011) Cardiovascular side effects of cancer therapies: a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 13:1–10

    PubMed  Google Scholar 

  • Esteve-Puig R, Canals F, Colome N, Merlino G, Recio JA (2009) Uncoupling of the LKB1-AMPKalpha energy sensor pathway by growth factors and oncogenic BRAF. PLoS One 4:e4771

    PubMed Central  PubMed  Google Scholar 

  • Ewer MS, Ewer SM (2010) Cardiotoxicity of anticancer treatments: what the cardiologist needs to know. Nat Rev Cardiol 7:564–575

    PubMed  Google Scholar 

  • Ferrer A, Caelles C, Massot N, Hegardt FG (1985) Activation of rat liver cytosolic 3-hydroxy-3-methylglutaryl Coenzyme A reductase kinase by adenosine 5′-monophosphate. Biochem Biophys Res Commun 132:497–504

    CAS  PubMed  Google Scholar 

  • Fogarty S, Hawley SA, Green KA, Saner N, Mustard KJ, Hardie DG (2010) Calmodulin-dependent protein kinase kinase-beta activates AMPK without forming a stable complex: synergistic effects of Ca2+ and AMP. Biochem J 426:109–118

    PubMed Central  CAS  PubMed  Google Scholar 

  • Forcet C, Billaud M (2007) Dialogue between LKB1 and AMPK: a hot topic at the cellular pole. Sci STKE 2007:pe51

    PubMed  Google Scholar 

  • Frederich M, Zhang L, Balschi JA (2005) Hypoxia and AMP independently regulate AMP-activated protein kinase activity in heart. Am J Physiol Heart Circ Physiol 288:H2412–H2421

    CAS  PubMed  Google Scholar 

  • Gabrielson K, Bedja D, Pin S, Tsao A, Gama L, Yuan B, Muratore N (2007) Heat shock protein 90 and ErbB2 in the cardiac response to doxorubicin injury. Cancer Res 67:1436–1441

    CAS  PubMed  Google Scholar 

  • Garcia-Haro L, Garcia-Gimeno MA, Neumann D, Beullens M, Bollen M, Sanz P (2010) The PP1-R6 protein phosphatase holoenzyme is involved in the glucose-induced dephosphorylation and inactivation of AMP-activated protein kinase, a key regulator of insulin secretion, in MIN6 beta cells. FASEB J 24:5080–5091

    PubMed  Google Scholar 

  • Gianni L, Herman EH, Lipshultz SE, Minotti G, Sarvazyan N, Sawyer DB (2008) Anthracycline cardiotoxicity: from bench to bedside. J Clin Oncol 26:3777–3784

    PubMed Central  PubMed  Google Scholar 

  • Giordanetto F, Karis D (2012) Direct AMP-activated protein kinase activators: a review of evidence from the patent literature. Expert Opin Ther Pat 22:1467–1477

    CAS  PubMed  Google Scholar 

  • Giri S, Nath N, Smith B, Viollet B, Singh AK, Singh I (2004) 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside inhibits proinflammatory response in glial cells: a possible role of AMP-activated protein kinase. J Neurosci 24:479–487

    CAS  PubMed  Google Scholar 

  • Gledhill JR, Montgomery MG, Leslie AGW, Walker JE (2007) Mechanism of inhibition of bovine F1-ATPase by resveratrol and related polyphenols. Proc Natl Acad Sci U S A 104:13632–13637

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gómez-Galeno JE, Dang Q, Nguyen TH, Boyer SH, Grote MP, Sun Z, Chen M, Craigo WA, van Poelje PD, MacKenna DA et al (2010) A potent and selective AMPK activator that inhibits de novo lipogenesis. ACS Med Chem Lett 1:478–482

    PubMed Central  PubMed  Google Scholar 

  • Goransson O, McBride A, Hawley SA, Ross FA, Shpiro N, Foretz M, Viollet B, Hardie DG, Sakamoto K (2007) Mechanism of action of A-769662, a valuable tool for activation of AMP-activated protein kinase. J Biol Chem 282:32549–32560

    PubMed Central  PubMed  Google Scholar 

  • Gowans GJ, Hawley SA, Ross FA, Hardie DG (2013) AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation. Cell Metab 18:556–566

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gratia S, Kay L, Potenza L, Seffouh A, Novel-Chate V, Schnebelen C, Sestili P, Schlattner U, Tokarska-Schlattner M (2012) Inhibition of AMPK signalling by doxorubicin: at the crossroads of the cardiac responses to energetic, oxidative, and genotoxic stress. Cardiovasc Res 95:290–299

    CAS  PubMed  Google Scholar 

  • Gu Y, Zhang Y, Shi X, Li X, Hong J, Chen J, Gu W, Lu X, Xu G, Ning G (2010) Effect of traditional Chinese medicine berberine on type 2 diabetes based on comprehensive metabonomics. Talanta 81:766–772

    CAS  PubMed  Google Scholar 

  • Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30:214–226

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hahn-Windgassen A, Nogueira V, Chen CC, Skeen JE, Sonenberg N, Hay N (2005) Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. J Biol Chem 280:32081–32089

    CAS  PubMed  Google Scholar 

  • Han Y, Wang Q, Song P, Zhu Y, Zou M-H (2010) Redox regulation of the AMP-activated protein kinase. PLoS One 5:e15420

    PubMed Central  PubMed  Google Scholar 

  • Hanks SK, Quinn AM, Hunter T (1988) The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 241:42–52

    CAS  PubMed  Google Scholar 

  • Hardie DG (2007) AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8:774–785

    CAS  PubMed  Google Scholar 

  • Hardie DG (2008a) AMPK: a key regulator of energy balance in the single cell and the whole organism. Int J Obes 32:S7–S12

    CAS  Google Scholar 

  • Hardie DG (2008b) Role of AMP-activated protein kinase in the metabolic syndrome and in heart disease. FEBS Lett 582:81–89

    CAS  PubMed  Google Scholar 

  • Hardie DG (2011) AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev 25:1895–1908

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hardie DG (2014a) AMP-activated protein kinase: maintaining energy homeostasis at the cellular and whole-body levels. Annu Rev Nutr 34:31–55

    CAS  PubMed  Google Scholar 

  • Hardie DG (2014b) AMPK: positive and negative regulation, and its role in whole-body energy homeostasis. Curr Opin Cell Biol 33C:1–7

    PubMed  Google Scholar 

  • Hardie DG (2014c) AMPK—sensing energy while talking to other signaling pathways. Cell Metab 20:939–952

    CAS  PubMed  Google Scholar 

  • Hardie DG, Ashford MLJ (2014) AMPK: regulating energy balance at the cellular and whole body levels. Physiology 29:99–107

    PubMed Central  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Hardie DG, Hawley SA (2001) AMP-activated protein kinase: the energy charge hypothesis revisited. BioEssays News Rev Mol Cell Dev Biol 23:1112–1119

    CAS  Google Scholar 

  • Hardie DG, Sakamoto K (2006) AMPK: a key sensor of fuel and energy status in skeletal muscle. Physiology (Bethesda) 21:48–60

    CAS  Google Scholar 

  • Hardie DG, Salt IP, Hawley SA, Davies SP (1999) AMP-activated protein kinase: an ultrasensitive system for monitoring cellular energy charge. Biochem J 338(Pt 3):717–722

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hardie DG, Scott JW, Pan DA, Hudson ER (2003) Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett 546:113–120

    CAS  PubMed  Google Scholar 

  • Hardie DG, Carling D, Gamblin SJ (2011) AMP-activated protein kinase: also regulated by ADP? Trends Biochem Sci 36:470–477

    CAS  PubMed  Google Scholar 

  • Hardie DG, Ross FA, Hawley SA (2012a) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13:251–262

    CAS  PubMed  Google Scholar 

  • Hardie DG, Ross FA, Hawley SA (2012b) AMP-activated protein kinase: a target for drugs both ancient and modern. Chem Biol 19:1222–1236

    CAS  PubMed  Google Scholar 

  • Haruta T, Uno T, Kawahara J, Takano A, Egawa K, Sharma PM, Olefsky JM, Kobayashi M (2000) A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1. Mol Endocrinol (Baltimore, MD) 14:783–794

    CAS  Google Scholar 

  • Hawley SA, Davison M, Woods A, Davies SP, Beri RK, Carling D, Hardie DG (1996) Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J Biol Chem 271:27879–27887

    CAS  PubMed  Google Scholar 

  • Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Makela TP, Alessi DR, Hardie DG (2003) 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 2:28

    PubMed Central  PubMed  Google Scholar 

  • Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM, Frenguelli BG, Hardie DG (2005) Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab 2:9–19

    CAS  PubMed  Google Scholar 

  • Hawley SA, Ross FA, Chevtzoff C, Green KA, Evans A, Fogarty S, Towler MC, Brown LJ, Ogunbayo OA, Evans AM et al (2010) Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab 11:554–565

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hawley SA, Fullerton MD, Ross FA, Schertzer JD, Chevtzoff C, Walker KJ, Peggie MW, Zibrova D, Green KA, Mustard KJ et al (2012) The ancient drug salicylate directly activates AMP-activated protein kinase. Science 336:918–922

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hawley SA, Ross FA, Gowans GJ, Tibarewal P, Leslie NR, Hardie DG (2014) Phosphorylation by Akt within the ST loop of AMPK-alpha1 down-regulates its activation in tumour cells. Biochem J 459:275–287

    PubMed Central  CAS  PubMed  Google Scholar 

  • Herrero‐Martín G, Høyer‐Hansen M, García‐García C, Fumarola C, Farkas T, López‐Rivas A, Jäättelä M (2009) TAK1 activates AMPK‐dependent cytoprotective autophagy in TRAIL‐treated epithelial cells. EMBO J 28:677–685

    PubMed Central  PubMed  Google Scholar 

  • Horie T, Ono K, Nishi H, Nagao K, Kinoshita M, Watanabe S, Kuwabara Y, Nakashima Y, Takanabe-Mori R, Nishi E et al (2010) Acute doxorubicin cardiotoxicity is associated with miR-146a-induced inhibition of the neuregulin-ErbB pathway. Cardiovasc Res 87:656–664

    PubMed Central  CAS  PubMed  Google Scholar 

  • Horman S, Vertommen D, Heath R, Neumann D, Mouton V, Woods A, Schlattner U, Wallimann T, Carling D, Hue L et al (2006) Insulin antagonizes ischemia-induced Thr172 phosphorylation of AMP-activated protein kinase alpha-subunits in heart via hierarchical phosphorylation of Ser485/491. J Biol Chem 281:5335–5340

    CAS  PubMed  Google Scholar 

  • Houde VP, Ritorto MS, Gourlay R, Varghese J, Davies P, Shpiro N, Sakamoto K, Alessi DR (2014) Investigation of LKB1 Ser431 phosphorylation and Cys433 farnesylation using mouse knockin analysis reveals an unexpected role of prenylation in regulating AMPK activity. Biochem J 458:41–56

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hu X, Xu X, Lu Z, Zhang P, Fassett J, Zhang Y, Xin Y, Hall JL, Viollet B, Bache RJ et al (2011) AMP activated protein kinase-alpha2 regulates expression of estrogen-related receptor-alpha, a metabolic transcription factor related to heart failure development. Hypertension 58:696–703

    PubMed Central  CAS  PubMed  Google Scholar 

  • Huang HC, Lin JK (2012) Pu-erh tea, green tea, and black tea suppresses hyperlipidemia, hyperleptinemia and fatty acid synthase through activating AMPK in rats fed a high-fructose diet. Food Funct 3:170–177

    CAS  PubMed  Google Scholar 

  • Hurley RL, Anderson KA, Franzone JM, Kemp BE, Means AR, Witters LA (2005) The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J Biol Chem 280:29060–29066

    CAS  PubMed  Google Scholar 

  • Hurley RL, Barré LK, Wood SD, Anderson KA, Kemp BE, Means AR, Witters LA (2006) Regulation of AMP-activated protein kinase by multisite phosphorylation in response to agents that elevate cellular cAMP. J Biol Chem 281:36662–36672

    CAS  PubMed  Google Scholar 

  • Ignoul S, Eggermont J (2005) CBS domains: structure, function, and pathology in human proteins. Am J Physiol Cell Physiol 289:C1369–C1378

    CAS  PubMed  Google Scholar 

  • Ikeda Y, Sato K, Pimentel DR, Sam F, Shaw RJ, Dyck JR, Walsh K (2009) Cardiac-specific deletion of LKB1 leads to hypertrophy and dysfunction. J Biol Chem 284:35839–35849

    PubMed Central  CAS  PubMed  Google Scholar 

  • Inoki K, Li Y, Xu T, Guan K-L (2003) Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 17:1829–1834

    PubMed Central  CAS  PubMed  Google Scholar 

  • Inoki K, Kim J, Guan K-L (2012) AMPK and mTOR in cellular energy homeostasis and drug targets. Annu Rev Pharmacol Toxicol 52:381–400

    CAS  PubMed  Google Scholar 

  • Jeon S-M, Chandel NS, Hay N (2012) AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485:661–665

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kahn BB, Alquier T, Carling D, Hardie DG (2005) AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 1:15–25

    CAS  PubMed  Google Scholar 

  • Kang S, Chemaly ER, Hajjar RJ, Lebeche D (2011) Resistin promotes cardiac hypertrophy via the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) and c-Jun N-terminal kinase/insulin receptor substrate 1 (JNK/IRS1) pathways. J Biol Chem 286:18465–18473

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kawaguchi T, Takemura G, Kanamori H, Takeyama T, Watanabe T, Morishita K, Ogino A, Tsujimoto A, Goto K, Maruyama R et al (2012) Prior starvation mitigates acute doxorubicin cardiotoxicity through restoration of autophagy in affected cardiomyocytes. Cardiovasc Res 96:456–465

    CAS  PubMed  Google Scholar 

  • Kazgan N, Williams T, Forsberg LJ, Brenman JE (2010) Identification of a nuclear export signal in the catalytic subunit of AMP-activated protein kinase. Mol Biol Cell 21:3433–3442

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kehat I, Molkentin JD (2010) Extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in cardiac hypertrophy. Ann NY Acad Sci 1188:96–102

    CAS  PubMed  Google Scholar 

  • Kelly M, Keller C, Avilucea PR, Keller P, Luo Z, Xiang X, Giralt M, Hidalgo J, Saha AK, Pedersen BK et al (2004) AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise. Biochem Biophys Res Commun 320:449–454

    CAS  PubMed  Google Scholar 

  • Kemp BE (2004) Bateman domains and adenosine derivatives form a binding contract. J Clin Invest 113:182–184

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kerrien S, Aranda B, Breuza L, Bridge A, Broackes-Carter F, Chen C, Duesbury M, Dumousseau M, Feuermann M, Hinz U et al (2012) The IntAct molecular interaction database in 2012. Nucleic Acids Res 40:D841–D846

    PubMed Central  CAS  PubMed  Google Scholar 

  • Khalil H, Peltzer N, Walicki J, Yang J-Y, Dubuis G, Gardiol N, Held W, Bigliardi P, Marsland B, Liaudet L et al (2012) Caspase-3 protects stressed organs against cell death. Mol Cell Biol 32:4523–4533

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kim TT, Dyck JRB (2015) Is AMPK the savior of the failing heart? Trends Endocrinol Metab 26(1):40–48

    CAS  PubMed  Google Scholar 

  • Kim AS, Miller EJ, Young LH (2009) AMP-activated protein kinase: a core signalling pathway in the heart. Acta Physiol 196:37–53

    CAS  Google Scholar 

  • Kim M-J, Jeon DS, Shin DI, Lee MY (2010) Role of AMP-activated protein kinase in cardioprotection in doxorubicin-induced cardiomyopathy of mice. J Am Coll Cardiol 55:A31.E294

    Google Scholar 

  • Kim AS, Miller EJ, Wright TM, Li J, Qi D, Atsina K, Zaha V, Sakamoto K, Young LH (2011) A small molecule AMPK activator protects the heart against ischemia-reperfusion injury. J Mol Cell Cardiol 51:24–32

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kim M, Shen M, Ngoy S, Karamanlidis G, Liao R, Tian R (2012a) AMPK isoform expression in the normal and failing hearts. J Mol Cell Cardiol 52:1066–1073

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kim SY, Jeong S, Jung E, Baik K-H, Chang MH, Kim SA, Shim J-H, Chun E, Lee K-Y (2012b) AMP-activated protein kinase-α1 as an activating kinase of TGF-β-activated kinase 1 has a key role in inflammatory signals. Cell Death Dis 3:e357

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kim EJ, Lee DH, Kim HJ, Lee SJ, Ban JO, Cho MC, Jeong HS, Yang Y, Hong JT, Yoon do Y (2012c) Thiacremonone, a sulfur compound isolated from garlic, attenuates lipid accumulation partially mediated via AMPK activation in 3T3-L1 adipocytes. J Nutr Biochem 23:1552–1558

    CAS  PubMed  Google Scholar 

  • Klaus A, Polge C, Zorman S, Auchli Y, Brunisholz R, Schlattner U (2012) A two-dimensional screen for AMPK substrates identifies tumor suppressor fumarate hydratase as a preferential AMPKα2 substrate. J Proteomics 75:3304–3313

    CAS  PubMed  Google Scholar 

  • Klaus A, Zorman S, Berthier A, Polge C, Ramirez S, Michelland S, Sève M, Vertommen D, Rider M, Lentze N et al (2013) Glutathione S-transferases interact with AMP-activated protein kinase: evidence for S-glutathionylation and activation in vitro. PLoS One 8:e62497

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ko HJ, Zhang Z, Jung DY, Jun JY, Ma Z, Jones KE, Chan SY, Kim JK (2009) Nutrient stress activates inflammation and reduces glucose metabolism by suppressing AMP-activated protein kinase in the heart. Diabetes 58:2536–2546

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kobayashi S, Volden P, Timm D, Mao K, Xu X, Liang Q (2010) Transcription factor GATA4 inhibits doxorubicin-induced autophagy and cardiomyocyte death. J Biol Chem 285:793–804

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kola B, Hubina E, Tucci SA, Kirkham TC, Garcia EA, Mitchell SE, Williams LM, Hawley SA, Hardie DG, Grossman AB et al (2005) Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J Biol Chem 280:25196–25201

    CAS  PubMed  Google Scholar 

  • Konishi M, Haraguchi G, Ohigashi H, Ishihara T, Saito K, Nakano Y, Isobe M (2011) Adiponectin protects against doxorubicin-induced cardiomyopathy by anti-apoptotic effects through AMPK up-regulation. Cardiovasc Res 89:309–319

    CAS  PubMed  Google Scholar 

  • Kovacic S, Soltys CL, Barr AJ, Shiojima I, Walsh K, Dyck JR (2003) Akt activity negatively regulates phosphorylation of AMP-activated protein kinase in the heart. J Biol Chem 278:39422–39427

    CAS  PubMed  Google Scholar 

  • Kubli DA, Gustafsson AB (2014) Cardiomyocyte health: adapting to metabolic changes through autophagy. Trends Endocrinol Metab 25:156–164

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kubota N, Yano W, Kubota T, Yamauchi T, Itoh S, Kumagai H, Kozono H, Takamoto I, Okamoto S, Shiuchi T et al (2007) Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metab 6:55–68

    CAS  PubMed  Google Scholar 

  • Kudo N, Barr AJ, Barr RL, Desai S, Lopaschuk GD (1995) 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 270:17513–17520

    CAS  PubMed  Google Scholar 

  • Kudo N, Gillespie JG, Kung L, Witters LA, Schulz R, Clanachan AS, Lopaschuk GD (1996) 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 1301:67–75

    PubMed  Google Scholar 

  • Kulkarni SS, Karlsson HKR, Szekeres F, Chibalin AV, Krook A, Zierath JR (2011) Suppression of 5′-nucleotidase enzymes promotes AMP-activated protein kinase (AMPK) phosphorylation and metabolism in human and mouse skeletal muscle. J Biol Chem 286:34567–34574

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kurth-Kraczek EJ, Hirshman MF, Goodyear LJ, Winder WW (1999) 5′ AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle. Diabetes 48:1667–1671

    CAS  PubMed  Google Scholar 

  • Lantier L, Fentz J, Mounier R, Leclerc J, Treebak JT, Pehmøller C, Sanz N, Sakakibara I, Saint-Amand E, Rimbaud S et al (2014) AMPK controls exercise endurance, mitochondrial oxidative capacity, and skeletal muscle integrity. FASEB J 28(7):3211–3224

    CAS  PubMed  Google Scholar 

  • Lee E-R, Kim J-Y, Kang Y-J, Ahn J-Y, Kim J-H, Kim B-W, Choi H-Y, Jeong M-Y, Cho S-G (2006) Interplay between PI3K/Akt and MAPK signaling pathways in DNA-damaging drug-induced apoptosis. Biochim Biophys Acta 1763:958–968

    CAS  PubMed  Google Scholar 

  • Li J, Miller EJ, Ninomiya-Tsuji J, Russell RR, Young LH (2005) AMP-activated protein kinase activates p38 mitogen-activated protein kinase by increasing recruitment of p38 MAPK to TAB1 in the ischemic heart. Circ Res 97:872–879

    CAS  PubMed  Google Scholar 

  • Li HL, Yin R, Chen D, Liu D, Wang D, Yang Q, Dong YG (2007) Long-term activation of adenosine monophosphate-activated protein kinase attenuates pressure-overload-induced cardiac hypertrophy. J Cell Biochem 100:1086–1099

    CAS  PubMed  Google Scholar 

  • Li X, Wang L, Zhou XE, Ke J, de Waal PW, Gu X, Tan MHE, Wang D, Wu D, Xu HE et al (2014) Structural basis of AMPK regulation by adenine nucleotides and glycogen. Cell Res. doi:10.1038/cr.2014.150

  • Liao C-C, Ou T-T, Huang H-P, Wang C-J (2014) The inhibition of oleic acid induced hepatic lipogenesis and the promotion of lipolysis by caffeic acid via up-regulation of AMP-activated kinase. J Sci Food Agric 94:1154–1162

    CAS  PubMed  Google Scholar 

  • Loewith R, Jacinto E, Wullschleger S, Lorberg A, Crespo JL, Bonenfant D, Oppliger W, Jenoe P, Hall MN (2002) Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 10:457–468

    CAS  PubMed  Google Scholar 

  • Lou H, Danelisen I, Singal PK (2005) Involvement of mitogen-activated protein kinases in adriamycin-induced cardiomyopathy. Am J Physiol Heart Circ Physiol 288:H1925–H1930

    CAS  PubMed  Google Scholar 

  • Luiken JJ, Coort SL, Willems J, Coumans WA, Bonen A, van der Vusse GJ, Glatz JF (2003) Contraction-induced fatty acid translocase/CD36 translocation in rat cardiac myocytes is mediated through AMP-activated protein kinase signaling. Diabetes 52:1627–1634

    CAS  PubMed  Google Scholar 

  • Ma H, Wang J, Thomas DP, Tong C, Leng L, Wang W, Merk M, Zierow S, Bernhagen J, Ren J et al (2010) Impaired macrophage migration inhibitory factor-AMP-activated protein kinase activation and ischemic recovery in the senescent heart. Circulation 122:282–292

    PubMed Central  CAS  PubMed  Google Scholar 

  • Mahlapuu M, Johansson C, Lindgren K, Hjalm G, Barnes BR, Krook A, Zierath JR, Andersson L, Marklund S (2004) Expression profiling of the gamma-subunit isoforms of AMP-activated protein kinase suggests a major role for gamma3 in white skeletal muscle. Am J Physiol Endocrinol Metab 286:E194–E200

    CAS  PubMed  Google Scholar 

  • Makinde AO, Gamble J, Lopaschuk GD (1997) Upregulation of 5′-AMP-activated protein kinase is responsible for the increase in myocardial fatty acid oxidation rates following birth in the newborn rabbit. Circ Res 80:482–489

    CAS  PubMed  Google Scholar 

  • Marsin A-S, Bertrand L, Rider MH, Deprez J, Beauloye C, Vincent MF, Van der Berghe G, Carling D, Hue L (2000) Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Curr Biol 10:1247–1255

    CAS  PubMed  Google Scholar 

  • Marsin A-S, Bouzin C, Bertrand L, Hue L (2002) The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-kinase. J Biol Chem 277:30778–30783

    CAS  PubMed  Google Scholar 

  • McBride A, Ghilagaber S, Nikolaev A, Hardie DG (2009) The glycogen-binding domain on the AMPK beta subunit allows the kinase to act as a glycogen sensor. Cell Metab 9:23–34

    PubMed Central  CAS  PubMed  Google Scholar 

  • McGaffin KR, Moravec CS, McTiernan CF (2009) Leptin signaling in the failing and mechanically unloaded human heart. Circ Heart Fail 2:676–683

    PubMed Central  CAS  PubMed  Google Scholar 

  • McGee SL, Howlett KF, Starkie RL, Cameron-Smith D, Kemp BE, Hargreaves M (2003) Exercise increases nuclear AMPK α2 in human skeletal muscle. Diabetes 52:926–928

    CAS  PubMed  Google Scholar 

  • McGee SL, van Denderen BJW, Howlett KF, Mollica J, Schertzer JD, Kemp BE, Hargreaves M (2008) AMP-activated protein kinase regulates GLUT4 transcription by phosphorylating histone deacetylase 5. Diabetes 57:860–867

    CAS  PubMed  Google Scholar 

  • McInnes KJ, Brown KA, Hunger NI, Simpson ER (2012) Regulation of LKB1 expression by sex hormones in adipocytes. Int J Obes 36:982–985

    CAS  Google Scholar 

  • Menna P, Salvatorelli E, Gianni L, Minotti G (2008) Anthracycline cardiotoxicity. Top Curr Chem 283:21–44

    CAS  PubMed  Google Scholar 

  • Mihaylova MM, Shaw RJ (2011) The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 13:1016–1023

    PubMed Central  CAS  PubMed  Google Scholar 

  • Miller EJ, Li J, Leng L, McDonald C, Atsumi T, Bucala R, Young LH (2008) Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart. Nature 451:578–582

    CAS  PubMed  Google Scholar 

  • Minokoshi Y, Kim Y-B, Peroni OD, Fryer LGD, Müller C, Carling D, Kahn BB (2002) Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415:339–343

    CAS  PubMed  Google Scholar 

  • Minokoshi Y, Alquier T, Furukawa N, Kim Y-B, Lee A, Xue B, Mu J, Foufelle F, Ferré P, Birnbaum MJ et al (2004) AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428:569–574

    CAS  PubMed  Google Scholar 

  • Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229

    CAS  PubMed  Google Scholar 

  • Minotti G, Salvatorelli E, Menna P (2010) Pharmacological foundations of cardio-oncology. J Pharmacol Exp Ther 334:2–8

    CAS  PubMed  Google Scholar 

  • Moreno D, Towler MC, Hardie DG, Knecht E, Sanz P (2010) The laforin-malin complex, involved in Lafora disease, promotes the incorporation of K63-linked ubiquitin chains into AMP-activated protein kinase beta subunits. Mol Biol Cell 21:2578–2588

    PubMed Central  CAS  PubMed  Google Scholar 

  • Morrison A, Yan X, Tong C, Li J (2011) Acute rosiglitazone treatment is cardioprotective against ischemia-reperfusion injury by modulating AMPK, Akt, and JNK signaling in nondiabetic mice. Am J Physiol Heart Circ Physiol 301:H895–H902

    CAS  PubMed  Google Scholar 

  • Mungai PT, Waypa GB, Jairaman A, Prakriya M, Dokic D, Ball MK, Schumacker PT (2011) Hypoxia triggers AMPK activation through reactive oxygen species-mediated activation of calcium release-activated calcium channels. Mol Cell Biol 31:3531–3545

    PubMed Central  CAS  PubMed  Google Scholar 

  • Musi N, Hirshman MF, Nygren J, Svanfeldt M, Bavenholm P, Rooyackers O, Zhou G, Williamson JM, Ljunqvist O, Efendic S et al (2002) Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 51:2074–2081

    CAS  PubMed  Google Scholar 

  • Musi N, Hirshman MF, Arad M, Xing Y, Fujii N, Pomerleau J, Ahmad F, Berul CI, Seidman JG, Tian R et al (2005) Functional role of AMP-activated protein kinase in the heart during exercise. FEBS Lett 579:2045–2050

    CAS  PubMed  Google Scholar 

  • Nagata D, Takeda R, Sata M, Satonaka H, Suzuki E, Nagano T, Hirata Y (2004) AMP-activated protein kinase inhibits angiotensin II-stimulated vascular smooth muscle cell proliferation. Circulation 110:444–451

    CAS  PubMed  Google Scholar 

  • Nakano A, Takashima S (2012) LKB1 and AMP-activated protein kinase: regulators of cell polarity. Genes Cells 17:737–747

    PubMed Central  CAS  PubMed  Google Scholar 

  • Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, Matsukura S (2001) A role for ghrelin in the central regulation of feeding. Nature 409:194–198

    CAS  PubMed  Google Scholar 

  • Neumann D, Suter M, Tuerk R, Riek U, Wallimann T (2007) Co-expression of LKB1, MO25alpha and STRADalpha in bacteria yield the functional and active heterotrimeric complex. Mol Biotechnol 36:220–231

    CAS  PubMed  Google Scholar 

  • Nojima H, Tokunaga C, Eguchi S, Oshiro N, Hidayat S, Yoshino K, Hara K, Tanaka N, Avruch J, Yonezawa K (2003) The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif. J Biol Chem 278:15461–15464

    CAS  PubMed  Google Scholar 

  • Oakhill JS, Chen Z-P, Scott JW, Steel R, Castelli LA, Ling N, Macaulay SL, Kemp BE (2010) β-Subunit myristoylation is the gatekeeper for initiating metabolic stress sensing by AMP-activated protein kinase (AMPK). Proc Natl Acad Sci U S A 107:19237–19241

    PubMed Central  CAS  PubMed  Google Scholar 

  • Oakhill JS, Steel R, Chen Z-P, Scott JW, Ling N, Tam S, Kemp BE (2011) AMPK is a direct adenylate charge-regulated protein kinase. Science 332:1433–1435

    CAS  PubMed  Google Scholar 

  • Oliveira SM, Zhang YH, Solis RS, Isackson H, Bellahcene M, Yavari A, Pinter K, Davies JK, Ge Y, Ashrafian H et al (2012) AMP-activated protein kinase phosphorylates cardiac troponin I and alters contractility of murine ventricular myocytes. Circ Res 110:1192–1201

    CAS  PubMed  Google Scholar 

  • O’Neill HM, Maarbjerg SJ, Crane JD, Jeppesen J, Jørgensen SB, Schertzer JD, Shyroka O, Kiens B, van Denderen BJ, Tarnopolsky MA et al (2011) AMP-activated protein kinase (AMPK) beta1beta2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise. Proc Natl Acad Sci U S A 108:16092–16097

    PubMed Central  PubMed  Google Scholar 

  • O’Neill HM, Holloway GP, Steinberg GR (2013) AMPK regulation of fatty acid metabolism and mitochondrial biogenesis: implications for obesity. Mol Cell Endocrinol 366:135–151

    PubMed  Google Scholar 

  • Paiva MA, Rutter-Locher Z, Goncalves LM, Providencia LA, Davidson SM, Yellon DM, Mocanu MM (2011) Enhancing AMPK activation during ischemia protects the diabetic heart against reperfusion injury. Am J Physiol Heart Circ Physiol 300:H2123–H2134

    PubMed Central  CAS  PubMed  Google Scholar 

  • Pang T, Xiong B, Li J-Y, Qiu B-Y, Jin G-Z, Shen J-K, Li J (2007) Conserved α-helix acts as autoinhibitory sequence in AMP-activated protein kinase α subunits. J Biol Chem 282:495–506

    CAS  PubMed  Google Scholar 

  • Pankuweit S, Ruppert V, Maisch B (2004) Inflammation in dilated cardiomyopathy. Herz 29:788–793

    PubMed  Google Scholar 

  • Park S, Scheffler TL, Rossie SS, Gerrard DE (2013) AMPK activity is regulated by calcium-mediated protein phosphatase 2A activity. Cell Calcium 53:217–223

    CAS  PubMed  Google Scholar 

  • Patten IS, Arany Z (2012) PGC-1 coactivators in the cardiovascular system. Trends Endocrinol Metab 23:90–97

    CAS  PubMed  Google Scholar 

  • Pinter K, Grignani RT, Czibik G, Farza H, Watkins H, Redwood C (2012) Embryonic expression of AMPK γ subunits and the identification of a novel γ2 transcript variant in adult heart. J Mol Cell Cardiol 53:342–349

    PubMed Central  CAS  PubMed  Google Scholar 

  • Polekhina G, Gupta A, van Denderen BJW, Feil SC, Kemp BE, Stapleton D, Parker MW (2005) Structural basis for glycogen recognition by AMP-activated protein kinase. Structure 1993(13):1453–1462

    Google Scholar 

  • Polge C, Jossier M, Crozet P, Gissot L, Thomas M (2008) Beta-subunits of the SnRK1 complexes share a common ancestral function together with expression and function specificities; physical interaction with nitrate reductase specifically occurs via AKINbeta1-subunit. Plant Physiol 148:1570–1582

    PubMed Central  CAS  PubMed  Google Scholar 

  • Qi J, Gong J, Zhao T, Zhao J, Lam P, Ye J, Li JZ, Wu J, Zhou H-M, Li P (2008) Downregulation of AMP-activated protein kinase by Cidea-mediated ubiquitination and degradation in brown adipose tissue. EMBO J 27:1537–1548

    PubMed Central  CAS  PubMed  Google Scholar 

  • Quentin T, Kitz J, Steinmetz M, Poppe A, Bar K, Kratzner R (2011) Different expression of the catalytic alpha subunits of the AMP activated protein kinase–an immunohistochemical study in human tissue. Histol Histopathol 26:589–596

    PubMed  Google Scholar 

  • Ramírez Ríos S, Lamarche F, Cottet-Rousselle C, Klaus A, Tuerk R, Thali R, Auchli Y, Brunisholz R, Neumann D, Barret L, Tokarska-Schlattner M, Schlattner U (2014) Regulation of brain-type creatine kinase by AMP-activated protein kinase: interaction, phosphorylation and ER localization. Biochim Biophys Acta 1837:1271–1283

    PubMed  Google Scholar 

  • Riek U, Scholz R, Konarev P, Rufer A, Suter M, Nazabal A, Ringler P, Chami M, Muller SA, Neumann D et al (2008) Structural properties of AMP-activated protein kinase: dimerization, molecular shape, and changes upon ligand binding. J Biol Chem 283:18331–18343

    CAS  PubMed  Google Scholar 

  • Ronnebaum SM, Patterson C (2010) The FoxO family in cardiac function and dysfunction. Annu Rev Physiol 72:81–94

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ronnebaum SM, Patterson C, Schisler JC (2014) Hey U(PS): metabolic and proteolytic homeostasis linked via AMPK and the ubiquitin proteasome system. Mol Endocrinol 28(10):1602–1615

    CAS  PubMed  Google Scholar 

  • Rubio T, Vernia S, Sanz P (2013) Sumoylation of AMPKbeta2 subunit enhances AMP-activated protein kinase activity. Mol Biol Cell 24:1801–1811, S1–S4

    PubMed Central  CAS  PubMed  Google Scholar 

  • Russell R III (2003) The role of AMP-activated protein kinase in fuel selection by the stressed heart. Curr Hypertens Rep 5:459–465

    PubMed  Google Scholar 

  • Russell RR III, Li J, Coven DL, Pypaert M, Zechner C, Palmeri M, Giordano FJ, Mu J, Birnbaum MJ, Young LH (2004) AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Invest 114:495–503

    PubMed Central  CAS  PubMed  Google Scholar 

  • Saks V, Favier R, Guzun R, Schlattner U, Wallimann T (2006) Molecular system bioenergetics: regulation of substrate supply in response to heart energy demands. J Physiol 577:769–777

    PubMed Central  CAS  PubMed  Google Scholar 

  • Salminen A, Hyttinen JM, Kaarniranta K (2011) AMP-activated protein kinase inhibits NF-kappaB signaling and inflammation: impact on healthspan and lifespan. J Mol Med (Berlin) 89:667–676

    CAS  Google Scholar 

  • Salt IP, Palmer TM (2012) Exploiting the anti-inflammatory effects of AMP-activated protein kinase activation. Expert Opin Investig Drugs 21:1155–1167

    CAS  PubMed  Google Scholar 

  • Salt I, Celler JW, Hawley SA, Prescott A, Woods A, Carling D, Hardie DG (1998a) AMP-activated protein kinase: greater AMP dependence, and preferential nuclear localization, of complexes containing the alpha2 isoform. Biochem J 334(Pt 1):177–187

    PubMed Central  CAS  PubMed  Google Scholar 

  • Salt IP, Johnson G, Ashcroft SJ, Hardie DG (1998b) AMP-activated protein kinase is activated by low glucose in cell lines derived from pancreatic beta cells, and may regulate insulin release. Biochem J 335(Pt 3):533–539

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, Sabatini DM (2008) The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320:1496–1501

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sanders MJ, Grondin PO, Hegarty BD, Snowden MA, Carling D (2007a) Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem J 403:139–148

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sanders MJ, Ali ZS, Hegarty BD, Heath R, Snowden MA, Carling D (2007b) Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662, a member of the thienopyridone family. J Biol Chem 282:32539–32548

    CAS  PubMed  Google Scholar 

  • Sartoretto JL, Kalwa H, Pluth MD, Lippard SJ, Michel T (2011) Hydrogen peroxide differentially modulates cardiac myocyte nitric oxide synthesis. Proc Natl Acad Sci U S A 108:15792–15797

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sasaki H, Asanuma H, Fujita M, Takahama H, Wakeno M, Ito S, Ogai A, Asakura M, Kim J, Minamino T et al (2009) Metformin prevents progression of heart failure in dogs: role of AMP-activated protein kinase. Circulation 119:2568–2577

    CAS  PubMed  Google Scholar 

  • Schilling J, Kelly DP (2011) The PGC-1 cascade as a therapeutic target for heart failure. J Mol Cell Cardiol 51:578–583

    PubMed Central  CAS  PubMed  Google Scholar 

  • Schlattner U, Tokarska-Schlattner M, Wallimann T (2006) Mitochondrial creatine kinase in human health and disease. Biochim Biophys Acta 1762:164–180

    CAS  PubMed  Google Scholar 

  • Scott JW, Hawley SA, Green KA, Anis M, Stewart G, Scullion GA, Norman DG, Hardie DG (2004) CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations. J Clin Invest 113:274–284

    PubMed Central  CAS  PubMed  Google Scholar 

  • Scott JW, van Denderen BJW, Jorgensen SB, Honeyman JE, Steinberg GR, Oakhill JS, Iseli TJ, Koay A, Gooley PR, Stapleton D et al (2008) Thienopyridone drugs are selective activators of AMP-activated protein kinase beta1-containing complexes. Chem Biol 15:1220–1230

    CAS  PubMed  Google Scholar 

  • Scott JW, Ling N, Issa SMA, Dite TA, O’Brien MT, Chen Z-P, Galic S, Langendorf CG, Steinberg GR, Kemp BE et al (2014) Small molecule drug A-769662 and AMP synergistically activate naive AMPK independent of upstream kinase signaling. Chem Biol 21(5):619–627

    CAS  PubMed  Google Scholar 

  • Sebbagh M, Santoni M-J, Hall B, Borg J-P, Schwartz MA (2009) Regulation of LKB1/STRAD localization and function by E-cadherin. Curr Biol 19:37–42

    PubMed Central  CAS  PubMed  Google Scholar 

  • Shaw RJ (2009) LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta Physiol 196:65–80

    CAS  Google Scholar 

  • Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, Cantley LC (2004) 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 101:3329–3335

    PubMed Central  CAS  PubMed  Google Scholar 

  • Shen CH, Yuan P, Perez-Lorenzo R, Zhang Y, Lee SX, Ou Y, Asara JM, Cantley LC, Zheng B (2013) Phosphorylation of BRAF by AMPK impairs BRAF-KSR1 association and cell proliferation. Mol Cell 52:161–172

    PubMed Central  CAS  PubMed  Google Scholar 

  • Shibata R, Ouchi N, Kihara S, Sato K, Funahashi T, Walsh K (2004) Adiponectin stimulates angiogenesis in response to tissue ischemia through stimulation of amp-activated protein kinase signaling. J Biol Chem 279:28670–28674

    CAS  PubMed  Google Scholar 

  • Shibata R, Sato K, Pimentel DR, Takemura Y, Kihara S, Ohashi K, Funahashi T, Ouchi N, Walsh K (2005) Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanisms. Nat Med 11:1096–1103

    PubMed Central  CAS  PubMed  Google Scholar 

  • Shinmura K, Tamaki K, Saito K, Nakano Y, Tobe T, Bolli R (2007) Cardioprotective effects of short-term caloric restriction are mediated by adiponectin via activation of AMP-activated protein kinase. Circulation 116:2809–2817

    CAS  PubMed  Google Scholar 

  • Soltys CL, Kovacic S, Dyck JR (2006) Activation of cardiac AMP-activated protein kinase by LKB1 expression or chemical hypoxia is blunted by increased Akt activity. Am J Physiol Heart Circ Physiol 290:H2472–H2479

    CAS  PubMed  Google Scholar 

  • Srivastava RAK, Pinkosky SL, Filippov S, Hanselman JC, Cramer CT, Newton RS (2012) AMP-activated protein kinase: an emerging drug target to regulate imbalances in lipid and carbohydrate metabolism to treat cardio-metabolic diseases. J Lipid Res 53:2490–2514

    PubMed Central  CAS  PubMed  Google Scholar 

  • Stapleton D, Mitchelhill KI, Gao G, Widmer J, Michell BJ, Teh T, House CM, Fernandez CS, Cox T, Witters LA et al (1996) Mammalian AMP-activated protein kinase subfamily. J Biol Chem 271:611–614

    CAS  PubMed  Google Scholar 

  • Steinberg GR (2013) AMPK and the endocrine control of energy metabolism. Mol Cell Endocrinol 366:125–126

    CAS  PubMed  Google Scholar 

  • Steinberg GR, Kemp BE (2009) AMPK in health and disease. Physiol Rev 89:1025–1078

    CAS  PubMed  Google Scholar 

  • Steinberg GR, Michell BJ, van Denderen BJW, Watt MJ, Carey AL, Fam BC, Andrikopoulos S, Proietto J, Görgün CZ, Carling D et al (2006) Tumor necrosis factor alpha-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling. Cell Metab 4:465–474

    CAS  PubMed  Google Scholar 

  • Strogolova V, Orlova M, Shevade A, Kuchin S (2012) Mitochondrial porin Por1 and its homolog Por2 contribute to the positive control of Snf1 protein kinase in Saccharomyces cerevisiae. Eukaryot Cell 11:1568–1572

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sukhodub A, Jovanovic S, Du Q, Budas G, Clelland AK, Shen M, Sakamoto K, Tian R, Jovanovic A (2007) AMP-activated protein kinase mediates preconditioning in cardiomyocytes by regulating activity and trafficking of sarcolemmal ATP-sensitive K(+) channels. J Cell Physiol 210:224–236

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sussman MA, Völkers M, Fischer K, Bailey B, Cottage CT, Din S, Gude N, Avitabile D, Alvarez R, Sundararaman B et al (2011) Myocardial AKT: the omnipresent nexus. Physiol Rev 91:1023–1070

    PubMed Central  CAS  PubMed  Google Scholar 

  • Suter M, Riek U, Tuerk R, Schlattner U, Wallimann T, Neumann D (2006) Dissecting the role of 5′-AMP for allosteric stimulation, activation, and deactivation of AMP-activated protein kinase. J Biol Chem 281:32207–32216

    CAS  PubMed  Google Scholar 

  • Suzuki A, Okamoto S, Lee S, Saito K, Shiuchi T, Minokoshi Y (2007) Leptin stimulates fatty acid oxidation and peroxisome proliferator-activated receptor alpha gene expression in mouse C2C12 myoblasts by changing the subcellular localization of the alpha2 form of AMP-activated protein kinase. Mol Cell Biol 27:4317–4327

    PubMed Central  CAS  PubMed  Google Scholar 

  • Suzuki T, Bridges D, Nakada D, Skiniotis G, Morrison SJ, Lin JD, Saltiel AR, Inoki K (2013) Inhibition of AMPK catabolic action by GSK3. Mol Cell 50:407–419

    PubMed Central  CAS  PubMed  Google Scholar 

  • Terai K, Hiramoto Y, Masaki M, Sugiyama S, Kuroda T, Hori M, Kawase I, Hirota H (2005) AMP-activated protein kinase protects cardiomyocytes against hypoxic injury through attenuation of endoplasmic reticulum stress. Mol Cell Biol 25:9554–9575

    PubMed Central  CAS  PubMed  Google Scholar 

  • Thornton C, Snowden MA, Carling D (1998) Identification of a novel AMP-activated protein kinase beta subunit isoform that is highly expressed in skeletal muscle. J Biol Chem 273:12443–12450

    CAS  PubMed  Google Scholar 

  • Tian R, Musi N, D’Agostino J, Hirshman MF, Goodyear LJ (2001) Increased adenosine monophosphate-activated protein kinase activity in rat hearts with pressure-overload hypertrophy. Circulation 104:1664–1669

    CAS  PubMed  Google Scholar 

  • Tokarska-Schlattner M, Zaugg M, da Silva R, Lucchinetti E, Schaub MC, Wallimann T, Schlattner U (2005) Acute toxicity of doxorubicin on isolated perfused heart: response of kinases regulating energy supply. Am J Physiol Heart Circ Physiol 289:H37–H47

    CAS  PubMed  Google Scholar 

  • Tokarska-Schlattner M, Lucchinetti E, Zaugg M, Kay L, Gratia S, Guzun R, Saks V, Schlattner U (2010) Early effects of doxorubicin in perfused heart: transcriptional profiling reveals inhibition of cellular stress response genes. Am J Physiol Regul Integr Comp Physiol 298:R1075–R1088

    CAS  PubMed  Google Scholar 

  • Townley R, Shapiro L (2007) Crystal structures of the adenylate sensor from fission yeast AMP-activated protein kinase. Science 315:1726–1729

    CAS  PubMed  Google Scholar 

  • Treebak JT, Birk JB, Hansen BF, Olsen GS, Wojtaszewski JFP (2009) A-769662 activates AMPK beta1-containing complexes but induces glucose uptake through a PI3-kinase-dependent pathway in mouse skeletal muscle. Am J Physiol Cell Physiol 297:C1041–C1052

    CAS  PubMed  Google Scholar 

  • Vincent O, Carlson M (1999) Gal83 mediates the interaction of the Snf1 kinase complex with the transcription activator Sip4. EMBO J 18:6672–6681

    PubMed Central  CAS  PubMed  Google Scholar 

  • Viollet B, Athea Y, Mounier R, Guigas B, Zarrinpashneh E, Horman S, Lantier L, Hebrard S, Devin-Leclerc J, Beauloye C et al (2009) AMPK: lessons from transgenic and knockout animals. Front Biosci (Landmark Ed) 14:19

    CAS  Google Scholar 

  • Viollet B, Foretz M, Schlattner U (2014) Bypassing AMPK phosphorylation. Chem Biol 21:567–569

    CAS  PubMed  Google Scholar 

  • Wallimann T, Tokarska-Schlattner M, Schlattner U (2011) The creatine kinase system and pleiotropic effects of creatine. Amino Acids 40:1271–1296

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wang L, Brautigan DL (2013) α-SNAP inhibits AMPK signaling to reduce mitochondrial biogenesis and dephosphorylates Thr172 in AMPKα in vitro. Nat Commun 4:1559

    PubMed Central  PubMed  Google Scholar 

  • Wang M, Unger RH (2005) Role of PP2C in cardiac lipid accumulation in obese rodents and its prevention by troglitazone. Am J Physiol Endocrinol Metab 288:E216–E221

    CAS  PubMed  Google Scholar 

  • Wang J, Ma H, Zhang X, He L, Wu J, Gao X, Ren J, Li J (2009) A novel AMPK activator from Chinese herb medicine and ischemia phosphorylate the cardiac transcription factor FOXO3. Int J Physiol Pathophysiol Pharmacol 1:116–126

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wang S, Song P, Zou MH (2012a) Inhibition of AMP-activated protein kinase alpha (AMPKalpha) by doxorubicin accentuates genotoxic stress and cell death in mouse embryonic fibroblasts and cardiomyocytes: role of p53 and SIRT1. J Biol Chem 287:8001–8012

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wang S, Song P, Zou MH (2012b) AMP-activated protein kinase, stress responses and cardiovascular diseases. Clin Sci 122:555–573

    PubMed Central  CAS  PubMed  Google Scholar 

  • Watt MJ, Dzamko N, Thomas WG, Rose-John S, Ernst M, Carling D, Kemp BE, Febbraio MA, Steinberg GR (2006) CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK. Nat Med 12:541–548

    CAS  PubMed  Google Scholar 

  • Winder WW, Hardie DG (1996) Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise. Am J Physiol Endocrinol Metab 270:E299–E304

    CAS  Google Scholar 

  • Winder WW, Hardie DG (1999) AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am J Physiol 277:E1–E10

    CAS  PubMed  Google Scholar 

  • Wolff NC, Vega-Rubin-de-Celis S, Xie X-J, Castrillon DH, Kabbani W, Brugarolas J (2011) Cell-type-dependent regulation of mTORC1 by REDD1 and the tumor suppressors TSC1/TSC2 and LKB1 in response to hypoxia. Mol Cell Biol 31:1870–1884

    PubMed Central  CAS  PubMed  Google Scholar 

  • Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LGD, Neumann D, Schlattner U, Wallimann T, Carlson M, Carling D (2003) LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol 13:2004–2008

    CAS  PubMed  Google Scholar 

  • Woods A, Dickerson K, Heath R, Hong S-P, Momcilovic M, Johnstone SR, Carlson M, Carling D (2005) Ca2+/calmodulin-dependent protein kinase kinase-β acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab 2:21–33

    CAS  PubMed  Google Scholar 

  • Wu Y, Song P, Xu J, Zhang M, Zou M-H (2007) Activation of protein phosphatase 2A by palmitate inhibits AMP-activated protein kinase. J Biol Chem 282:9777–9788

    CAS  PubMed  Google Scholar 

  • Xiao B, Heath R, Saiu P, Leiper FC, Leone P, Jing C, Walker PA, Haire L, Eccleston JF, Davis CT et al (2007) Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature 449:496–500

    CAS  PubMed  Google Scholar 

  • Xiao B, Sanders MJ, Underwood E, Heath R, Mayer FV, Carmena D, Jing C, Walker PA, Eccleston JF, Haire LF et al (2011) Structure of mammalian AMPK and its regulation by ADP. Nature 472:230–233

    PubMed Central  CAS  PubMed  Google Scholar 

  • Xiao B, Sanders MJ, Carmena D, Bright NJ, Haire LF, Underwood E, Patel BR, Heath RB, Walker PA, Hallen S et al (2013) Structural basis of AMPK regulation by small molecule activators. Nat Commun 4:3017

    PubMed Central  PubMed  Google Scholar 

  • Xie Z, Dong Y, Zhang M, Cui MZ, Cohen RA, Riek U, Neumann D, Schlattner U, Zou MH (2006a) Activation of protein kinase C zeta by peroxynitrite regulates LKB1-dependent AMP-activated protein kinase in cultured endothelial cells. J Biol Chem 281:6366–6375

    CAS  PubMed  Google Scholar 

  • Xie M, Zhang D, Dyck JR, Li Y, Zhang H, Morishima M, Mann DL, Taffet GE, Baldini A, Khoury DS et al (2006b) A pivotal role for endogenous TGF-beta-activated kinase-1 in the LKB1/AMP-activated protein kinase energy-sensor pathway. Proc Natl Acad Sci U S A 103:17378–17383

    PubMed Central  CAS  PubMed  Google Scholar 

  • Yang HJ, Jang D-J, Hwang J-T (2012) Anti-diabetic effects of Korean red pepper via AMPK and PPAR-γ activation in C2C12 myotubes. J Funct Foods 4:552–558

    CAS  Google Scholar 

  • Young LH (2008) AMP-activated protein kinase conducts the ischemic stress response orchestra. Circulation 117:832–840

    PubMed  Google Scholar 

  • Yun H, Ha J (2011) AMP-activated protein kinase modulators: a patent review (2006–2010). Expert Opin Ther Pat 21:983–1005

    CAS  PubMed  Google Scholar 

  • Zaha VG, Young LH (2012) AMP-activated protein kinase regulation and biological actions in the heart. Circ Res 111:800–814

    CAS  PubMed  Google Scholar 

  • Zhang P, Hu X, Xu X, Fassett J, Zhu G, Viollet B, Xu W, Wiczer B, Bernlohr DA, Bache RJ et al (2008) AMP activated protein kinase-alpha2 deficiency exacerbates pressure-overload-induced left ventricular hypertrophy and dysfunction in mice. Hypertension 52:918–924

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zhang BB, Zhou G, Li C (2009) AMPK: an emerging drug target for diabetes and the metabolic syndrome. Cell Metab 9:407–416

    PubMed  Google Scholar 

  • Zhang YL, Guo H, Zhang CS, Lin SY, Yin Z, Peng Y, Luo H, Shi Y, Lian G, Zhang C et al (2013) AMP as a low-energy charge signal autonomously initiates assembly of AXIN-AMPK-LKB1 complex for AMPK activation. Cell Metab 18:546–555

    CAS  PubMed  Google Scholar 

  • Zhang CS, Jiang B, Li M, Zhu M, Peng Y, Zhang YL, Wu YQ, Li TY, Liang Y, Lu Z et al (2014) The lysosomal v-ATPase-ragulator complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism. Cell Metab 20:526–540

    CAS  PubMed  Google Scholar 

  • Zheng B, Jeong JH, Asara JM, Yuan YY, Granter SR, Chin L, Cantley LC (2009) Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. Mol Cell 33:237–247

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zhu L, Chen L, Zhou X-M, Zhang Y-Y, Zhang Y-J, Zhao J, Ji S-R, Wu J-W, Wu Y (2011) Structural insights into the architecture and allostery of full-length AMP-activated protein kinase. Structure 19:515–522

    CAS  PubMed  Google Scholar 

  • Zmijewski JW, Banerjee S, Bae H, Friggeri A, Lazarowski ER, Abraham E (2010) Exposure to hydrogen peroxide induces oxidation and activation of AMP-activated protein kinase. J Biol Chem 285:33154–33164

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zou MH, Hou XY, Shi CM, Nagata D, Walsh K, Cohen RA (2002) Modulation by peroxynitrite of Akt- and AMP-activated kinase-dependent Ser1179 phosphorylation of endothelial nitric oxide synthase. J Biol Chem 277:32552–32557

    CAS  PubMed  Google Scholar 

  • Zou MH, Kirkpatrick SS, Davis BJ, Nelson JS, Wiles WG IV, Schlattner U, Neumann D, Brownlee M, Freeman MB, Goldman MH (2004) Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species. J Biol Chem 279:43940–43951

    CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank all group members involved in the work cited in this review. Work of the authors on AMPK was funded by the EU FP6 and FP7 programs (contract LSHM-CT-2004-005272 EXGENESIS to U.S.; Marie-Curie grants ANTHRAWES, 041870 and ANTHRAPLUS, 249202 to M.T.S.), the French Agence Nationale de Recherche (ANR, chaire d’excellence given to U.S.), the French Région Rhône-Alpes, the French Fondation pour la Recherche Médicale, and the National Council of Science and Technology of Mexico (CONACYT).

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  1. Laboratory of Fundamental and Applied Bioenergetics, Université Grenoble Alpes, Grenoble, France

    Martin Pelosse, Malgorzata Tokarska-Schlattner & Uwe Schlattner

  2. INSERM, U1055, Grenoble, France

    Martin Pelosse, Malgorzata Tokarska-Schlattner & Uwe Schlattner

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  1. Martin Pelosse
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Correspondence to Uwe Schlattner .

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  1. Randall Div. of Cell and Mol. Biophysics and Cardiovascular Division Guy’s Campus, Faculty of Life Sciences and Medicine King’s College London, London, United Kingdom

    Elisabeth Ehler

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Pelosse, M., Tokarska-Schlattner, M., Schlattner, U. (2015). AMP-Activated Protein Kinase: A Metabolic Stress Sensor in the Heart. In: Ehler, E. (eds) Cardiac Cytoarchitecture. Springer, Cham. https://doi.org/10.1007/978-3-319-15263-9_10

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