2022
Atrial AMP-activated protein kinase is critical for prevention of dysregulation of electrical excitability and atrial fibrillation
Su KN, Ma Y, Cacheux M, Ilkan Z, Raad N, Muller GK, Wu X, Guerrera N, Thorn SL, Sinusas AJ, Foretz M, Viollet B, Akar JG, Akar FG, Young LH. Atrial AMP-activated protein kinase is critical for prevention of dysregulation of electrical excitability and atrial fibrillation. JCI Insight 2022, 7: e141213. PMID: 35451373, PMCID: PMC9089788, DOI: 10.1172/jci.insight.141213.Peer-Reviewed Original ResearchConceptsTranscription factorsKey transcription factorMaster metabolic regulatorIon channel subunitsGap junction proteinTranscriptional reprogrammingAMPK deletionProtein kinaseBiological functionsTranscriptional downregulationMetabolic regulatorChannel subunitsIon channelsAMPK expressionMetabolic stressAtrial fibrillationAMPKJunction proteinsElectrical excitabilityHomeostatic roleStructural remodelingConnexinsAtrial ion channelsRemodelingDownregulation
2015
LKB1 deletion causes early changes in atrial channel expression and electrophysiology prior to atrial fibrillation
Kim GE, Ross JL, Xie C, Su KN, Zaha VG, Wu X, Palmeri M, Ashraf M, Akar JG, Russell KS, Akar FG, Young LH. LKB1 deletion causes early changes in atrial channel expression and electrophysiology prior to atrial fibrillation. Cardiovascular Research 2015, 108: 197-208. PMID: 26378152, PMCID: PMC4571838, DOI: 10.1093/cvr/cvv212.Peer-Reviewed Original ResearchConceptsLiver kinase B1Protein kinaseLKB1 deletionMetabolic regulator AMPAtrial fibrillationChannel expressionMHC-CreElectrophysiological functionKnockout mouse modelRelated kinasesLKB1 pathwayGene expressionPerpetuation of AFKinase B1Neonatal atrial myocytesΑMHC-CreKinasePostnatal day 1Patch-clamp recordingsAtrial growthWeeks of ageDeletionSodium current densityAction potential generationSpecific roleAMPK: energy sensor and survival mechanism in the ischemic heart
Qi D, Young LH. AMPK: energy sensor and survival mechanism in the ischemic heart. Trends In Endocrinology And Metabolism 2015, 26: 422-429. PMID: 26160707, PMCID: PMC4697457, DOI: 10.1016/j.tem.2015.05.010.BooksConceptsIschemic heartAMPK activationEndoplasmic reticulum stressFatty acid metabolismCardioprotective strategiesContractile dysfunctionMyocardial infarctionMyocardial ischemiaPotential therapeutic applicationsVascular diseaseMyocardial necrosisPharmacological activationReticulum stressAcid metabolismProtein kinaseIschemiaMitochondrial functionEnergy sensorCellular metabolismSurvival mechanismCritical regulatorActivationHeartNovel mechanismTherapeutic applications
2012
AMP-Activated Protein Kinase Regulation and Biological Actions in the Heart
Zaha VG, Young LH. AMP-Activated Protein Kinase Regulation and Biological Actions in the Heart. Circulation Research 2012, 111: 800-814. PMID: 22935535, PMCID: PMC4397099, DOI: 10.1161/circresaha.111.255505.BooksConceptsAMPK pathwayProtein kinase regulationCellular fuel gaugeStress-activated kinasesRegulation of AMPKMaster metabolic regulatorNovel molecular mechanismBiological actionsKinase regulationDiverse biological actionsAMPK regulationProtein kinaseMolecular mechanismsMetabolic regulatorFuel gaugeImportant biological actionsRecent discoveryKinaseAMPKRegulationNew insightsPharmacological activationPathwayImportant roleTherapeutic potentialCerulein hyperstimulation decreases AMP-activated protein kinase levels at the site of maximal zymogen activation
Shugrue C, Alexandre M, de Villalvilla A, Kolodecik TR, Young LH, Gorelick FS, Thrower EC. Cerulein hyperstimulation decreases AMP-activated protein kinase levels at the site of maximal zymogen activation. AJP Gastrointestinal And Liver Physiology 2012, 303: g723-g732. PMID: 22821946, PMCID: PMC3468535, DOI: 10.1152/ajpgi.00082.2012.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAminoimidazole CarboxamideAMP-Activated Protein KinasesAnimalsCells, CulturedCeruletideCyclic AMP-Dependent Protein KinasesEnzyme PrecursorsGene Expression RegulationMaleMetforminOctoxynolPancreasPhosphorylationPyrazolesPyrimidinesRatsRats, Sprague-DawleyRibonucleotidesSodium Dodecyl SulfateConceptsAdenosine monophosphate-activated protein kinaseZymogen activationAMPK activityPancreatic acinar cellsMonophosphate-activated protein kinaseVacuolar ATPase activityAMPK levelsDigestive enzyme zymogensAMPK effectsProtein kinaseProtein kinase levelsE subunitAcinar cellsTime-dependent translocationCompound CCellular modelPancreatitis responsesATPase activityDifferential centrifugationPremature activationChymotrypsin activityActivationInitiating eventSoluble fractionCerulein hyperstimulation
2009
A Crystallized View of AMPK Activation
Young LH. A Crystallized View of AMPK Activation. Cell Metabolism 2009, 10: 5-6. PMID: 19583947, DOI: 10.1016/j.cmet.2009.06.008.Commentaries, Editorials and LettersConceptsAMPK activationAMPK catalytic subunitKey metabolic regulatorAutoinhibitory sequenceCatalytic subunitKinase domainProtein kinaseMetabolic regulatorStructural interactionsCrystallized viewNovel therapeutic approachesActivationKinaseSubunitsRegulatorEnhanced understandingRecent workSequenceTherapeutic approachesMolecular mechanicsDomainAMP‐activated protein kinase: a core signalling pathway in the heart
Kim AS, Miller EJ, Young LH. AMP‐activated protein kinase: a core signalling pathway in the heart. Acta Physiologica 2009, 196: 37-53. PMID: 19239414, DOI: 10.1111/j.1748-1716.2009.01978.x.BooksConceptsProtein kinaseEssential cellular processesTumor suppressor LKB1Downstream AMPK targetsProduction of ATPProtein phosphataseAMPK targetsActivated AMPKIntracellular glycogen accumulationCellular processesUpstream kinaseFatty acid metabolismCardiac myocyte hypertrophyAMPK activationAMPK activityImportant intracellularMolecular mechanismsMajor regulatorAMPKProtein synthesisKinaseAcid metabolismOral hypoglycaemic drugsGlycogen accumulationType 2 diabetes
2007
Aging-Associated Reductions in AMP-Activated Protein Kinase Activity and Mitochondrial Biogenesis
Reznick RM, Zong H, Li J, Morino K, Moore IK, Yu HJ, Liu ZX, Dong J, Mustard KJ, Hawley SA, Befroy D, Pypaert M, Hardie DG, Young LH, Shulman GI. Aging-Associated Reductions in AMP-Activated Protein Kinase Activity and Mitochondrial Biogenesis. Cell Metabolism 2007, 5: 151-156. PMID: 17276357, PMCID: PMC1885964, DOI: 10.1016/j.cmet.2007.01.008.Peer-Reviewed Original ResearchConceptsIntracellular lipid metabolismMitochondrial biogenesisAMPK activityMitochondrial functionProtein kinase activityLipid metabolismProtein kinaseKinase activityAge-associated reductionBiogenesisOld ratsAMPKSkeletal muscleRecent studiesInsulin resistanceChronic activationMetabolismAcute stimulationFat oxidationImportant roleAcid feedingKinaseRatsActivityRegulation
2006
AMP-activated protein kinase regulates the assembly of epithelial tight junctions
Zhang L, Li J, Young LH, Caplan MJ. AMP-activated protein kinase regulates the assembly of epithelial tight junctions. Proceedings Of The National Academy Of Sciences Of The United States Of America 2006, 103: 17272-17277. PMID: 17088526, PMCID: PMC1859922, DOI: 10.1073/pnas.0608531103.Peer-Reviewed Original ResearchConceptsTight junction assemblyJunction assemblyProtein kinaseLKB1-dependent phosphorylationCell polarization processCellular energy statusActivation of AMPKTight junctionsEukaryotic cellsTight junction structureAMPKMDCK cellsEpithelial tight junctionsEnergy statusKinaseEpithelial cellsAbsence of Ca2AssemblyTransepithelial electrical resistanceParacellular fluxZonula occludens-1CellsRecent studiesOccludens-1LKB1Activation of AMPK α- and γ-isoform complexes in the intact ischemic rat heart
Li J, Coven DL, Miller EJ, Hu X, Young ME, Carling D, Sinusas AJ, Young LH. Activation of AMPK α- and γ-isoform complexes in the intact ischemic rat heart. AJP Heart And Circulatory Physiology 2006, 291: h1927-h1934. PMID: 16648175, DOI: 10.1152/ajpheart.00251.2006.Peer-Reviewed Original ResearchConceptsAMPK activityAMPK complexAlpha subunit activationDifferent subunit isoformsSerine-threonine kinaseCellular metabolic processesGamma subunit isoformsRegulatory betaAlpha-subunit contentHeterotrimeric complexProtein kinaseAMPK αMultiple isoformsKinase activitySubunit isoformsMetabolic processesAMPK phosphorylationAMPKIsoformsPhysiological regulationKinaseMutationsComplexesKey rolePathophysiological importance
2005
AMP-Activated Protein Kinase Activates p38 Mitogen-Activated Protein Kinase by Increasing Recruitment of p38 MAPK to TAB1 in the Ischemic Heart
Li J, Miller EJ, Ninomiya-Tsuji J, Russell RR, Young LH. AMP-Activated Protein Kinase Activates p38 Mitogen-Activated Protein Kinase by Increasing Recruitment of p38 MAPK to TAB1 in the Ischemic Heart. Circulation Research 2005, 97: 872-879. PMID: 16179588, DOI: 10.1161/01.res.0000187458.77026.10.Peer-Reviewed Original ResearchMeSH KeywordsAminoimidazole CarboxamideAMP-Activated Protein KinasesAnimalsAnisomycinCell HypoxiaEnzyme ActivationGlucoseGlucose Transporter Type 4Intracellular Signaling Peptides and ProteinsMaleMAP Kinase Kinase 3MiceMice, Inbred C57BLMice, TransgenicMultienzyme ComplexesMyocardial IschemiaP38 Mitogen-Activated Protein KinasesProtein Serine-Threonine KinasesProtein TransportRatsRats, Sprague-DawleyRibonucleotidesConceptsMitogen-activated protein kinaseP38 mitogen-activated protein kinaseMAPK kinase 3P38 MAPK activationAlpha2 catalytic subunitProtein kinaseMAPK activationCatalytic subunitGlucose transportStress-signaling pathwaysAMPK activator 5Role of AMPKProtein kinase 1Direct molecular targetP38 MAPK inhibitorMouse heartsAMPK complexProtein TAB1Scaffold proteinGLUT4 translocationUpstream kinaseAMPK activationKinase 3Kinase 1MAPK inhibitorAMP-Activated Protein Kinase: A Key Stress Signaling Pathway in the Heart
Young LH, Li J, Baron SJ, Russell RR. AMP-Activated Protein Kinase: A Key Stress Signaling Pathway in the Heart. Trends In Cardiovascular Medicine 2005, 15: 110-118. PMID: 16039971, DOI: 10.1016/j.tcm.2005.04.005.BooksConceptsLeft ventricular contractile dysfunctionVentricular contractile dysfunctionFatty acid oxidationProtein kinaseCardiovascular actionsHeart failureContractile dysfunctionWolff-ParkinsonWhite syndromeTransgenic miceGlycogen overloadStress Signaling PathwaysImportant regulatory mechanismSignaling pathwaysHeartAcid oxidationGlucose transportMolecular mechanismsAnabolic pathwaysRegulatory mechanismsAMPAMPK – A pivotal rheostat in the control of cardiac metabolism
Miller E, Russell R, Li J, Young L. AMPK – A pivotal rheostat in the control of cardiac metabolism. Drug Discovery Today Disease Mechanisms 2005, 2: 93-100. DOI: 10.1016/j.ddmec.2005.05.008.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsMyocardial stress responseRegulation of AMPKProtein kinaseCentral regulatorStress responseAMPKNon-metabolic actionsCoronary artery diseaseNovel cardioprotective strategiesType 2 diabetesPotential novel approachArtery diseaseCardioprotective strategiesCardiac metabolismMetabolic actionsPossible roleKinaseRheostatRegulatorRegulationMetabolismDiabetesDiseaseDual Mechanisms Regulating AMPK Kinase Action in the Ischemic Heart
Baron SJ, Li J, Russell RR, Neumann D, Miller EJ, Tuerk R, Wallimann T, Hurley RL, Witters LA, Young LH. Dual Mechanisms Regulating AMPK Kinase Action in the Ischemic Heart. Circulation Research 2005, 96: 337-345. PMID: 15653571, DOI: 10.1161/01.res.0000155723.53868.d2.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine MonophosphateAdenosine TriphosphateAminoimidazole CarboxamideAMP-Activated Protein Kinase KinasesAMP-Activated Protein KinasesAnimalsInfusions, IntravenousMaleMultienzyme ComplexesMyocardial IschemiaMyocardiumPhosphorylationProtein KinasesProtein Serine-Threonine KinasesRatsRats, Sprague-DawleyRecombinant ProteinsRibonucleotidesConceptsRecombinant AMPKAMPKK activityAMPK phosphorylationPhosphorylation of Thr172Gamma regulatory subunitsIschemic heartImportant signaling proteinAlpha catalytic subunitRat heartHeterotrimeric AMPKAMPKKHeterotrimeric complexActivation loopRegulatory subunitKinase actionSignaling proteinsCatalytic subunitProtein kinaseAMPK activityLow-flow ischemiaGamma subunitsAMPKInteraction of AMPPhosphorylationAddition of AMP
2004
Role of the nitric oxide pathway in AMPK-mediated glucose uptake and GLUT4 translocation in heart muscle
Li J, Hu X, Selvakumar P, Russell RR, Cushman SW, Holman GD, Young LH. Role of the nitric oxide pathway in AMPK-mediated glucose uptake and GLUT4 translocation in heart muscle. AJP Endocrinology And Metabolism 2004, 287: e834-e841. PMID: 15265762, DOI: 10.1152/ajpendo.00234.2004.Peer-Reviewed Original ResearchMeSH KeywordsAminoimidazole CarboxamideAMP-Activated Protein KinasesAnimalsBiological TransportEnzyme ActivationGlucoseGlucose Transporter Type 4Hypoglycemic AgentsIn Vitro TechniquesMaleMonosaccharide Transport ProteinsMultienzyme ComplexesMuscle ProteinsNitric OxideNitric Oxide SynthaseNitric Oxide Synthase Type IIIPapillary MusclesProtein Serine-Threonine KinasesProtein TransportRatsRats, Sprague-DawleyRibonucleotidesConceptsGLUT4 translocationAMPK stimulationGlucose transportAMPK catalytic subunitGlucose uptakeCell surfaceGlucose transporter GLUT4Serine-threonine kinaseEndothelial NO synthasePotential downstream mediatorsVesicular traffickingCatalytic subunitProtein kinaseAICAR treatmentCellular metabolismNitric oxide pathwayAMPKDownstream mediatorTranslocationEssential roleHeart muscleOxide pathwayCyclase pathwayPathwayAICAR
2003
Physiological role of AMP-activated protein kinase in the heart: graded activation during exercise
Coven DL, Hu X, Cong L, Bergeron R, Shulman GI, Hardie DG, Young LH. Physiological role of AMP-activated protein kinase in the heart: graded activation during exercise. AJP Endocrinology And Metabolism 2003, 285: e629-e636. PMID: 12759223, DOI: 10.1152/ajpendo.00171.2003.Peer-Reviewed Original ResearchConceptsAMPK activityProtein kinasePhysiological roleTotal AMPK activityAlpha2 catalytic subunitCellular metabolic processesAlpha catalytic subunitCardiac AMPK activityAMPK effectsAMPK activationMetabolic processesAMPKAkt phosphorylationKinasePhosphorylationSkeletal muscleSubunitsSubstrate metabolismActivationActivity increasesLesser extentMyocardial substrate metabolismMin of treadmillHigh-intensity exerciseActivity
2002
AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation
Zong H, Ren JM, Young LH, Pypaert M, Mu J, Birnbaum MJ, Shulman GI. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2002, 99: 15983-15987. PMID: 12444247, PMCID: PMC138551, DOI: 10.1073/pnas.252625599.Peer-Reviewed Original ResearchMeSH KeywordsAdenine NucleotidesAdenylate KinaseAnimalsCalcium-Calmodulin-Dependent Protein Kinase Type 2Calcium-Calmodulin-Dependent Protein Kinase Type 4Calcium-Calmodulin-Dependent Protein KinasesEnergy MetabolismEnzyme InductionGene Expression RegulationGenes, DominantGuanidinesMiceMice, TransgenicMitochondria, MuscleMuscle ProteinsMuscle, SkeletalPhosphocreatinePropionatesTranscription FactorsConceptsMitochondrial biogenesisPeroxisome proliferator-activated receptor-gamma coactivator-1alphaDominant negative mutantProliferator-activated receptor-gamma coactivator-1alphaRole of AMPReceptor-gamma coactivator-1alphaGamma coactivator-1alphaProtein kinaseAMPK inactivationEnergy deprivationBiogenesisAMPK activityDN-AMPKMuscle AMPKCritical adaptationKinase IVCritical regulatorAMP kinaseCoactivator-1alphaMitochondrial contentAMPKFuel sensorEnergy statusKinase
2001
Activation of glucose transport in the ischemic heart: Translocation of GLUT4 and GLUT1 by 5′-AMP-activated protein kinase
Young L, Russell R, Coven D, Shulman G, Sinusas A. Activation of glucose transport in the ischemic heart: Translocation of GLUT4 and GLUT1 by 5′-AMP-activated protein kinase. Journal Of Molecular And Cellular Cardiology 2001, 33: a145. DOI: 10.1016/s0022-2828(01)90556-5.Peer-Reviewed Original Research
1999
Regulation of myocardial glucose uptake and transport during ischemia and energetic stress
Young L, Russell R, Yin R, Caplan M, Ren J, Bergeron R, Shulman G, Sinusas A. Regulation of myocardial glucose uptake and transport during ischemia and energetic stress. The American Journal Of Cardiology 1999, 83: 25-30. PMID: 10750583, DOI: 10.1016/s0002-9149(99)00253-2.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsEnergetic stressEnergy-generating metabolic pathwaysMonophosphate-activated protein kinaseGlucose uptakeGlucose transport proteinProtein kinaseTransporter translocationTransport proteinsMolecular mechanismsMetabolic pathwaysCardiac glucose uptakeGlucose transporterCellular mechanismsGlucose transportFuel gaugeKinaseTranslocationGlucose entryModerate regional ischemiaSubsequent metabolismGlucose utilization increasesImportant roleUptakeGLUT4Stress