Developmental Enhancement of Adenylate Kinase-AMPK Metabolic Signaling Axis Supports Stem Cell Cardiac Differentiation 英文参考文献.docVIP

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Developmental Enhancement of Adenylate Kinase-AMPK Metabolic Signaling Axis Supports Stem Cell Cardiac Differentiation 英文参考文献.doc

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Developmental Enhancement of Adenylate Kinase-AMPK Metabolic Signaling Axis Supports Stem Cell Cardiac Differentiation 英文参考文献

DevelopmentalEnhancementofAdenylateKinase-AMPK MetabolicSignalingAxisSupportsStemCellCardiac Differentiation PetrasP.Dzeja*.,SusanChung.,RandolphS.Faustino,AttaBehfar,AndreTerzic* MarriottHeartDiseaseResearchProgram,DivisionofCardiovascularDiseases,DepartmentsofMedicine,MolecularPharmacologyandExperimentalTherapeutics,and MedicalGenetics,MayoClinic,Rochester,Minnesota,UnitedStatesofAmerica Abstract Background: Energetic and metabolic circuits that orchestrate cell differentiation arelargely unknown. Adenylate kinase (AK)andassociatedAMP-activatedproteinkinase(AMPK)constituteamajormetabolicsignalingaxis,yettheroleofthis systeminguidingdifferentiationandlineagespecificationremainsundefined. Methods and Results: Cardiac stem cell differentiation is the earliest event in organogenesis, and a suitable model of developmental bioenergetics. Molecular profiling of embryonic stem cells during cardiogenesis revealed here a distinct expressionpatternofadenylatekinaseandAMPKgenesthatencodetheAK-AMP-AMPKmetabolicsurveillanceaxis.Cardiac differentiationupregulatedcytosolicAK1isoform,doubledAMP-generatingadenylatekinaseactivity,andincreasedAMP/ ATP ratio. At cell cycle initiation, AK1 translocated into the nucleus and associated with centromeres during energy- consumingmetaphase.Concomitantly,thecardiacAMP-signalreceptorAMPKa2wasupregulatedandredistributedtothe nuclear compartment as signaling-competent phosphorylated p-AMPKa(Thr172). The cardiogenic growth factor TGF-b promotedAK1expression,whileknockdownofAK1,AK2andAK5activitieswithsiRNAorsuppressionbyhyperglycemia disrupted cardiogenesis compromising mitochondrial and myofibrillar network formation and contractile performance. Induction of creatine kinase, the alternate phosphotransfer pathway, compensated for adenylate kinase-dependent energeticdeficits. Conclusions: Developmental deployment and upregulation of the adenylate kinase/AMPK tandem provides a nucleocytosolic energetic and metabolic signaling vector integral to