title: AMP-activated protein kinase regulates E3 ligases in rodent heart.
abstract: BACKGROUND
  The degradation of proteins by the ubiquitin proteasome system (UPS) is required for the maintenance of cellular homeostasis in the heart. An important regulator of metabolic homeostasis is AMP-activated protein kinase (AMPK). AMPK activation inhibits protein synthesis and activates autophagy, but whether AMPK plays a role in regulating protein breakdown through the UPS in the heart is not known.
  
  
  OBJECTIVE
  To determine whether AMPK enhances UPS-mediated protein degradation by directly regulating the ubiquitin ligases Atrogin-1 and muscle RING finger protein 1 (MuRF1) in the heart.
  
  
  RESULTS
  Nutrient deprivation and pharmacological or genetic activation of AMPK increased mRNA expression and protein levels of Atrogin-1 and MuRF1 and consequently enhanced protein degradation in neonatal cardiomyocytes. Inhibition of AMPK abrogated these effects. Using gene reporter and chromatin immunoprecipitation assays, we found that AMPK regulates MuRF1 expression by acting through the myocyte enhancer factor 2 (MEF2). We further validated these findings in vivo using MEF2-LacZ reporter mice. Furthermore, we demonstrated in adult cardiomyocytes that MuRF1 is necessary for AMPK-mediated proteolysis through the UPS in the heart. Consequently, MuRF1 knockout mice were protected from severe cardiac dysfunction during fasting.
  
  
  CONCLUSIONS
  AMPK regulates the transcription of Atrogin-1 and MuRF1 and enhances UPS-mediated protein degradation in heart. Specifically, AMPK regulates MuRF1 through the transcription factor MEF2. The absence of MuRF1 in the heart preserves cardiac function during fasting. The results strengthen the hypothesis that AMPK serves as a modulator of intracellular protein degradation in the heart.
authors.affiliation: Department of Internal Medicine, Division of Cardiology, University of Texas Health Science Center, Houston, TX 77030, USA.
authors.forename: Kedryn K
authors.initials: KK
authors.lastname: Baskin
authors.forename: Heinrich
authors.initials: H
authors.lastname: Taegtmeyer
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D047369:Chromatin Immunoprecipitation; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D005947:Glucose / Q000172:deficiency; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology*; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D009124:Muscle Proteins; D018006:Myogenic Regulatory Factors; D012333:RNA, Messenger; D000070584:Tripartite Motif Proteins; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases; D055372:AMP-Activated Protein Kinases; D005947:Glucose