title: Mutation in the γ2-subunit of AMP-activated protein kinase stimulates cardiomyocyte proliferation and hypertrophy independent of glycogen storage.
abstract: BACKGROUND
  AMP-activated protein kinase is a master regulator of cell metabolism and an attractive drug target for cancer and metabolic and cardiovascular diseases. Point mutations in the regulatory γ2-subunit of AMP-activated protein kinase (encoded by Prkag2 gene) caused a unique form of human cardiomyopathy characterized by cardiac hypertrophy, ventricular preexcitation, and glycogen storage. Understanding the disease mechanisms of Prkag2 cardiomyopathy is not only beneficial for the patients but also critical to the use of AMP-activated protein kinase as a drug target.
  
  
  OBJECTIVE
  We sought to identify the pro-growth-signaling pathway(s) triggered by Prkag2 mutation and to distinguish it from the secondary response to glycogen storage.
  
  
  RESULTS
  In a mouse model of N488I mutation of the Prkag2 gene (R2M), we rescued the glycogen storage phenotype by genetic inhibition of glucose-6-phosphate-stimulated glycogen synthase activity. Ablation of glycogen storage eliminated the ventricular preexcitation but did not affect the excessive cardiac growth in R2M mice. The progrowth effect in R2M hearts was mediated via increased insulin sensitivity and hyperactivity of Akt, resulting in activation of mammalian target of rapamycin and inactivation of forkhead box O transcription factor-signaling pathways. Consequently, cardiac myocyte proliferation during the postnatal period was enhanced in R2M hearts followed by hypertrophic growth in adult hearts. Inhibition of mammalian target of rapamycin activity by rapamycin or restoration of forkhead box O transcription factor activity by overexpressing forkhead box O transcription factor 1 rescued the abnormal cardiac growth.
  
  
  CONCLUSIONS
  Our study reveals a novel mechanism for Prkag2 cardiomyopathy, independent of glycogen storage. The role of γ2-AMP-activated protein kinase in cell growth also has broad implications in cardiac development, growth, and regeneration.
authors: From the Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington, Seattle (M.K., L.G.-M., G.G., Y.-Y.Y., S.C.K., J.X., W.W., R.T.); and MRC Protein Phosphorylation unit, College of Life Sciences, University of Dundee, Dundee, United Kingdom (R.W.H., K.S.). R.W.H. and K.S. are currently affiliated with Nestlé Institute of Health Sciences SA, Campus EPFL, Innovation Park, bâtiment G, Lausanne, Switzerland.
authors: Maengjo
authors: M
authors: Kim
authors: Roger W
authors: RW
authors: Hunter
authors: Lorena
authors: L
authors: Garcia-Menendez
authors: Guohua
authors: G
authors: Gong
authors: Yu-Ying
authors: YY
authors: Yang
authors: Stephen C
authors: SC
authors: Kolwicz
authors: Jason
authors: J
authors: Xu
authors: Kei
authors: K
authors: Sakamoto
authors: Wang
authors: W
authors: Wang
authors: Rong
authors: R
authors: Tian
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000502:physiology*; D000818:Animals; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002455:Cell Division; D049108:Cell Enlargement; D004195:Disease Models, Animal; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D055879:Gene Knock-In Techniques; D005816:Genetic Complementation Test; D019298:Glucose-6-Phosphate / Q000378:metabolism / Q000494:pharmacology; D006003:Glycogen / Q000096:biosynthesis*; D006008:Glycogen Storage Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006006:Glycogen Synthase / Q000235:genetics / Q000502:physiology; D007333:Insulin Resistance / Q000235:genetics; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D011226:Pre-Excitation Syndromes / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D019298:Glucose-6-Phosphate; D006003:Glycogen; D006006:Glycogen Synthase; C546843:mTOR protein, mouse; C514862:Akt1 protein, mouse; C576788:PRKAG2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D020123:Sirolimus
keywords: cardiac hypertrophy; glycogen storage; mutation in AMPK γ2 subunit; proliferation