title: Aberrant activation of AMP-activated protein kinase remodels metabolic network in favor of cardiac glycogen storage.
abstract: AMP-activated protein kinase (AMPK) responds to impaired cellular energy status by stimulating substrate metabolism for ATP generation. Mutation of the gamma2 regulatory subunit of AMPK in humans renders the kinase insensitive to energy status and causes glycogen storage cardiomyopathy via unknown mechanisms. Using transgenic mice expressing one of the mutant gamma2 subunits (N488I) in the heart, we found that aberrant high activity of AMPK in the absence of energy deficit caused extensive remodeling of the substrate metabolism pathways to accommodate increases in both glucose uptake and fatty acid oxidation in the hearts of gamma2 mutant mice via distinct, yet synergistic mechanisms resulting in selective fuel storage as glycogen. Increased glucose entry in the gamma2 mutant mouse hearts was directed through the remodeled metabolic network toward glycogen synthesis and, at a substantially higher glycogen level, recycled through the glycogen pool to enter glycolysis. Thus, the metabolic consequences of chronic activation of AMPK in the absence of energy deficiency is distinct from those previously reported during stress conditions. These findings are of particular importance in considering AMPK as a target for the treatment of metabolic diseases.
authors: NMR Laboratory for Physiological Chemistry, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115, USA.
authors: Ivan
authors: I
authors: Luptak
authors: Mei
authors: M
authors: Shen
authors: Huamei
authors: H
authors: He
authors: Michael F
authors: MF
authors: Hirshman
authors: Nicolas
authors: N
authors: Musi
authors: Laurie J
authors: LJ
authors: Goodyear
authors: Jie
authors: J
authors: Yan
authors: Hiroko
authors: H
authors: Wakimoto
authors: Hiroyuki
authors: H
authors: Morita
authors: Michael
authors: M
authors: Arad
authors: Christine E
authors: CE
authors: Seidman
authors: J G
authors: JG
authors: Seidman
authors: Joanne S
authors: JS
authors: Ingwall
authors: James A
authors: JA
authors: Balschi
authors: Rong
authors: R
authors: Tian
mesh_terms: D055372:AMP-Activated Protein Kinases; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics*; D004789:Enzyme Activation / Q000235:genetics; D006003:Glycogen / Q000378:metabolism*; D006008:Glycogen Storage Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009097:Multienzyme Complexes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015219:Substrate Cycling / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D009097:Multienzyme Complexes; D006003:Glycogen; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases