title: The 5'-AMP-activated protein kinase gamma3 isoform has a key role in carbohydrate and lipid metabolism in glycolytic skeletal muscle.
abstract: 5'-AMP-activated protein kinase (AMPK) is a metabolic stress sensor present in all eukaryotes. A dominant missense mutation (R225Q) in pig PRKAG3, encoding the muscle-specific gamma3 isoform, causes a marked increase in glycogen content. To determine the functional role of the AMPK gamma3 isoform, we generated transgenic mice with skeletal muscle-specific expression of wild type or mutant (225Q) mouse gamma3 as well as Prkag3 knockout mice. Glycogen resynthesis after exercise was impaired in AMPK gamma3 knock-out mice and markedly enhanced in transgenic mutant mice. An AMPK activator failed to increase skeletal muscle glucose uptake in AMPK gamma3 knock-out mice, whereas contraction effects were preserved. When placed on a high fat diet, transgenic mutant mice but not knock-out mice were protected against excessive triglyceride accumulation and insulin resistance in skeletal muscle. Transfection experiments reveal the R225Q mutation is associated with higher basal AMPK activity and diminished AMP dependence. Our results validate the muscle-specific AMPK gamma3 isoform as a therapeutic target for prevention and treatment of insulin resistance.
authors.affiliation: Department of Surgical Sciences and the Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Barnes
authors.forename: Stefan
authors.initials: S
authors.lastname: Marklund
authors.forename: Tatiana L
authors.initials: TL
authors.lastname: Steiler
authors.forename: Mark
authors.initials: M
authors.lastname: Walter
authors.forename: Göran
authors.initials: G
authors.lastname: Hjälm
authors.forename: Valerie
authors.initials: V
authors.lastname: Amarger
authors.forename: Margit
authors.initials: M
authors.lastname: Mahlapuu
authors.forename: Ying
authors.initials: Y
authors.lastname: Leng
authors.forename: Carina
authors.initials: C
authors.lastname: Johansson
authors.forename: Dana
authors.initials: D
authors.lastname: Galuska
authors.forename: Kerstin
authors.initials: K
authors.lastname: Lindgren
authors.forename: Magnus
authors.initials: M
authors.lastname: Abrink
authors.forename: David
authors.initials: D
authors.lastname: Stapleton
authors.forename: Juleen R
authors.initials: JR
authors.lastname: Zierath
authors.forename: Leif
authors.initials: L
authors.lastname: Andersson
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D019556:COS Cells; D018076:DNA, Complementary / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006019:Glycolysis; D007328:Insulin / Q000378:metabolism; D050356:Lipid Metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008957:Models, Genetic; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism*; D020125:Mutation, Missense; D020033:Protein Isoforms; D011494:Protein Kinases / Q000737:chemistry* / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine; D013696:Temperature; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D018076:DNA, Complementary; D007328:Insulin; D009097:Multienzyme Complexes; D020033:Protein Isoforms; D012333:RNA, Messenger; D014280:Triglycerides; D006003:Glycogen; D011494:Protein Kinases; C526221:Prkag3 protein, mouse; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose