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Research article2004Peer reviewed

The 5 '-AMP-activated protein kinase gamma 3 isoform has a key role in carbohydrate and lipid metabolism in glycolytic skeletal muscle

Barnes BR, Marklund S, Steiler TL, Walter M, Hjalm G, Amarger V, Mahlapuu M, Leng Y, Johansson C, Galuska D, Lindgren K, Abrink M, Stapleton D, Zierath JR, Andersson L

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

Published in

Journal of Biological Chemistry
2004, Volume: 279, number: 37, pages: 38441-38447
Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

      SLU Authors

      • Hjälm, Göran

        • Department of Molecular Biosciences, Swedish University of Agricultural Sciences

          • Åbrink, Magnus

            • Department of Molecular Biosciences, Swedish University of Agricultural Sciences

            • UKÄ Subject classification

            Veterinary Science
            Animal and Dairy Science

            Publication identifier

            DOI: https://doi.org/10.1074/jbc.M405533200

            Permanent link to this page (URI)

            https://res.slu.se/id/publ/3864