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J. Biol. Chem., Vol. 279, Issue 37, 38441-38447, September 10, 2004

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The 5'-AMP-activated Protein Kinase 3 Isoform Has a Key Role in Carbohydrate and Lipid Metabolism in Glycolytic Skeletal Muscle^*

From the ^aDepartment of Surgical Sciences and the Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden SE-171 77, the ^cDepartment of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala Biomedical Center, Uppsala, Sweden SE-751 24, ^eSt. Vincent's Institute, Victoria, Fitzroy 3065, Australia, the ^gDepartment of Molecular Biosciences, Swedish University of Agricultural Sciences, Uppsala, Sweden SE-751 23, ^hArexis AB, Arvid Wallgrens Backe, Göteborg, Sweden SE-413 46, and the ^kDepartment of Medical Biochemistry and Microbiology, Uppsala University, Uppsala Biomedical Center, Uppsala, Sweden SE-751 24

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 3 isoform, causes a marked increase in glycogen content. To determine the functional role of the AMPK 3 isoform, we generated transgenic mice with skeletal muscle-specific expression of wild type or mutant (225Q) mouse 3 as well as Prkag3 knockout mice. Glycogen resynthesis after exercise was impaired in AMPK 3 knock-out mice and markedly enhanced in transgenic mutant mice. An AMPK activator failed to increase skeletal muscle glucose uptake in AMPK 3 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 3 isoform as a therapeutic target for prevention and treatment of insulin resistance.

Received for publication, May 18, 2004 , and in revised form, June 23, 2004.

^* This work was supported by grants from the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning, the Swedish Medical Research Council, the Swedish Diabetes Association, the Foundation for Scientific Studies of Diabetology, and the Novo-Nordisk Research Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^b These authors contributed equally to this work.

^d Funded by the Agricultural Functional Genomics program, Swedish University of Agricultural Sciences, Uppsala.

^f A National Health and Medical Research Council of Australia Dora Lush Scholar.

ⁱ An R. D. Wright Fellow.

^j To whom correspondence may be addressed: Dept. of Surgical Sciences, Section for Integrative Physiology, Karolinska Institute, von Eulers väg 4, II, SE-171 77 Stockholm, Sweden. Tel.: 46-8-524-87-580; Fax: 46-8-33-54-36; E-mail: Juleen.Zierath{at}fyfa.ki.se. l To whom correspondence may be addressed: Dept. of Medical Biochemistry and Microbiology, Uppsala University, Uppsala Biomedical Center, Box 597, SE-751 24 Uppsala, Sweden. Tel.: 46-18-471-4904; Fax: 46-18-471-4833; E-mail: Leif.Andersson{at}imbim.uu.se.

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