The 5′-AMP-activated Protein Kinase γ3 Isoform Has a Key Role in Carbohydrate and Lipid Metabolism in Glycolytic Skeletal Muscle
| Autor: | Göran Hjälm, Leif Andersson, Carina Johansson, Margit Mahlapuu, Tatiana L. Steiler, Valérie Amarger, Juleen R. Zierath, Brian R. Barnes, Dana Galuska, Ying Leng, Stefan L. Marklund, Mark R. Walter, Magnus Åbrink, Kerstin Lindgren, David Stapleton |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Blood Glucose
medicine.medical_specialty DNA Complementary Swine Transgene Mutation Missense Mice Transgenic AMP-Activated Protein Kinases Protein Serine-Threonine Kinases Transfection Biochemistry 5'-AMP-Activated Protein Kinase Mice chemistry.chemical_compound AMP-activated protein kinase Multienzyme Complexes Internal medicine medicine Animals Insulin Protein Isoforms Glycolysis RNA Messenger Muscle Skeletal Protein kinase A Molecular Biology Triglycerides Mice Knockout Models Genetic Glycogen biology Reverse Transcriptase Polymerase Chain Reaction Temperature AMPK Skeletal muscle Cell Biology Lipid Metabolism Molecular biology Glucose Endocrinology medicine.anatomical_structure chemistry COS Cells biology.protein Protein Kinases |
| Zdroj: | Journal of Biological Chemistry. 279:38441-38447 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m405533200 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|