The 5'-AMP-activated protein kinase gamma3 isoform has a key role in carbohydrate and lipid metabolism in glycolytic skeletal muscle

• 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.

Nyckelord

Animals

Blood Glucose/metabolism

COS Cells

DNA; Complementary/metabolism

Glucose/metabolism

Glycogen/metabolism

Glycolysis

Insulin/metabolism

Lipids/*metabolism

Mice

Mice; Knockout

Mice; Transgenic

Models; Genetic

Multienzyme Complexes/*chemistry/*genetics

Muscle; Skeletal/*metabolism

Mutation; Missense

Protein Isoforms

Protein Kinases/*chemistry/*genetics

Protein-Serine-Threonine Kinases/*chemistry/*genetics

RNA; Messenger/metabolism

Research Support; Non-U.S. Gov't

Reverse Transcriptase Polymerase Chain Reaction

Swine

Temperature

Transfection

Triglycerides/metabolism

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)