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.
Barnes
Brian R
BR
Department of Surgical Sciences and the Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Marklund
Stefan
S
Steiler
Tatiana L
TL
Walter
Mark
M
Hjälm
Göran
G
Amarger
Valerie
V
Mahlapuu
Margit
M
Leng
Ying
Y
Johansson
Carina
C
Galuska
Dana
D
Lindgren
Kerstin
K
Abrink
Magnus
M
Stapleton
David
D
Zierath
Juleen R
JR
Andersson
Leif
L
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
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