Opposite transcriptional regulation in skeletal muscle of AMP-activated protein kinase gamma3 R225Q transgenic versus knock-out mice.
AMP-activated protein kinase (AMPK) is an evolutionarily conserved heterotrimer important for metabolic sensing in all eukaryotes. The muscle-specific isoform of the regulatory gamma-subunit of the kinase, AMPK gamma3, has an important role in glucose uptake, glycogen synthesis, and fat oxidation in white skeletal muscle, as previously demonstrated by physiological characterization of AMPK gamma3 mutant (R225Q) transgenic (TgPrkag3(225Q)) and gamma3 knock-out (Prkag3(-/-)) mice. We determined AMPK gamma3-dependent regulation of gene expression by analyzing global transcription profiles in glycolytic skeletal muscle from gamma3 mutant transgenic and knock-out mice using oligonucleotide microarray technology. Evidence is provided for coordinated and reciprocal regulation of multiple key components in glucose and fat metabolism, as well as skeletal muscle ergogenics in TgPrkag3(225Q) and Prkag3(-/-) mice. The differential gene expression profile was consistent with the physiological differences between the models, providing a molecular mechanism for the observed phenotype. The striking pattern of opposing transcriptional changes between TgPrkag3(225Q) and Prkag3(-/-) mice identifies differentially expressed targets being truly regulated by AMPK and is consistent with the view that R225Q is an activating mutation, in terms of its downstream effects. Additionally, we identified a wide array of novel targets and regulatory pathways for AMPK in skeletal muscle.
Nilsson
Elisabeth C
EC
Arexis AB, Biotech Center, Arvid Wallgrens Backe 20, SE-413 46 Göteborg, Sweden.
Long
Yun Chau
YC
Martinsson
Sofia
S
Glund
Stephan
S
Garcia-Roves
Pablo
P
Svensson
L Thomas
LT
Andersson
Leif
L
Zierath
Juleen R
JR
Mahlapuu
Margit
M
D055372:AMP-Activated Protein Kinases; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D020033:Protein Isoforms; D011494:Protein Kinases / Q000235:genetics* / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D018075:RNA, Complementary / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
D015415:Biomarkers; D008055:Lipids; D009097:Multienzyme Complexes; D020033:Protein Isoforms; D018075:RNA, Complementary; D012313:RNA; D006003:Glycogen; D011494:Protein Kinases; C526221:Prkag3 protein, mouse; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D010100:Oxygen