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E-mail contact: SBJorgensen{at}ifi.ku.dk
We tested the hypothesis that 5′AMP-activated protein kinase (AMPK) plays an important role in regulating the acute, exercise-induced activation of metabolic genes in skeletal muscle, which were dissected from whole-body α2- and α1-AMPK knockout (KO) and wild-type (WT) mice at rest, after treadmill running (90 min), and in recovery. Running increased α1-AMPK kinase activity, phosphorylation (P) of AMPK, and acetyl-CoA carboxylase (ACC)β in α2-WT and α2-KO muscles and increased α2-AMPK kinase activity in α2-WT. In α2-KO muscles, AMPK-P and ACCβ-P were markedly lower compared with α2-WT. However, in α1-WT and α1-KO muscles, AMPK-P and ACCβ-P levels were identical at rest and increased similarly during exercise in the two genotypes. The α2-KO decreased peroxisome-proliferator-activated receptor γ coactivator (PGC)-1α, uncoupling protein-3 (UCP3), and hexokinase II (HKII) transcription at rest but did not affect exercise-induced transcription. Exercise increased the mRNA content of PGC-1α, Forkhead box class O (FOXO)1, HKII, and pyruvate dehydrogenase kinase 4 (PDK4) similarly in α2-WT and α2-KO mice, whereas glucose transporter GLUT 4, carnitine palmitoyltransferase 1 (CPTI), lipoprotein lipase, and UCP3 mRNA were unchanged by exercise in both genotypes. CPTI mRNA was lower in α2-KO muscles than in α2-WT muscles at all time-points. In α1-WT and α1-KO muscles, running increased the mRNA content of PGC-1α and FOXO1 similarly. The α2-KO was associated with lower muscle adenosine 5′-triphosphate content, and the inosine monophosphate content increased substantially at the end of exercise only in α2-KO muscles. In addition, subcutaneous injection of 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) increased the mRNA content of PGC-1α, HKII, FOXO1, PDK4, and UCP3, and α2-KO abolished the AICAR-induced increases in PGC-1α and HKII mRNA. In conclusion, KO of the α2- but not the α1-AMPK isoform markedly diminished AMPK activation during running. Nevertheless, exercise-induced activation of the investigated genes in mouse skeletal muscle was not impaired in α1- or α2-AMPK KO muscles. Although it cannot be ruled out that activation of the remaining α-isoform is sufficient to increase gene activation during exercise, the present data do not support an essential role of AMPK in regulating exercise-induced gene activation in skeletal muscle.
Key Words: gene transcription • mRNA • AICAR • PGC-1α • PDK4 • adenosine nucleotides • inosine monophosphate
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