Effects of α‐AMPK knockout on exercise‐induced gene activation in mouse skeletal muscle

SB Jørgensen, JFP Wojtaszewski, B Viollet… - The FASEB …, 2005 - Wiley Online Library
SB Jørgensen, JFP Wojtaszewski, B Viollet, F Andreelli, JB Birk, Y Hellsten, P Schjerling
The FASEB journal, 2005Wiley Online Library
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 …
Abstract
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 FOXOl 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.
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