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2 5'AMP Activated Protein Kinase enhances Pyruvate Dehydrogenase activity during exercise
1 Guldbergs Plads 8 1th, Copenhagen, 2200, Denmark
2 Department of Human Physiology, CMRC, Copenhagen, Denmark
3 Department of Human Physiology, Institute of Exercise and Sport Physiology, Copenhagen, Denmark
4 Dep. of Endocrinology Metabolism and Cancer, Institute Cochin, INSERM, CNRS, Rene Descartes University, Paris, France
5 Copenhagen Muscle Research Centre, Dep. for Molecular Muscle Biology, Rigshospitalet, Copenhagen, Denmark
6 United States
* To whom correspondence should be addressed. E-mail: jwojtaszewski{at}ifi.ku.dk.
5'AMP activated protein kinase (AMPK) was recently suggested to regulate pyruvate dehydrogenase (PDH) activity and thus pyruvate entry into the mitochondrion. We aimed to provide evidence for a direct link between AMPK and PDH in resting and metabolically challenged (exercised) skeletal muscle. Compared to rest treadmill running increased 
1-AMPK activity in 2KO mice (by 90%, P<0.01), and increased 2-AMPK activity in WT mice (by 110%, P<0.05), leading to increased AMPK Thr172 (WT: by 40%, 2KO: by 100%, P<0.01) and ACC
Ser227 phosphorylation (WT: by 70%, 2KO by 210%, P<0.01). Compared to rest, exercise significantly induced PDH-E1 site 1 (WT: by 20%, 2KO: by 62%, P<0.01) and site 2 (only 2KO: by 83%, P<0.01) dephosphorylation and PDHa activity (by ~200% in both genotypes (P<0.01)). Compared with WT, PDH dephosphorylation and activation was markedly enhanced in the 2KO mice both at rest and during exercise. The increased PDHa activity during exercise was associated with elevated glycolytic flux, and muscles from the 2KO mice displayed marked lactate accumulation and deranged energy homeostasis. Whereas mitochondrial DNA content was normal, the expression of several mitochondrial proteins was significantly decreased in muscle of 2KO mice. In isolated resting EDL muscles, activation of AMPK signaling by AICAR did not change PDH-E1 phosphorylation in either genotype. PDH is activated in mouse skeletal muscle in response to exercise and is independent of 2-AMPK expression. During exercise, 2-AMPK knockout muscles display deranged energy homeostasis despite enhanced glycolytic flux and PDHa activity. This may be linked to decreased mitochondrial oxidative capacity.
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