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Lack of AMPK2 enhances pyruvate dehydrogenase activity during exercise

¹Section of Human Physiology, Department of Exercise and Sport Sciences, and ²Department of Molecular Biology, Copenhagen Muscle Research Centre, University of Copenhagen; ³Department of Molecular Muscle Biology, Rigshospitalet, Copenhagen, and Department of Biomedical Science, University of Copenhagen, Copenhagen, Denmark; ⁴Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (UMR8104); and ⁵Institut National de la Santé et de la Recherche Médicale, U567, Paris, France

Submitted 18 June 2007 ; accepted in final form 19 August 2007

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 with rest, treadmill running increased AMPK1 activity in ₂KO mice (90%, P < 0.01) and increased AMPK2 activity in wild-type (WT) mice (110%, P < 0.05), leading to increased AMPK Thr¹⁷² (WT: 40%, ₂KO: 100%, P < 0.01) and ACC Ser²²⁷ phosphorylation (WT: 70%, ₂KO: 210%, P < 0.01). Compared with rest, exercise significantly induced PDH-E₁ site 1 (WT: 20%, ₂KO: 62%, P < 0.01) and site 2 (only ₂KO: 83%, P < 0.01) dephosphorylation and PDH_a [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 PDH_a 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 AMPK2 expression. During exercise, ₂KO muscles display deranged energy homeostasis despite enhanced glycolytic flux and PDH_a activity. This may be linked to decreased mitochondrial oxidative capacity.

adenosine 5'-monophosphate-activated protein kinase; 5-aminoimidazole-4-carboxamide-1--D-ribofuranoside; treadmill running; glucose metabolism

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