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This Article Full Text Full Text (PDF) All Versions of this Article: 297/1/E92    most recent 00076.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Leick, L. Articles by Pilegaard, H. PubMed PubMed Citation Articles by Leick, L. Articles by Pilegaard, H.

PGC-1 mediates exercise-induced skeletal muscle VEGF expression in mice

¹Centre of Inflammation and Metabolism and Copenhagen Muscle Research Centre, Department of Biology, Section of Molecular, Cellular, and Integrative Physiology; ²Copenhagen Muscle Research Centre, Molecular Physiology Group, Section of Human Physiology, Department of Exercise and Sport Sciences, University of Copenhagen, Copenhagen, Denmark; and ³Institute of Neurosciences and Department of Cellular Biology, Physiology, and Immunology, Autonomous University of Barcelona, Barcelona, Spain

Submitted 6 February 2009 ; accepted in final form 22 April 2009

The aim of the present study was to test the hypothesis that PGC-1 is required for exercise-induced VEGF expression in both young and old mice and that AMPK activation leads to increased VEGF expression through a PGC-1-dependent mechanism. Whole body PGC-1 knockout (KO) and littermate wild-type (WT) mice were submitted to either 1) 5 wk of exercise training, 2) lifelong (from 2 to 13 mo of age) exercise training in activity wheel, 3) a single exercise bout, or 4) 4 wk of daily subcutaneous AICAR or saline injections. In skeletal muscle of PGC-1 KO mice, VEGF protein expression was 60–80% lower and the capillary-to-fiber ratio 20% lower than in WT. Basal VEGF mRNA expression was similar in WT and PGC-1 KO mice, but acute exercise and AICAR treatment increased the VEGF mRNA content in WT mice only. Exercise training of young mice increased skeletal muscle VEGF protein expression 50% in WT mice but with no effect in PGC-1 KO mice. Furthermore, a training-induced prevention of an age-associated decline in VEGF protein content was observed in WT but not in PGC-1 KO muscles. In addition, repeated AICAR treatments increased skeletal muscle VEGF protein expression 15% in WT but not in PGC-1 KO mice. This study shows that PGC-1 is essential for exercise-induced upregulation of skeletal muscle VEGF expression and for a training-induced prevention of an age-associated decline in VEGF protein content. Furthermore, the findings suggest an AMPK-mediated regulation of VEGF expression through PGC-1.

exercise training; angiogenesis; adenosine 5'-monophosphate-activated protein kinase; peroxisome proliferator-activated receptor- coactivator-1; vascular endothelial growth factor