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

1 Centre of Inflammation and Metabolism and Copenhagen Muscle Research Centre, Department of Biology, Section of Molecular, Cellular, and Integrative Physiology; 2 Copenhagen Muscle Research Centre, Molecular Physiology Group, Section of Human Physiology, Department of Exercise and Sport Sciences, University of Copenhagen, Copenhagen, Denmark; and 3 Institute 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 Address for reprint requests and other correspondence: L. Leick, Dept. of Biology, Univ. of Copenhagen, Universitetsparken 13, 2100 Copenhagen, Denmark (e-mail: LLeick{at}bio.ku.dk )