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

Leick L, Hellsten Y, Fentz J, Lyngby SS, Wojtaszewski JF, Hidalgo J, Pilegaard H. PGC-1 alpha mediates exercise-induced skeletal muscle VEGF expression in mice. Am J Physiol Endocrinol Metab 297: E92-E103, 2009. First published April 28, 2009; doi: 10.1152/ajpendo.00076.2009.-The aim of the present study was to test the hypothesis that PGC-1 alpha 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 alpha-dependent mechanism. Whole body PGC-1 alpha 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 alpha KO mice, VEGF protein expression was similar to 60-80% lower and the capillary-to-fiber ratio similar to 20% lower than in WT. Basal VEGF mRNA expression was similar in WT and PGC-1 alpha 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 similar to 50% in WT mice but with no effect in PGC-1 alpha 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 alpha KO muscles. In addition, repeated AICAR treatments increased skeletal muscle VEGF protein expression similar to 15% in WT but not in PGC-1 alpha KO mice. This study shows that PGC-1 alpha 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 alpha.