Submitted on February 6, 2009
Revised on April 22, 2009
Accepted on April 22, 2009
PGC-1
mediates exercise-induced skeletal muscle VEGF expression in mice
Lotte Leick1*, Ylva Hellsten2, Joakim Fentz2, Stine Secher Lyngby2, Jorgen F.P. Wojtaszewski3, Juan Hidalgo4, and Henriette Pilegaard2
1 Copenhagen University
2 University of Copenhagen
3 Copenhagen Muscle Research Centre
4 Universidad Autonoma de Barcelona
* To whom correspondence should be addressed. E-mail: lleick{at}aki.ku.dk.
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 knock-out (KO) and littermate wildtype (WT) mice were submitted to either: 1) five weeks of exercise training, 2) lifelong (from 2 - 13 month of age) exercise training in activity wheel, 3) a single exercise bout, 4) four weeks 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 was ~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 up regulation 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.
