PGC-1alpha mediates exercise-induced skeletal muscle VEGF expression in mice.
The aim of the present study was to test the hypothesis that PGC-1alpha 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-1alpha-dependent mechanism. Whole body PGC-1alpha 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-1alpha KO mice, VEGF protein expression was approximately 60-80% lower and the capillary-to-fiber ratio approximately 20% lower than in WT. Basal VEGF mRNA expression was similar in WT and PGC-1alpha 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 approximately 50% in WT mice but with no effect in PGC-1alpha KO mice. Furthermore, a training-induced prevention of an age-associated decline in VEGF protein content was observed in WT but not in PGC-1alpha KO muscles. In addition, repeated AICAR treatments increased skeletal muscle VEGF protein expression approximately 15% in WT but not in PGC-1alpha KO mice. This study shows that PGC-1alpha 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-1alpha.
Leick
Lotte
L
Department of Biology, University of Copenhagen, Universitetsparken 13, 2100 Copenhagen, Denmark. LLeick@bio.ku.dk
Hellsten
Ylva
Y
Fentz
Joachim
J
Lyngby
Stine S
SS
Wojtaszewski
Jørgen F P
JF
Hidalgo
Juan
J
Pilegaard
Henriette
H
D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010805:Physical Conditioning, Animal / Q000502:physiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
D007004:Hypoglycemic Agents; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C485290:Ppargc1a protein, mouse; D012265:Ribonucleotides; D015534:Trans-Activators; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000620:Aminoimidazole Carboxamide; C031143:AICA ribonucleotide