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

Abstract

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.

Resveratrol modulates the angiogenic response to exercise training in skeletal muscles of aged men

“…This finding is in accordance with previous observations of a higher capillary-to-fiber ratio and increased VEGF mRNA levels in skeletal muscles of aged men after 8 wk of aerobic exercise training (13). One of the main hypotheses of the present study was that resveratrol would further enhance training-induced angiogenesis by promoting VEGF expression, as previously described (33,47). However, in contrast, the group that received resveratrol supplementation in combination with exercise training did not show an increase in the capillary-tofiber ratio or muscle VEGF protein levels.…”

“…SIRT-1 and AMPK regulate the activation and expression of the transcriptional coactivator peroxisome proliferator-activated receptor-␥ coactivator (PGC)-1␣ (27,29,54). Thus, resveratrol promotes PGC-1␣ (30,52), which, in turn, has been found to be essential for basal and exercise-induced increases in VEGF and for capillary growth in the skeletal muscle of young (6) and aged rodents (33,34). In addition, SIRT-1 may promote angiogenesis by deacetylating and inhibiting the angiostatic transcription factor forkhead box protein O1 (FoxO1) (47).…”

AMPKα is essential for acute exercise-induced gene responses but not for exercise training-induced adaptations in mouse skeletal muscle

“…Exercise-induced angiogenesis and VEGF content have previously been shown to be controlled by PGC-1␣ (10,33). However, in AMPK␣2 KD mice, exercise results in higher VEGF mRNA levels than in WT mice (66).…”

“…Interestingly, SIRT1 activity is increased through an AMPKmediated increase in NAD ϩ /NADH ratio (7). Additional studies support an AMPK-PGC-1␣ pathway mediating mitochondrial and metabolic gene expression/adaptations; both AMPK and PGC-1␣ regulate gene expression of mitochondrial proteins {cytochrome c (cyt c), cytochrome c oxidase I [COX-I; subunit of electron transport chain (ETC) complex IV], citrate synthase (CS), ATP-synthase, ␦-aminolevulinate synthase, mitochondrial transcription factor A} (22,25,35,62), metabolic and angiogenic proteins (GLUT4, VEGF) (25,33,43,66), and PGC-1␣ itself (19). A single injection of the AMP-mimetic compound 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside (AICAR) has been shown to activate AMPK and increase PGC-1␣, HKII, and VEGF mRNA levels in skeletal muscles of wild-type (WT) but not AMPK␣2-deficient mice (27,66).…”

The Long-Term Effects of Colostrum Supplementation and Sprint-Endurance Training on Plasma VEGF Levels in Male Wistar Rats

“…It was revealed that glycogen levels in skeletal muscle dropped during exercise, thereby resulting in increased cAMP phosphorylation; then, increased PGC-1α led in turn to the increase of VEGF gene expression. 38 In this regard, an inverse relationship was reported to exist between the level of interleukin-6 (IL-6) released from the skeletal muscle in the last stages of exercise and muscle glycogen content after exercise. More precisely, the less the muscle glycogen storage is at the end of exercise, the more the IL-6 release from skeletal muscles would be in the last stages of exercise.…”