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Aim: The polyphenol resveratrol has in animal studies been shown to influence several pathways of importance for angiogenesis in skeletal muscle. The aim was to examine the angiogenic effect of resveratrol supplementation with parallel exercise training in aged men. Methods: Forty-three healthy physically inactive aged men (65±1 years) were divided into A) a training group that conducted 8 weeks of intense exercise training where half of the subjects received a daily intake of either 250 mg trans resveratrol (n=14) and the other half received placebo (n=13); and B) a non-training group that received either 250 mg trans resveratrol (n=9) or placebo (n=7). Results: The group that trained with placebo showed a ~20% increase in capillary to fiber (C:F) ratio, an increase in the muscle protein expression of vascular endothelial growth factor (VEGF), VEGF receptor-2, and tissue inhibitor of matrix metalloproteinase (TIMP-1) but unaltered thrombospodin-1 (TSP-1) levels. Muscle interstitial VEGF and TSP-1 protein levels were unchanged after the training period. The group training with resveratrol supplementation did not show an increase in C:F ratio or an increase in muscle VEGF protein. Muscle TIMP-1 protein levels were lower in the training and resveratrol group than in the training and placebo group. Both training groups showed an increase in Forkhead box O1 protein. In the non-training groups, TIMP-1 protein was lower in the resveratrol group than the placebo group after 8 weeks. Conclusion: These data show that exercise training has a strong angiogenic effect whereas resveratrol supplementation may limit basal and training-induced angiogenesis.

Background: The aim was to test the hypothesis that one week of bed rest will reduce mitochondrial number and expression and activity of oxidative proteins in human skeletal muscle, but that exercise-induced intracellular signaling as well as mRNA and microRNA (miR) responses are maintained after bed rest. Research Design and Methods: Twelve young, healthy, male subjects completed 7 days of bed rest with vastus lateralis muscle biopsies taken before and after bed rest. In addition, muscle biopsies were obtained from 6 of the subjects prior to, immediately after and 3h after 45 min one-legged knee extensor exercise performed before and after bed rest. Results: Maximal oxygen uptake decreased 5% and exercise endurance decreased non-significantly 25% by bed rest. Bed rest reduced skeletal muscle mitochondrial DNA/nuclear DNA content 15%, hexokinase II and sirtuin 1 protein content ~45%, 3-hydroxyacyl-CoA dehydrogenase and citrate synthase activity ~8% as well as miR-1 and miR-133a content ~10%. Cytochrome c and vascular endothelial growth factor (VEGF) protein content as well as capillarization did however not change significantly with bed rest. Acute exercise increased AMP-activated protein kinase phosphorylation, peroxisome proliferator activated receptor ¿ coactivator-1a and VEGF mRNA content in skeletal muscle before bed rest, but the responses were abolished after bed rest. Conclusion: The present findings indicate that only 7 days of physical inactivity reduce skeletal muscle metabolic capacity as well as abolish exercise-induced adaptive gene responses likely reflecting the interference with the ability of skeletal muscle to adapt to exercise.

The transcriptional coactivator peroxisome proliferator activated receptor (PPAR)-¿ coactivator (PGC)-1a plays a role in regulation of several metabolic pathways. By use of whole body PGC-1a knockout (KO) mice we investigated the role of PGC-1a in fasting, acute exercise and exercise training induced regulation of key proteins in gluconeogenesis and metabolism in the liver. In both wild type (WT) and PGC-1a KO mice liver, the mRNA content of the gluconeogenic proteins glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) was upregulated during fasting. Pyruvate carboxylase (PC) remained unchanged after fasting in WT mice, but was upregulated in PGC-1a KO mice. In response to a single exercise bout G6Pase mRNA was upregulated in both genotypes, whereas no significant changes were detected in PEPCK or PC mRNA. While G6Pase and PC protein remained unchanged, liver PEPCK protein content was higher in trained than untrained mice of both genotypes. The mRNA content of the mitochondrial proteins Cytochrome c (Cyt c) and cytochrome oxidase (COX) I was unchanged in response to fasting. The mRNA and protein content of Cyt c and COXI increased in the liver in response to a single exercise bout and prolonged exercise training, respectively, in WT mice, but not in PGC-1a KO mice. Neither fasting nor exercise affected the mRNA expression of antioxidant enzymes in the liver and knockout of PGC-1a had no effect. In conclusion, these results suggest that PGC-1a plays a pivotal role in regulation of Cyt c and COXI expression in the liver in response to a single exercise bout and prolonged exercise training, which implies that exercise training induced improvements in oxidative capacity of the liver is regulated by PGC-1a.