Leick Lotte, Hellsten Ylva, Fentz Joachim, Lyngby Stine S, Wojtaszewski Jørgen F P, Hidalgo Juan, Pilegaard Henriette
Department of Biology, University of Copenhagen, Universitetsparken 13, 2100 Copenhagen, Denmark.
Am J Physiol Endocrinol Metab. 2009 Jul;297(1):E92-103. doi: 10.1152/ajpendo.00076.2009. Epub 2009 Apr 28.
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.
在年轻和老年小鼠中，运动诱导的血管内皮生长因子（VEGF）表达需要过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α），并且腺苷酸活化蛋白激酶（AMPK）激活通过依赖PGC-1α的机制导致VEGF表达增加。将全身PGC-1α基因敲除（KO）小鼠及其同窝野生型（WT）小鼠分为四组，分别进行如下处理：1）5周的运动训练；2）终身（2至13月龄）在活动轮中进行运动训练；3）单次运动；4）连续4周每日皮下注射AICAR或生理盐水。在PGC-1α KO小鼠的骨骼肌中，VEGF蛋白表达比WT小鼠低约60-80%，毛细血管与肌纤维比例低约20%。WT小鼠和PGC-1α KO小鼠的基础VEGF mRNA表达相似，但急性运动和AICAR处理仅增加了WT小鼠的VEGF mRNA含量。年轻小鼠的运动训练使WT小鼠骨骼肌VEGF蛋白表达增加约50%，但对PGC-1α KO小鼠无影响。此外，在WT小鼠中观察到训练可预防与年龄相关的VEGF蛋白含量下降，但在PGC-1α KO小鼠的肌肉中未观察到。此外，重复AICAR处理使WT小鼠骨骼肌VEGF蛋白表达增加约15%，但对PGC-1α KO小鼠无影响。本研究表明，PGC-1α对于运动诱导的骨骼肌VEGF表达上调以及训练诱导的预防与年龄相关的VEGF蛋白含量下降至关重要。此外，研究结果提示AMPK通过PGC-1α介导对VEGF表达的调节。
