Human VEGF gene expression in skeletal muscle: effect of acute normoxic and hypoxic exercise

1999 ◽  
Vol 277 (6) ◽  
pp. H2247-H2252 ◽  
Author(s):  
R. S. Richardson ◽  
H. Wagner ◽  
S. R. D. Mudaliar ◽  
R. Henry ◽  
E. A. Noyszewski ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Acute Exercise ◽  
Work Rate ◽  
Northern Analysis ◽  
Endothelial Cell Proliferation ◽  
Vastus Lateralis Muscle ◽  
Mrna Levels ◽  
Vegf Mrna ◽  
Exercise Induced

Vascular endothelial growth factor (VEGF) is involved in extracellular matrix changes and endothelial cell proliferation, both of which are precursors to new capillary growth. Angiogenesis is a vital adaptation to exercise training, and the exercise-induced reduction in intracellular[Formula: see text] has been proposed as a stimulus for this process. Thus we studied muscle cell[Formula: see text] [myoglobin[Formula: see text]([Formula: see text])] during exercise in normoxia and in hypoxia (12% O2) and studied the mRNA levels of VEGF in six untrained subjects after a single bout of exercise by quantitative Northern analysis. Single-leg knee extension provided the acute exercise stimulus: a maximal test followed by 30 min at 50% of the peak work rate achieved in this graded test. Because peak work rate was not affected by hypoxia, the absolute and relative work rates were identical in hypoxia and normoxia. Three pericutaneous needle biopsies were collected from the vastus lateralis muscle, one at rest and then the others at 1 h after exercise in normoxia or hypoxia. At rest (control), VEGF mRNA levels were very low (0.38 ± 0.04 VEGF/18S). After exercise in normoxia or hypoxia, VEGF mRNA levels were much greater (16.9 ± 6.7 or 7.1 ± 1.8 VEGF/18S, respectively). In contrast, there was no measurable basic fibroblast growth factor mRNA response to exercise at this 1-h postexercise time point. Magnetic resonance spectroscopy of myoglobin confirmed a reduction in[Formula: see text] in hypoxia (3.8 ± 0.3 mmHg) compared with normoxia (7.2 ± 0.6 mmHg) but failed to reveal a relationship between [Formula: see text] during exercise and VEGF expression. This VEGF mRNA increase in response to acute exercise supports the concept that VEGF is involved in exercise-induced skeletal muscle angiogenesis but questions the importance of a reduced cellular [Formula: see text]as a stimulus for this response.

Effect of acute exercise and exercise training on VEGF splice variants in human skeletal muscle

2004 ◽  
Vol 287 (2) ◽  
pp. R397-R402 ◽  
Author(s):  
Lotte Jensen ◽  
Henriette Pilegaard ◽  
P. Darrell Neufer ◽  
Ylva Hellsten
Keyword(s):  
Skeletal Muscle ◽  
Exercise Training ◽  
Human Skeletal Muscle ◽  
Acute Exercise ◽  
Splice Variants ◽  
Knee Extensor ◽  
Vastus Lateralis Muscle ◽  
Mrna Levels ◽  
Vegf Mrna ◽  
Exercise Induced

The present study investigated the effect of an acute exercise bout on the mRNA response of vascular endothelial growth factor (VEGF) splice variants in untrained and trained human skeletal muscle. Seven habitually active young men performed one-legged knee-extensor exercise training at an intensity corresponding to ∼70% of the maximal workload in an incremental test five times/week for 4 wk. Biopsies were obtained from the vastus lateralis muscle of the trained and untrained leg 40 h after the last training session. The subjects then performed 3 h of two-legged knee-extensor exercise, and biopsies were obtained from both legs after 0, 2, 6, and 24 h of recovery. Real-time PCR was used to examine the expression of VEGF mRNA containing exon 1 and 2 (all VEGF isoforms), exon 6 or exon 7, and VEGF165mRNA. Acute exercise induced an increase ( P < 0.05) in total VEGF mRNA levels as well as VEGF165and VEGF splice variants containing exon 7 at 0, 2, and 6 h of recovery. The increase in VEGF mRNA was higher in the untrained than in the trained leg ( P < 0.05). The results suggest that in human skeletal muscle, acute exercise increases total VEGF mRNA, an increase that appears to be explained mainly by an increase in VEGF165mRNA. Furthermore, 4 wk of training attenuated the exercise-induced response in skeletal muscle VEGF165mRNA.

Exercise adaptation attenuates VEGF gene expression in human skeletal muscle

2000 ◽  
Vol 279 (2) ◽  
pp. H772-H778 ◽  
Author(s):  
R. S. Richardson ◽  
H. Wagner ◽  
S. R. D. Mudaliar ◽  
E. Saucedo ◽  
R. Henry ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Exercise Training ◽  
Human Skeletal Muscle ◽  
Acute Exercise ◽  
Vastus Lateralis ◽  
Northern Analysis ◽  
Endothelial Cell Proliferation ◽  
Vastus Lateralis Muscle ◽  
Mrna Levels ◽  
Exercise Adaptation

Angiogenesis is a component of the multifactoral adaptation to exercise training, and vascular endothelial growth factor (VEGF) is involved in extracellular matrix changes and endothelial cell proliferation. However, there is limited evidence supporting the role of VEGF in the exercise training response. Thus we studied mRNA levels of VEGF, using quantitative Northern analysis, in untrained and trained human skeletal muscle at rest and after a single bout of exercise. Single leg knee-extension provided the acute exercise stimulus and the training modality. Four biopsies were collected from the vastus lateralis muscle at rest in the untrained and trained conditions before and after exercise. Training resulted in a 35% increase in muscle oxygen consumption and an 18% increase in number of capillaries per muscle fiber. At rest, VEGF/18S mRNA levels were similar before (0.38 ± 0.04) and after (1.2 ± 0.4) training. When muscle was untrained, acute exercise greatly elevated VEGF/18S mRNA levels (16.9 ± 6.7). The VEGF/18S mRNA response to acute exercise in the trained state was markedly attenuated (5.4 ± 1.3). These data support the concept that VEGF is involved in exercise-induced skeletal muscle angiogenesis and appears to be subject to a negative feedback mechanism as exercise adaptations occur.

Nitric oxide synthase inhibition attenuates the skeletal muscle VEGF mRNA response to exercise

2000 ◽  
Vol 88 (4) ◽  
pp. 1192-1198 ◽  
Author(s):  
Timothy P. Gavin ◽  
David A. Spector ◽  
Harrieth Wagner ◽  
Ellen C. Breen ◽  
Peter D. Wagner
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Growth Factor ◽  
Methyl Ester ◽  
Acute Exercise ◽  
Transforming Growth Factor ◽  
No Production ◽  
Vegf Mrna ◽  
Exercise Induced ◽  
Response To Exercise

Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and transforming growth factor-β1 (TGF-β1) mRNA increase in rat skeletal muscle in response to a single acute exercise bout. Nitric oxide (NO) is released locally by muscle vascular endothelium and muscle fibers during exercise, contributes to the blood flow response to exercise, and regulates mitochondrial respiration. We hypothesized that a reduction in NO production, via NO synthase inhibition, would demonstrate a link between NO and the VEGF, bFGF, and TGF-β1 gene responses to exercise. To investigate this hypothesis, 9-wk-old female Wistar rats were divided into eight treatment groups ( n = 6 each): 1) saline + rest, 2) saline + exercise, 3) 30 mg/kg N ω-nitro-l-arginine methyl ester (l-NAME, a known NOS inhibitor) + rest, 4) 30 mg/kgl-NAME + exercise, 5) 300 mg/kg l-NAME + rest, 6) 300 mg/kg l-NAME + exercise, 7) 300 mg/kg N ω-nitro-d-arginine methyl ester (d-NAME, inactive enantiomer of l-NAME) + rest, and 8) 300 mg/kg d-NAME + exercise. Exercise consisted of 1 h of running at 20 m/min on a 10° incline. VEGF, TGF-β1, and bFGF mRNA from left gastrocnemius were analyzed by quantitative Northern blot. Submaximal exercise for 1 h increased VEGF mRNA 4.2-fold and TGF-β1 mRNA 1.5-fold in untreated rats but did not increase bFGF mRNA. The exercise-induced increase in VEGF mRNA was attenuated ∼50% by 30 and 300 mg/kgl-NAME; the TGF-β1 mRNA increase was unaffected by 300 mg/kg l-NAME. In addition, 300 mg/kgd-NAME had no effect on the exercise-induced increase in VEGF mRNA. Administration of 300 mg/kg l-NAME had no effect on bFGF mRNA. These findings suggest that NO is important in the regulation of the VEGF gene response to exercise through increases in VEGF transcription or by increases in the VEGF mRNA half-life.

Effect of captopril on skeletal muscle angiogenic growth factor responses to exercise

2000 ◽  
Vol 88 (5) ◽  
pp. 1690-1697 ◽  
Author(s):  
Timothy P. Gavin ◽  
David A. Spector ◽  
Harrieth Wagner ◽  
Ellen C. Breen ◽  
Peter D. Wagner
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Molecular Mechanisms ◽  
Acute Exercise ◽  
Transforming Growth Factor ◽  
Enzyme Inhibitor ◽  
Transforming Growth Factor Β ◽  
Mrna Levels ◽  
Vegf Mrna ◽  
Female Wistar Rats

Acute exercise increases vascular endothelial growth factor (VEGF), transforming growth factor-β1 (TGF-β1), and basic fibroblast growth factor (bFGF) mRNA levels in skeletal muscle, with the greatest increase in VEGF mRNA. VEGF functions via binding to the VEGF receptors Flk-1 and Flt-1. Captopril, an angiotensin-converting enzyme inhibitor, has been suggested to reduce the microvasculature in resting and exercising skeletal muscle. However, the molecular mechanisms responsible for this reduction have not been investigated. We hypothesized that this might occur via reduced VEGF, TGF-β1, bFGF, Flk-1, and Flt-1 gene expression at rest and after exercise. To investigate this, 10-wk-old female Wistar rats were placed into four groups ( n = 6 each): 1) saline + rest; 2) saline + exercise; 3) 100 mg/kg ip captopril + rest; and 4) 100 mg/kg ip captopril + exercise. Exercise consisted of 1 h of running at 20 m/min on a 10° incline. VEGF, TGF-β1, bFGF, Flk-1, and Flt-1 mRNA were analyzed from the left gastrocnemius by quantitative Northern blot. Exercise increased VEGF mRNA 4.8-fold, TGF-β1 mRNA 1.6-fold, and Flt-1 mRNA 1.7-fold but did not alter bFGF or Flk-1 mRNA measured 1 h after exercise. Captopril did not affect the rest or exercise levels of VEGF, TGF-β1, bFGF, and Flt-1 mRNA. Captopril did reduce Flk-1 mRNA 30–40%, independently of exercise. This is partially consistent with the suggestion that captopril may inhibit capillary growth.

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

2009 ◽  
Vol 297 (1) ◽  
pp. E92-E103 ◽  
Author(s):  
Lotte Leick ◽  
Ylva Hellsten ◽  
Joachim Fentz ◽  
Stine S. Lyngby ◽  
Jørgen F. P. Wojtaszewski ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Exercise Training ◽  
Protein Expression ◽  
Protein Content ◽  
Acute Exercise ◽  
Whole Body ◽  
Vegf Expression ◽  
Vegf Mrna ◽  
Exercise Induced ◽  
Vegf Protein

The aim of the present study was to test the hypothesis that PGC-1α 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-1α-dependent mechanism. Whole body PGC-1α 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-1α KO mice, VEGF protein expression was ∼60–80% lower and the capillary-to-fiber ratio ∼20% lower than in WT. Basal VEGF mRNA expression was similar in WT and PGC-1α 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-1α KO mice. Furthermore, a training-induced prevention of an age-associated decline in VEGF protein content was observed in WT but not in PGC-1α KO muscles. In addition, repeated AICAR treatments increased skeletal muscle VEGF protein expression ∼15% in WT but not in PGC-1α KO mice. This study shows that PGC-1α 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-1α.

Muscle microvascular adaptation and angiogenic gene induction in response to exercise training are attenuated in middle-aged rats

2015 ◽  
Vol 11 (1) ◽  
pp. 23-33
Author(s):  
J. Suzuki
Keyword(s):  
Exercise Training ◽  
Acute Exercise ◽  
Young Group ◽  
Treadmill Running ◽  
Mrna Levels ◽  
Aged Rats ◽  
Middle Aged ◽  
Vegf Mrna ◽  
Aged Group ◽  
Exercise Induced

This study was designed to investigate exercise-induced changes in muscle capillarisation, the mRNA expression of angiogenic genes, and microRNA levels in young and middle-aged rats. Rats in the training groups were subjected to treadmill running 5 days a week for 3 weeks. The exercise protocol for the young (12-week old) group was 20-25 m/min, 40-60 min/day with a gradient of 15%, and for the middle-aged (12-month old) group was 18-20 m/min, 40-60 min/day with a gradient of 5%. The enzyme histochemical identification of capillary profiles was performed on cross-sections of gastrocnemius muscle. Total RNA was isolated, reverse transcription was performed, and mRNA and microRNA levels were determined by real-time PCR. The capillary-to-fibre ratio was significantly increased by exercise training in the young group (by 10%), but only slightly in the middle-aged (by 5%) group. Vascular endothecial growth factor (VEGF) mRNA levels were at significantly higher values after acute exercise (1.6-fold) and the 3-week training protocol (1.9-fold) in the young group, but not in the middle-aged group. VEGF protein expression levels were significantly increased after training in the young group only. Endothelial nitric oxide synthase, VEGF-R2 and thrombospondin-1 mRNA levels were significantly lower in the middle-aged group than in the young group. Anti-angiogenic miR-195 levels were significantly enhanced by exercise training in the middle-aged group only. These results indicated that the exercise-induced adaptation of muscle capillarity was attenuated in middle-aged rats, possibly by the lower induction of VEGF and up-regulation of anti-angiogenic miRNA expression.

Effect of nitric oxide synthase inhibition on mitochondrial biogenesis in rat skeletal muscle

2007 ◽  
Vol 102 (1) ◽  
pp. 314-320 ◽  
Author(s):  
G. D. Wadley ◽  
G. K. McConell
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Mitochondrial Biogenesis ◽  
Acute Exercise ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Exercise Induced ◽  
Edl Muscle ◽  
Oxide Synthase

The purpose of this study was to determine whether nitric oxide synthase (NOS) inhibition decreased basal and exercise-induced skeletal muscle mitochondrial biogenesis. Male Sprague-Dawley rats were assigned to one of four treatment groups: NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME, ingested for 2 days in drinking water, 1 mg/ml) followed by acute exercise, no l-NAME ingestion and acute exercise, rest plus l-NAME, and rest without l-NAME. The exercised rats ran on a treadmill for 53 ± 2 min and were then killed 4 h later. NOS inhibition significantly ( P < 0.05; main effect) decreased basal peroxisome proliferator-activated receptor-γ coactivator 1β (PGC-1β) mRNA levels and tended ( P = 0.08) to decrease mtTFA mRNA levels in the soleus, but not the extensor digitorum longus (EDL) muscle. This coincided with significantly reduced basal levels of cytochrome c oxidase (COX) I and COX IV mRNA, COX IV protein and COX enzyme activity following NOS inhibition in the soleus, but not the EDL muscle. NOS inhibition had no effect on citrate synthase or β-hydroxyacyl CoA dehydrogenase activity, or cytochrome c protein abundance in the soleus or EDL. NOS inhibition did not reduce the exercise-induced increase in peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) mRNA in the soleus or EDL. In conclusion, inhibition of NOS appears to decrease some aspects of the mitochondrial respiratory chain in the soleus under basal conditions, but does not attenuate exercise-induced mitochondrial biogenesis in the soleus or in the EDL.

Exercise-induced expression of angiogenesis-related transcription and growth factors in human skeletal muscle

1999 ◽  
Vol 276 (2) ◽  
pp. H679-H685 ◽  
Author(s):  
Thomas Gustafsson ◽  
Adrian Puntschart ◽  
Lennart Kaijser ◽  
Eva Jansson ◽  
Carl Johan Sundberg
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Mrna Expression ◽  
Human Skeletal Muscle ◽  
Hypoxia Inducible Factor ◽  
Lactate Concentration ◽  
Knee Extension ◽  
Vegf Mrna ◽  
Exercise Induced ◽  
Vegf Mrna Expression

mRNA expression of vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), and hypoxia-inducible factor (HIF) subunits HIF-1α and HIF-1β in human skeletal muscle was studied during endurance exercise at different degrees of oxygen delivery. Muscle biopsies were taken before and after 45 min of one-legged knee-extension exercise performed under conditions of nonrestricted or restricted blood flow (∼15–20% lower) at the same absolute workload. Exercise increased VEGF mRNA expression by 178% and HIF-1β by 340%, but not HIF-1α and FGF-2. No significant differences between the restricted and nonrestricted groups were observed. The exercise-induced increase in VEGF mRNA was correlated to the exercise changes in HIF-1α and HIF-1β mRNA. The changes in VEGF, HIF-1α, and HIF-1β mRNAs were correlated to the exercise-induced increase in femoral venous plasma lactate concentration. It is concluded that 1) VEGF but not FGF-2 gene expression is upregulated in human skeletal muscle by a single bout of dynamic exercise and that there is a graded response in VEGF mRNA expression related to the metabolic stress and 2) the increase in VEGF mRNA expression correlates to the changes in both HIF-1α and HIF-1β mRNA.

VEGF gene expression is upregulated in electrically stimulated rat skeletal muscle

1995 ◽  
Vol 269 (5) ◽  
pp. H1827-H1831 ◽  
Author(s):  
J. Hang ◽  
L. Kong ◽  
J. W. Gu ◽  
T. H. Adair
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Motor Nerve ◽  
Physiological Role ◽  
Northern Analysis ◽  
Mrna Levels ◽  
Vascular Endothelial ◽  
Vegf Gene ◽  
Vegf Expression ◽  
Vegf Mrna

Vascular endothelial growth factor (VEGF; also called vascular permeability factor) is a secreted mitogen with distinct target cell specificity for vascular endothelial cells. Hypoxia upregulates VEGF expression, making it a likely mediator of the angiogenesis that occurs in poorly perfused tissues. The purpose of this study was to determine whether VEGF gene expression is upregulated in chronically stimulated skeletal muscles, where hypoxia is thought to trigger the growth of blood vessels. The right anterior tibialis and extensor digitorum longus muscles of 12 rats were stimulated electrically (10 Hz, 300 microseconds pulses) for up to 21 days by way of the peroneal motor nerve. The contralateral muscles served as control. Northern analysis showed that VEGF mRNA levels increased by approximately sixfold after 4 days of stimulation and then decreased gradually over the next several days. VEGF mRNA levels were still elevated by two- to threefold after 21 days of stimulation. Higher VEGF mRNA levels in the early stages of muscle stimulation and gradually decreasing levels in later stages are consistent with a metabolic hypothesis in which tissue oxygenation controls VEGF expression. These studies support the hypothesis that VEGF has a physiological role in promoting angiogenesis in stimulated skeletal muscle.

Effect of birth weight and 12 weeks of exercise training on exercise-induced AMPK signaling in human skeletal muscle

2013 ◽  
Vol 304 (12) ◽  
pp. E1379-E1390 ◽  
Author(s):  
Brynjulf Mortensen ◽  
Janne R. Hingst ◽  
Nicklas Frederiksen ◽  
Rikke W. W. Hansen ◽  
Caroline S. Christiansen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Birth Weight ◽  
Exercise Training ◽  
Acute Exercise ◽  
Mrna Levels ◽  
Ampk Activation ◽  
Ampk Signaling ◽  
Protein Levels ◽  
Before And After ◽  
Exercise Induced

Subjects with a low birth weight (LBW) display increased risk of developing type 2 diabetes (T2D). We hypothesized that this is associated with defects in muscle adaptations following acute and regular physical activity, evident by impairments in the exercise-induced activation of AMPK signaling. We investigated 21 LBW and 21 normal birth weight (NBW) subjects during 1 h of acute exercise performed at the same relative workload before and after 12 wk of exercise training. Multiple skeletal muscle biopsies were obtained before and after exercise. Protein levels and phosphorylation status were determined by Western blotting. AMPK activities were measured using activity assays. Protein levels of AMPKα1 and -γ1 were significantly increased, whereas AMPKγ3 levels decreased with training independently of group. The LBW group had higher exercise-induced AMPK Thr172 phosphorylation before training and higher exercise-induced ACC2 Ser221 phosphorylation both before and after training compared with NBW. Despite exercise being performed at the same relative intensity (65% of V̇o2peak), the acute exercise response on AMPK Thr172, ACC2 Ser221, AMPKα2β2γ1, and AMPKα2β2γ3 activities, GS activity, and adenine nucleotides as well as hexokinase II mRNA levels were all reduced after exercise training. Increased exercise-induced muscle AMPK activation and ACC2 Ser221 phosphorylation in LBW subjects may indicate a more sensitive AMPK system in this population. Long-term exercise training may reduce the need for AMPK to control energy turnover during exercise. Thus, the remaining γ3-associated AMPK activation by acute exercise after exercise training might be sufficient to maintain cellular energy balance.

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