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Department of Medicine, University of California San Diego, La Jolla, California 92093-0623
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We investigated whether 1) 5 days
of exercise training would reduce the acute exercise-induced increase
in skeletal muscle growth factor gene expression; and 2)
reductions in the increase in growth factor gene expression in response
to short-term exercise training would be coincident with increases in
skeletal muscle oxidative potential. Female Wistar rats were used. Six
groups (rest; exercise for 1-5 consecutive days) were used to
measure the growth factor response through the early phases of an
exercise training program. Vascular endothelial growth factor (VEGF),
transforming growth factor-
1 (TGF-1), and
basic fibroblast growth factor (bFGF) mRNA were analyzed from the left
gastrocnemius by quantitative Northern blot. Citrate synthase activity
was analyzed from the right gastrocnemius. VEGF and
TGF-1 mRNA increased after each of 5 days of exercise
training, whereas exercise on any day did not increase bFGF mRNA. On
day 1, the VEGF mRNA response was significantly greater than
on days 2-5. However, the reduced increase in VEGF mRNA
observed on days 2-5 was not coincident with increases
in citrate synthase activity. These findings suggest that, in skeletal muscle, 1) VEGF and TGF-1 mRNA are increased
through 5 days of exercise training and 2) the reduced
exercise-induced increase in VEGF mRNA responses on days
2-5 does not result from increases in oxidative potential.
vascular endothelial growth factor; transforming growth
factor-1; basic fibroblast growth factor; Northern
analysis; citrate synthase activity
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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REGULARLY PERFORMED ENDURANCE exercise induces major adaptations in skeletal muscle. These include training-induced changes in muscle substrate utilization, mitochondrial content, biochemical enzyme/protein activities, and capillarization (see Refs. 1, 6, 21, and 23 for review). In addition, despite extensive characterization of these training-induced changes, very little is known about the molecular events responsible for initiating and maintaining these adaptations.
Among the early gene responses are increases in various growth factors
that are believed to be important regulators of exercise-induced skeletal muscle angiogenesis. In rats, a single, 1-h exercise bout [20
m/min, 10° incline, which represents 55% of maximal O2 uptake (
O2 max); Ref. 7],
produces rapid (increased immediately postexercise) and transient
(returns to baseline 4 h postexercise) increases in mRNA of
vascular endothelial growth factor (VEGF), transforming growth
factor-1 (TGF-1), and basic fibroblast
growth factor (bFGF) (7). These exercise-induced growth
factor gene responses are smaller in response to exercise of lower
intensity (15 min, 10° incline), consistent with reports that
exercise intensity can influence exercise-induced angiogenesis (16, 12). In addition, the increases in VEGF and
TGF-1 mRNA are greater in response to hypoxic exercise
(7). Chandel et al. (8) have shown that the
hypoxic activation of VEGF transcription may be regulated via a
mitochondrial-dependent signaling process involving reactive oxygen
species (ROS).
In skeletal muscle, there is an intimate relationship between capillarity and metabolic requirements. It is from this relationship that the theory of metabolically regulated exercise-induced angiogenesis arises. In this theory, prolonged imbalances between the perfusion capabilities of the blood vessels and the metabolic requirements of the tissue cells lead to modification of the vasculature to satisfy the tissue needs (1). In human skeletal muscle, the VEGF response to acute exercise is attenuated concomitant with increases in skeletal muscle aerobic capacity, oxidative potential, and capillarity after 8 wk of endurance exercise training, suggesting that VEGF expression is subject to a negative feedback mechanism as exercise adaptations occur (32).
Relatively recently, evidence has been reported that some training adaptations may occur already within 1-2 wk after the commencement of an exercise training program. Short-term exercise training can produce increases in mitochondrial potential (9, 28, 29, 39). Starritt et al. (39) recently demonstrated that citrate synthase activity (CSA) increases within the first 5 days of exercise training, whereas mitochondrial ATP production rate is increased within 10 days. In rats, a single acute treadmill exercise bout can produce a transient increase in citrate synthase mRNA, whereas 1 wk of exercise training can produce a 30% increase in CSA (29). After short-term exercise training, exercise at the same contractile activity results in a smaller decrease in high-energy phosphates, smaller increases in Pi and creatine, slower glycogen depletion, lower lactate production, and a greater reliance on fat oxidation for energy at the same contractile activity (9, 13-15, 37). These exercise-induced adaptations are beneficial in that subsequent exercise bouts result in smaller disturbances in intracellular homeostasis.
The purpose of this study was to investigate the effects of a
short-term exercise training program on the angiogenic growth factor
response to exercise. First, we determined the acute exercise intensity
that produced the greatest increase in angiogenic growth factors (15, 20, or 25 m/min at 10° incline). Second, using this exercise
intensity, we exercised animals for 5 consecutive days. We hypothesized
that 1) 5 days of exercise training would produce consistent
increases in angiogenic growth factor responses and 2) if a
reduction in the exercise-induced increase in growth factor mRNA
response was observed during the training program, this reduced response would be related to changes in oxidative potential. We demonstrate here that 1) VEGF and TGF-1 are
consistently increased during 5 consecutive days of exercise training;
2) the VEGF mRNA response to exercise is greatest after
exercise on day 1; and 3) the reduction in the
exercise-induced increase in VEGF mRNA responses to exercise on
days 2-5 is not related to increases in oxidative potential.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study was approved by the University of California, San Diego, Animal Subjects Committee. Female Wistar rats were used throughout the study. Age was 64 ± 2 days, and weight was 199 ± 12 g (means ± SD). All rats were first familiarized with a rodent treadmill (Omnipacer model LC-4, Omnitech, Columbus, OH) and taught to run at 20 m/min, 10° incline for 5 min, 48 h before the experimental protocol. At 10° inclination, the maximal treadmill running speed sustained for 2 min during an incremental maximal test for rats of this age, weight, sex, and strain is 40 m/min (unpublished observations). Animals were housed in their cages and allowed standard rat food and water ad libitum throughout the study.
Two separate protocols were used, with different groups of rats. In
protocol A, to investigate the effect of exercise intensity on the angiogenic growth factor response to exercise, rats were randomly assigned into four groups (n = 6 per group):
group 1 was kept at rest and groups 2-4
performed 1 h of treadmill running at either 15, 20, or 25 m/min,
10° incline, respectively. Exercise at 20 m/min and 10° incline
represents 55% of O2 max in similar animals (7). In protocol B, to
investigate the angiogenic growth factor response to 5 days of
consecutive exercise, rats were randomly assigned into six groups
(n = 6 per group): group 1 remained at rest
and groups 2-6 performed 1 h of treadmill running at 20 m/min, 10° incline, for either 1, 2, 3, 4, or 5 consecutive days, respectively.
After completion of the final exercise bout, all animals were
anesthetized with 2% halothane in O2, the left
gastrocnemius muscles (both heads) were removed, and total cellular RNA
was isolated. Muscle samples were removed within 20 min after the completion of exercise. In protocol B, the right
gastrocnemius muscles were also removed for the measurement of CSA.
Samples were stored at 
80°C until analysis.
RNA isolation and Northern analysis.
The methods used for RNA isolation from rat gastrocnemius muscles and
Northern blotting for VEGF, TGF-1, and bFGF have been described in detail previously (7). Briefly, total
cellular RNA was isolated and separated by electrophoresis in a 6.6%
formaldehyde-1% agarose gel. Fractionated RNA was transferred by
Northern blot to Zeta-probe membrane (Bio-Rad, Hercules, CA),
cross-linked to the membrane by ultraviolet irradiation for 1 min, and
stored at 4°C. The blots were then probed with oligolabeled
[
-32P]deoxycytidine triphosphate cDNA probes for VEGF,
TGF-1, and bFGF. Prehybridization and hybridization were
performed in 50% formamide, 5× saline sodium citrate (SSC), 10×
Denhardt's solution, 50 mM sodium phosphate, 1% SDS, and 250 µg/ml
salmon sperm DNA at 42°C. Blots were washed with 2× SSC and 0.1%
SDS at room temperature and 0.1× SSC and 0.1% SDS at 55°C (bFGF and
TGF-1) or 65°C (VEGF). Blots were exposed to XAR-5
X-ray film (Eastman Kodak, New Haven, CT) by use of a Cronex Lightning
Plus screen at 80°. Autoradiographs were quantitated by
densitometry within the linear range of signals and normalized to
ribosomal 18S RNA levels.
CSA.
CSA from the right gastrocnemius was determined spectrophotometrically
at 30°C by the method of Srere (38). To prevent sampling bias and to be consistent in treatment with the homogenized tissue used
for RNA analysis, the whole muscle was pulverized under liquid nitrogen, and 0.1 g was homogenized and sonicated at 4°C. The homogenate was frozen overnight at 20°C and rehomogenized and resonicated at 4°C. The samples were stored at 20°C until
analysis (1 wk). The homogenate was diluted in an EDTA and EGTA
phosphate buffer to a convenient concentration. Spectrophotometry was
performed in Tris buffer. The acetyl-coenzyme A reagent was in the form of a sodium salt (Sigma Chemical, St. Louis, MO). The homogenate from
each sample was assayed in triplicate.
Statistical treatment.
Quantitative densitometry was used to measure the mRNA levels for VEGF,
TGF-1, and bFGF. Lane loading variation was controlled for by normalization of growth factor densitometric signals with the
ribosomal 18S RNA. A one-way analysis of variance was used to determine
changes in mRNA (protocol A: exercise intensity or protocol B: day of exercise training) and CSA
(protocol B). Fisher's least significant differences
test was used to determine significance between conditions. In
protocol B, one sample was lost during mRNA processing from
each of the rest, 1-day, 2-day, and 4-day groups. These samples were
not replaced. Significance was established at P 
0.05 for
all statistical sets, and reported data are means ± SE.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Protocol A.
Figure 1 shows representative Northern
blots in which VEGF (A), TGF-1
(B), and bFGF (C) mRNA levels were examined after
the single, 1-h submaximal exercise runs at 15, 20, and 25 m/min. It is
clear that VEGF mRNA increased with increasing exercise intensity
between 15 and 20 m/min but was not further increased at 25 m/min.
Figure 2 portrays the quantitative
densitometry for VEGF (A), TGF-1
(B), and bFGF (C) mRNA normalized to 18S
ribosomal RNA. Figure 2A demonstrates that exercise
increases VEGF mRNA at all treadmill speeds (rest: 1.0 ± 0.1; 15 m/min: 2.9 ± 0.2; 20 m/min: 5.0 ± 0.7; 25 m/min: 4.5 ± 0.6). However, in contrast to the exercise intensity increases
observed between 15 and 20 m/min, an increase from 20 to 25 m/min did
not further increase VEGF mRNA. The TGF-1 mRNA response
to increasing exercise intensity is displayed in Fig. 2B.
Exercise intensity does increase TGF-1 mRNA, with
statistically significant increases at 20 and 25 m/min (rest: 1.0 ± 0.1; 15 m/min: 1.3 ± 0.2; 20 m/min: 2.1 ± 0.1; 25 m/min:
2.0 ± 0.1). Similar to the VEGF mRNA results,
TGF-1 mRNA was not further increased by exercise at 25 m/min. A small but significant increase in bFGF mRNA was observed only
with running at 20 m/min (rest: 1.0 ± 0.1; 15 m/min: 1.1 ± 0.1; 20 m/min: 1.3 ± 0.1; 25 m/min: 1.1 ± 0.1).
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Protocol B.
Figure 3 shows representative Northern
blots for VEGF (A), TGF-1 (B), and
bFGF (C) mRNA levels examined at rest and after 1 h of
submaximal running for 1-5 days of consecutive exercise training.
It is clear that VEGF mRNA is increased by exercise after each day of
the exercise training program and is greatest after the first day. In
contrast, the increase in TGF-1 mRNA is unchanged after
exercise on days 1-5. We observed no increase in bFGF
mRNA with exercise training in this protocol.
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1
(B), and bFGF (C) mRNA normalized to 18S
ribosomal RNA. Exercise increases VEGF mRNA after each of 5 consecutive
days of exercise training, with the largest increase observed after exercise on the first day (rest: 1.0 ± 0.1; day 1:
4.9 ± 1.2; days 2-5 mean: 2.9 ± 0.3) (Fig.
4A). We observed a small but consistent increase in
TGF-1 after exercise throughout the 5-day exercise training program (rest: 1.0 ± 0.1; days 1-5 mean:
1.7 ± 0.2) (Fig. 4B). In this protocol, there was no
increase in bFGF mRNA (Fig. 4C). There was no significant
difference in 18S rRNA throughout the training program (range:
79.2 ± 8.6 to 109.6 ± 14.8 arbitrary units).
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1 mRNA (r = 0.19, P = 0.34), or bFGF mRNA (r = 0.08, P = 0.67).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The principal findings of the present study are 1) VEGF
and TGF-1 mRNA are increased after each of 5 consecutive
days of exercise training; 2) the exercise-induced increase
in the VEGF mRNA response after days 2-5 of exercise
training was smaller than after day 1; and 3)
differences in growth factor gene expression through the first 5 days
of an exercise training program do not correlate with differences in
oxidative potential as assessed by CSA. These results demonstrate that
increases observed after a single acute exercise bout are not unique to
the initial exercise bout but are observed throughout the first 5 days
of an exercise training program.
Exercise intensity and growth factor responses.
Previously, the exercise-induced responses in growth factor gene
expression were shown to be sensitive to reductions in exercise intensity (7). Our results reiterate that VEGF,
TGF-1, and bFGF are sensitive to reductions in work
intensities from 20 to 15 m/min; however, we did not see corresponding
increases in gene expression when the workload was increased similarly
from 20 to 25 m/min (Figs. 1 and 2). The observation that increases in
exercise-intensity can produce increases in angiogenic growth factor
responses is consistent with previous reports that exercise intensity
can influence the quantitative increase in exercise-induced
angiogenesis (EIA). Although it is difficult to compare increases in
capillarization across studies due to differences in training duration
and animal models, Gute and colleagues (18, 19) performed
two separate training studies using the same analytic techniques and
the same strain of rats. In analyzing the data from Gute and colleagues and calculating a weighted average of capillary-to-fiber (C/F) ratio
based on the estimated fiber mass of red, white, and mixed portions of
the rat gastrocnemius (4), endurance training defined by
the authors as low intensity (10-12 wk, 30 m/min, 0% incline, 60 min/day) increased the weighted C/F 10%, whereas endurance training
defined by the authors as high intensity (12-14 wk, 32 m/min, 15%
incline, 90 min/day) increased the weighted C/F 34%. From this
analysis, it can be concluded that exercise intensity can influence EIA.
Growth factor gene expression regulation in response to acute
exercise.
One theory regarding EIA in skeletal muscle suggests that prolonged
imbalances between the perfusion capabilities of blood vessels and the
metabolic requirements of tissue cells leads to decreased oxygenation,
with the long-term result being a modification of the vasculature to
satisfy the tissue needs (1). In response to greater work
intensities and the greater demand for ATP production, blood flow is
increased to promote the delivery of substrates, including
O2, and the removal of metabolites. Increased blood flow is
the principal defense for maintaining capillary
PO2 and therefore the driving force for
O2 consumption (22). It has been hypothesized
that intracellular PO2 falls progressively in response to increases in work (35). However, experimental
data in humans do not support this hypothesis (30). In
humans, intracellular PO2 falls rapidly on
commencement of exercise and progressively during exercise at
intensities less than ~50% of
O2 max. Further increases in work rate,
however, do not further reduce intracellular
PO2. Our results from protocol A are
consistent with the hypothesis that intracellular
PO2 can regulate skeletal muscle VEGF and
TGF-1 gene expression in that we show no greater increase in VEGF or TGF-1 mRNA when work rate was
increased above 50%, a workload during which intracellular
PO2 would not be expected to change on the
basis of human measurements of intracellular PO2. Whether the same relationship of
intracellular PO2 to exercise intensity holds
for the rat is unknown.
1 mRNA was slightly but significantly
increased. It might be hypothesized that passive hyperperfusion, as
performed by Roca et al., would increase the release of vasodilators,
including the release of nitric oxide (NO), in response to the increase
in shear stress (25). NO has been shown to regulate VEGF
gene expression both in resting and exercising skeletal muscle
(5, 11). Thus, if NO was released during passive
hyperperfusion, it did not increase VEGF mRNA. Recently, we
demonstrated that NO synthase (NOS) inhibition via nitro-L-arginine methyl ester (L-NAME)
attenuates the exercise-induced increase in VEGF mRNA
(11). In this report, we also demonstrated that
D-NAME, the inactive enantiomer of L-NAME,
increased mean arterial pressure to the same extent as a similar dosage
of L-NAME, suggesting that some NOS inhibition had
occurred. However, D-NAME did not affect the
exercise-induced increase in VEGF gene expression (11). This result suggests that either different
NOS isoforms or the location of different NOS isoforms within the
vasculature and muscle fibers may differentially and selectively
regulate blood pressure and VEGF gene expression.
Growth factor gene expression regulation in response to short-term
exercise training.
In addition to tissue hypoxia, various other metabolites have been
implicated as regulators of angiogenesis during exercise. Among these
are increases in lactate, reductions in pH, inadequate rephosphorylation of ATP, and subsequent accumulation of ADP and adenosine (23). With an increase in oxidative potential,
less perturbation is observed in many oxidative metabolites
(6). Less perturbation in PCr, Cr, and Pi
during submaximal exercise can be observed after just 3-4 days of
endurance exercise training (13). There are reports that
CSA, a commonly measured enzymatic marker of oxidative potential, can
increase within the first week of an exercise training program
(9, 28, 37, 39). Recently, Richardson et al.
(32) showed that, after 8 wk of exercise training, which
produced increases in CSA, aerobic capacity, and capillarization, VEGF
mRNA was reduced in response to acute exercise. Because exercise training increases oxidative potential, with the accompanying improvement in cell homeostasis being consistent with the metabolic theory of angiogenesis, we had hypothesized that possible reductions in
growth factor gene expression during the 5 days of exercise training
would be related to increases in oxidative potential. Contrary to this
hypothesis, the smaller exercise-induced increase in VEGF mRNA observed
after exercise on days 2-5 was not coincident with an
increase in CSA (Figs. 4 and 5). Although increased oxidative potential
does not explain the reduction in the exercise-induced increase in VEGF
mRNA on days 2-5, it must be noted that both VEGF and
TGF-1 mRNA are increased throughout the 5 days of
exercise training. Our results do not preclude the hypothesis that the regulators of exercise-induced growth factor gene expression may originate from metabolism.
1
mRNA, but not bFGF mRNA, were demonstrated after 1 h of exercise
at 20 m/min, 10° incline (10, 11), but in contrast to
Breen et al. (7) and our results from protocol
A. In the present report, every effort was made to remove all
muscle samples in an expedient fashion. We have hypothesized previously
that our inability to demonstrate an increase in bFGF mRNA when muscle
samples were harvested ~40 min after exercise was due to the rapid
decline in the exercise-induced increase in bFGF gene expression
(10). Breen et al. (7) demonstrated that bFGF
mRNA was increased only immediately after exercise, whereas both VEGF
and TGF-1 were still elevated 2 h after exercise.
In the present report, the observation that bFGF mRNA is not
consistently increased with exercise may suggest an unintentional and
random yet systematic bias to a small difference in the time required
for tissue removal between the two protocols.
In summary, we have demonstrated that the angiogenic growth factor
responses to a single bout of exercise in the rat are not increased
when exercise intensity is increased above 50% of maximum. This
relationship is consistent with the hypothesis that intracellular PO2 regulates VEGF and TGF-1
gene expression. During the initial stages of an exercise training
program, both VEGF and TGF-1 mRNA are consistently
increased in response to exercise. However, a smaller increase in VEGF
mRNA was observed after exercise on days 2-5 (compared
with day 1). The lower VEGF mRNA on days 2-5
is not related to increases in oxidative potential.
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ACKNOWLEDGEMENTS |
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We thank Ellen C. Breen, Sean C. Newcomer, David A. Spector, and Harrieth Wagner for their assistance.
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FOOTNOTES |
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This study was supported by National Heart, Lung, and Blood Institute Grants HL-17731 and National Research Service Award HL-09624 (to T. P. Gavin). T. P. Gavin was supported by State of California, Tobacco Related Disease Research Program Grant 8KT-0081 during the preparation of this manuscript.
Address for reprint requests and other correspondence: T. P. Gavin, 371 Ward Sports Medicine Bldg., East Carolina Univ., Greenville, NC 27858 (E-mail: gavint{at}mail.ecu.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 26 April 2000; accepted in final form 10 October 2000.
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TOP
ABSTRACT
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METHODS
RESULTS
DISCUSSION
REFERENCES
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