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O2 max and cardiac hypertrophy
1 Department of Physiology and Biomedical Engineering and 2 Department of Sport Sciences, Norwegian University of Science and Technology, N-7489 Trondheim, Norway
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIAL AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Physiological studies of long-term cardiovascular adaptation to
exercise require training regimens that give robust conditioning effects and adequate testing procedures to quantify the outcome. We
developed a valid and reproducible protocol for measuring maximal oxygen uptake (
O2 max), which was
reached at a 25° inclination with a respiratory exchange ratio > 1.05 and blood lactate > 6 mmol/l. The effect of
intensity-controlled aerobic endurance training was studied in adult
female and male rats that ran 2 h/day, 5 days/wk, in intervals of 8 min
at 85-90% of O2 max and 2 min at
50-60% of O2 max, with adjustment
of exercise level according to O2 max
every week. After 7 wk, the increase in
O2 max plateaued at 60-70% above
sedentary controls. Ventricular weights and myocyte length were up
25-30% and 6-12%, respectively. Work economy, oxygen pulse,
and heart rate were sufficiently changed to indicate substantial
cardiovascular adaptation. The model mimics important human responses
to training and could be used in future studies on cellular, molecular,
and integrative mechanisms of improved cardiovascular function.
oxygen pulse; heart rate; respiratory exchange ratio; maximal oxygen uptake
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIAL AND METHODS
RESULTS
DISCUSSION
REFERENCES
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RECENT STUDIES SUGGEST
that endurance training increases cardiovascular capacity and
quality of life and reduces mortality in patients with heart failure
(5, 36). The paucity of data on cellular and molecular
mechanisms of improved heart function calls for well-defined
experimental models of endurance training that evoke adaptations
similar to those after aerobic training in humans (7,
21). Endurance training could increase exercise capacity
as measured by maximal oxygen uptake
(O2 max), improve work economy, and
enhance anaerobic threshold (15). Cardiac effects should
include reduced resting and submaximal heart rates (HR), increased
ventricular weights and volumes, and myocyte hypertrophy.
In the adult rat treadmill-running model, the previously published
training regimens used are known to elicit minor effects on ventricular
mass and/or cardiac myocyte dimensions (22, 23, 30).
Studies have shown a 0-20% increase in left ventricular weight
and myocyte length (1, 2, 22, 23, 34). Several studies did
not find any significant change in myocardial mass as a result of
treadmill training in female rats and concluded that ventricular
enlargement in female rats depends critically on the mode of training,
with effects observed only with swim training (10, 14, 27, 28,
34). In contrast, treadmill training increases
O2 max and work economy by 10-20% and reduces resting HR by ~5% both in male and female rats
(10, 24).
Even though the intensity of the load required to induce physical conditioning increases as the performance improves during the course of training (3), most studies use a fixed exercise intensity throughout the experiment. Our working hypothesis was that adjustment of the training load relative to the level of the fitness of the individual should evoke adaptations similar to those induced by aerobic training in humans.
The aims of the present study were as follows: 1) establish a valid and reliable treadmill protocol for evaluating endurance capacity in rats and 2) determine the effect of intensity-controlled treadmill running on endurance capacity, ventricular weights, and cardiac myocyte dimensions in male and female rats.
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MATERIAL AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIAL AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Study Population and Design
A total of 46 adult female and 12 adult male (270-300 g) Sprague-Dawley rats (Møllegaards Breeding Center, Lille Skensved, Denmark) were maintained with 4 rats in each cage, with a volume of 46 liters. Light was controlled on a 12:12-h light-dark cycle. The training and test protocols were performed during the rats' dark cycle except for evaluation of basal metabolism and resting HR. Temperature was 22.5 ± 1.4°C, and humidity was 55.6 ± 4.0%. Animals were fed a pellet rodent diet ad libitum and had free access to water. After each training or test session, each rat was rewarded with 0.5 g of chocolate (Crispo, Nidar Bergene, Norway). Sedentary rats were given the same amount of chocolate. None of the rats were excluded from the study because they avoided running. Strewment was changed every 4 days, and the same person handled the rats throughout the study. The experimental procedures conform with the "European Convention for the Protection of Vertebrate Animals Used for Experimental and other Scientific Purposes," and the protocol was approved by the Norwegian Council for Animal Research. The rats were assigned into six groups, as described in Table 1. HR was measured in all animals in groups II-VI, and blood lactate was measured in three animals from group I after establishing the optimal inclination for measuringO2 max.
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Test Protocol
From human studies (3), it is known that inclination of the treadmill affects oxygen uptake at maximal aerobic exercise. To establish the optimal protocol for assessingO2 max, rats (group I) were
tested at five different inclinations (0°, 15°, 20°, 25°, and
30°). To avoid bias caused by conditioning, the sequence of testing
was randomized, and each test was separated by 1 day. Each rat had a
15-min warmup at 40-50% of O2 max before the O2 max protocol. Treadmill
speed was increased by 0.03 m/s every 2 min. After the optimal protocol
for measuring O2 max was established,
the reproducibility of basal metabolism and submaximal work economy was
examined in another set of rats (group II). After a 15-min
warmup at 40-50% of O2 max, the
rats exercised for 4 min at 50, 60, and 70% of
O2 max. In test 1, four
animals exercised at increasing intensities (50, 60, and 70% of
O2 max), and four animals exercised at decreasing intensities (70, 60, and 50% of
O2 max). In test 2, the
stages were given in reverse order. At each level, oxygen uptake, HR,
and running speed were recorded. From a metabolic point of view, oxygen
uptake was expected to be the same at corresponding exercise
intensities in different tests, regardless of whether the exercise
stages were given in increasing or decreasing order. The reason for
choosing 4 min at each submaximal stage was that oxygen uptake leveled
off after ~3 min at each exercise stage after changing work load
(data not shown), which concurs with what has been shown in human
studies (3). A potential disadvantage of starting at 70%
of O2 max was that this intensity might
have exceeded the anaerobic threshold for treadmill-running rats. In
that case, differences in oxygen uptake between increasing and
decreasing exercise stages would have been expected. Thus oxygen uptake
at lower exercise levels would have been higher because of oxygen
deficit, causing a higher cost of running. The reproducibility of
O2 max and maximal HR (25°
inclination of the treadmill) was examined in a third set of rats
(group III). A 1-day rest period separated tests.
Training Protocol
In the training protocols, rats were assigned to either treadmill running or sedentary control. To determine the effect of training (25° inclination) on oxygen uptake, HR, ventricular weights, and left ventricular cellular dimensions, we first studied two groups (groups IV and VI) of sedentary and exercising female rats. Six trained and six sedentary rats were euthanized after 4 and 13 wk. To study whether male and female rats achieved the similar training responses, we trained a group of male rats (group V) until the training effect onO2 max leveled off. To assess running
economy and HR after the training periods, oxygen uptake and HR were
measured at the same absolute exercise intensity before and after the
training period. After 2 days of training, all rats avoided the
electrical grid with 2 ± 1 touches per training session. After 2 wk of training, the rats would typically jump onto the treadmill when
their cages were placed next to it.
Oxygen Uptake and HR
The oxygen uptake and respiratory exchange ratio were measured using an oxygen analyzer based on a paramagnetic oxygen transducer (Servomex type 1155, Servomex) and carbon dioxide analyzer (LAIR 12, M&C Instruments). Ambient air was pumped through the metabolic chamber at a flow rate of 4.5 l/min, and samples of extracted air (200 ml/min) were directed to the oxygen and carbon dioxide analyzers. The analyzers were calibrated with known gas mixtures every day and had an accuracy of measurement of ±2%. The treadmill was placed in a metabolic chamber with a total volume of 11 liters. A custom-made stainless steel grid at the end of the lane supplied an electrical stimulus (0.25 mÅ, 1 stimulus of 200-ms duration every second) to keep the rats running on the lane. In treadmill construction, care was taken to avoid the rats pinching their feet. Pilot experiments showed that the natural running behavior included periods of stopping and sniffing on the treadmill belt. Therefore, the lane of the treadmill was made 70 cm long to avoid unnecessary contact with the electrical grid.Each rat had a 15-min warmup at 40-50% of
O2 max before the
O2 max protocol. Treadmill speed was
increased by 0.03 m/s every 2 min. The criteria for reaching
O2 max were a leveling off of oxygen
uptake despite increased workload, a respiratory exchange ratio above
1.05, and an unhemolyzed blood lactate concentration above 6 mmol/l
(3). Lactate measurement was performed using a YSI model
1500 Sport Lactate Analyzer (Yellow Springs Instruments). A
blood sample of 35 µl was drawn from a polyethylene (PE)-50
catheter in the jugular vein for measurement of blood lactate
immediately after O2 max completion. To
measure maximal HR, we used a modified protocol established by
Ingjer (19). After completion of the
O2 max test, the rat ran at a work
intensity corresponding to 50-60% of
O2 max directly followed by a
supramaximal intensity run, which led to exhaustion within ~3 min,
that is, when the rat was no longer able to keep running on the lane.
The highest HR during the supramaximal run was recorded as maximal HR.
To determine the reproducibility of submaximal oxygen uptake
(O2), each rat worked at fixed
exercise stages, 50, 60, and 70% of
O2 max for 4 min at each intensity.
HR was measured by connecting a frequency-modulated acoustical HR
transmitter (operating at ~130 kHz) to implanted wires as described
below (17). Resting metabolism and resting HR were measured as the rat spent 24 h in a Plexiglas metabolic chamber with strewment, water, and food. In the light cycle, resting metabolism and HR were measured while the rat was sleeping. The total volume of
the metabolic chamber was 3.6 liters. Air was pumped through the
chamber at a rate of 4.0 l/min, and samples of extracted air were
directed to the oxygen and carbondioxyd analyzers. The measurements were performed at least 10 h after training. To indirectly assess ventricular stroke volumes at rest and during exercise, we calculated mean oxygen pulse values (O2/HR)
(33).
Training Procedure
Trained rats exercised on the treadmill 2 h/day, 5 days/wk, for 4, 7, or 13 wk. At the start of every week,O2 max was measured as described,
and workloads were adjusted accordingly. In training rats, exercise
intervals alternated between 8 min at 85-90% of
O2 max and 2 min at 50-60% of
O2 max. Before the first interval, each
rat performed a 20-min warmup at 40-50% of
O2 max. At the day of
O2 max testing, trained rats performed
eight intervals after the test. In sedentary rats, treadmill running
skill was maintained by a 15-min run at 0° inclination at 0.15 m/s
for 3 days/wk.
Surgical Procedures
All instrumentation was performed using sterile surgical procedures. Implantation of the HR recorder and positioning of the PE-50 catheter into the right jugular vein were performed under anesthesia by subcutaneous injection of 0.3 ml/100 g midazolam (Dormicum "Roche") and fentanyl-fluanison (Hypnorm). A pair of thin enamel-insulated copper wires with tinned ends, connected to the HR transmitter, were subcutaneously advanced from the dorsal aspect of the cervical region of the rat and implanted at midchest to record the HR. The cylindrical transmitter (5 × 15 mm) was stitched on the rat's neck. The catheter was subcutaneously advanced to the dorsal aspect of the cervical region of the rat, where it was exteriorized. The rats were given 48 h of recovery before any kind of test was performed.Isolation of Left Ventricular Myocytes
After 4, 7, or 13 wk of the experimental period, the animals were anesthetized with diethyl ether and heparinized (0.2 ml heparin, 1,000 IU/ml iv; Novo Nordisk, Copenhagen, Denmark). Hearts were rapidly removed from the animals, kept for 1 min in ice-cold perfusion buffer, and connected to an aortic cannula of a standard Langendorff retrograde perfusion system. To balance the variation of myocytes isolated, one heart from either group was taken each day. Myocytes were isolated from septal plus left ventricular free wall portions of the myocardium using a modified protocol from Holt and Christensen (18). The heart was retrogradely perfused via the aorta (7.5 ml/min) for 10 min with medium A, which consisted of 24 g of Joklik's medium (Life Technologies, Paisley, Scotland) mixed in 2,000 ml of deionized water added with (in mM) 1.2 MgSO4, 1.0 DL-carnitine (Sigma, St Louis, MO), and 23.8 NaHCO3. Medium A was equilibrated with 5% CO2-95% O2 for 15 min (at 37°C; pH 7.4). After 10 min, the hearts were perfused for 20 min with medium B (7.5 ml/min), which consisted of 300 ml of medium A mixed with 150 U/ml collagenase (Worthington, Freeland, NJ) and 0.1% bovine serum albumin (Sigma). After 10 min, medium B was collected for later use. The hearts were cut down into medium C, which contained 125 ml of medium A supplied with 1% bovine serum albumin and 1.5 mM CaCl, equilibrated with 5% CO2-95% O2. The atria, great vessels, and right ventricle were removed. The left and right ventricles were weighed. The left ventricular tissue was cut into small pieces, put into medium C, and shaken for 10 min (at 37°C; 5% CO2-95% O2, 100 rpm). The supernatant was removed, 20 ml of medium B was added, and the tissue was shaken for 30 min (at 37°C; 5% CO2-95% O2, 150 rpm). Thereafter, 10 ml of medium C was added to each cell suspension before centrifugation for 20 s at 600 rpm (at 37°C). The supernatant was gently removed, and another 10 ml of medium C was added. After centrifugation, the supernatant was gently removed, and 5 ml of medium C was added before filtering through a nylon mesh (250 µm). Coverslips were coated with 10 mg/ml laminin (Life Technologies) in Medium 199. Isolated myocytes on coated coverslips (~2 ± 103 cells/cm2) were placed in a cell chamber on an inverted microscope (Diaphot-TMD, Nikon, Tokyo, Japan) and stimulated electrically by bipolar pulses (5-ms duration, 5 Hz; at 37°C) using platinum electrodes on either side of the chamber. Cells that remained rod shaped, without blebs or other visible morphological alterations, and that responded adequately on electrical stimulation were measured for length and midpoint width. The cells on the coverslips were stored in Medium 199 (M7528, Sigma) mixed with 2 mg/ml serum albumin, 2 mM DL-carnitine, 5 mM creatine, 5 mM taurine, 0.1 mM insulin, 10
10 M triodothyronine (T3) (all from Sigma),
100 U/ml penicillin, and 100 µg/ml streptomyocin (both from Life
Technologies, Gaithersburg, MD) equilibrated with 5%
CO2-95% O2 (at 37°C; pH 7.4).
Scaling
As demonstrated below, body weight was higher in male rats than female rats and markedly higher in sedentary compared with trained male rats. Changes in ventricular weights and oxygen uptake may not be entirely due to training regimens. Some could be due to growth-related changes in body weight. For example, it may be that training-induced ventricular hypertrophy in rats could be overestimated due to less body fat compared with control rats. It was, therefore, necessary to normalize oxygen uptake and ventricular weights according to correct scaling procedure, which involves the correct normalization of a physiological variable to a body dimension (3). Usually, this is done by dividing, for example, ventricular weights by body weight. It has previously been shown that this is valid only if body weight is expressed as lean body mass (4). However, if lean body mass is not defined, left ventricular mass should be expressed in relation to body mass raised to the power of 0.78 (4). According to the theoretical models and empirical studies, oxygen uptake should be expressed in relation to body mass raised to the power of 0.75, over a wide range of body weights, when individuals with different body weights are compared (29). Because no significant differences in body weights were observed in female rats, oxygen uptake was expressed as milliliters per kilogram per minute when the aim was to compare trained and sedentary female rats.Statistical Analysis
Data are expressed as means ± SD. Friedman tests applying appropriate procedures for multiple comparisons (8) were used to determine changes in oxygen uptakes, respiratory exchange ratios, and body weights throughout the experimental period as well as differences in oxygen uptake using different inclinations of the treadmill. A Mann-Whitney U-test was used to evaluate differences among groups. P < 0.05 was considered statistically significant.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIAL AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Test Protocols
Inclination of the treadmill significantly affected the highest oxygen uptake measured;O2 max was
reached at 25° inclination of the treadmill (Table
2). The procedures were valid and
reproducible for evaluating oxygen uptake and HR at rest and during
exercise. As shown in Fig. 1, results
were similar in three tests, excluding potential learning effects
caused by unfamiliarity with the apparatus and discomfort in the test
situation. The coefficients of variation for basal metabolism and
resting HR were 2.8% and 3.2%, respectively. The
O2 max for tests 1,
2, and 3 were 79.9 ± 3.2, 80.2 ± 2.9, and 80.3 ± 3.1 ml · kg1 · min1,
respectively. Results were equivalent in rats with the catheter (n = 3) or HR recorder (group II-VI).
As shown in Fig. 2, A and B, there were linear increases in oxygen uptake and HR with
increased power output. Figure 2A also shows that the oxygen
uptake reached a plateau despite increased power output. The oxygen
pulse increased up to the intensity corresponding to
O2 max, where it leveled off and
declined (Fig. 2C). Figure 3
demonstrates that there was a linear relationship between oxygen uptake
and HR. However, maximal HR was not reached at
O2 max but at exercise intensities
above those corresponding to O2 max.
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Training Effects
After 7 wk of training,O2 max
reached a plateau 60% and 70% above controls in female and male rats,
respectively. As seen from Fig.
4A, male rats had higher
O2 max (in ml · kg1 · min1) than
female rats except at wk 7. The running speed at
O2 max increased from 0.36 ± 0.03 to 0.60 ± 0.04 m/s after 13 wk of training in female rats. The
corresponding values for male rats trained for 7 wk were 0.40 ± 0.02 and 0.65 ± 0.02 m/s. No gender or group differences in body
mass were observed at pretest, and body mass was 277 ± 10 and
287 ± 11 g for female and male rats, respectively. However,
after 7 wk, only male rats had increased body weight, by 28% and 60%
in the trained and sedentary groups, respectively (Table
3). When properly scaled for body mass,
O2 max (in
ml · kg0.75 · min1) in
trained male rats was ~15% higher than in trained females throughout
the study (Fig. 4B). No training or gender effects were
observed in maximal HR or resting oxygen uptake. Average values were
647 ± 10 beats/min and 14 ± 2 ml · kg0.75 · min1. In
trained female rats, resting HR decreased by 24 and 69 beats/min at 4 and 13 wk, respectively, whereas trained male rats decreased resting HR
by 56 beats/min at 7 wk (Table 3). Work economy, measured as oxygen
uptake (in
ml · kg0.75 · min1) at a
given running speed, did not differ between trained groups. The average
improvements at 4, 7, and 13 wk of training were 16 ± 4.7%.
Figure 5A presents work
economy for female rats after 13 wk of endurance training compared with
sedentary controls. Because there were no differences in body mass in
female rats, the relationship is expressed as milliliters per kilogram
per minute. In rats with identical
O2 max, work economy differed by as
much as 15% (P < 0.05; data not shown). The
submaximal respiratory exchange ratio was significantly reduced by the
training regimen (Table 4) and did not
differ between trained female (13 wk) and male rats (data not shown).
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At all submaximal exercise intensities (<70% of
O2 max), HR was reduced by 13 ± 2.1% (P < 0.01) and 11 ± 1.7%
(P < 0.01) after 13 and 7 wk of training in female
(Fig. 5B) and male rats, respectively. In female rats
trained for 4 wk, the corresponding reduction was 7 ± 2.2%
(P < 0.01).
No gender effect was observed in the resting and submaximal oxygen
pulse. Training increased the resting oxygen pulse by ~25% in both
male and female rats (13 wk). The maximal oxygen pulse (in
ml · kg0.75 · beat1) in
trained male rats was ~17 ± 3.1% higher compared with trained female rats (13 wk). The oxygen pulse at increasing intensities for
female rats is presented in Fig. 5C.
Training-Induced Cardiac Hypertrophy
In female rats, 4 wk of endurance training increased left and right ventricular weights by 10% and 12%, and, at 13 wk, the increases were 34% and 30%, respectively. The corresponding increases for trained male rats were 25% and 23% at 7 wk (Table 3). Table 3 further shows that, in sedentary males, ventricular weights were ~45% and 10% higher than in sedentary and trained female rats (13 wk), respectively. When normalized to body weight (Table 5), there were no gender differences in ventricular weights in training or control rats. However, in relation to controls, and due to the substantial increase in body weight in sedentary males, trained males showed a more pronounced ventricular hypertrophy than female rats, expressed in relation to body mass.
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There were no gender differences in myocyte dimensions in sedentary animals. Endurance training increased left ventricular myocyte size by longitudinal growth, whereas width remained unchanged (Table 3).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIAL AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The present experiments demonstrate that intensity-controlled treadmill running induces substantial endurance conditioning and myocardial hypertrophy in rats. The results suggest that the present training protocol could be used in future studies of the cellular, molecular, and integrative mechanisms of improved cardiac function in both healthy animals and models of cardiovascular disease.
Test Protocols
Maximal oxygen uptake.
O2 max was significantly affected by
the inclination of the treadmill. Maximum values were 7-25%
higher at 25° compared with the other inclinations. Thus use of
inappropriate treadmill inclination might hide training-induced
adaptations if the true O2 max is not
reached. An inclined (vs. level) treadmill offers the same advantage
when testing rats as it does when testing humans; it recruits a larger
muscle mass and a slower cadence. At 25° inclination, there was no
further increase in oxygen uptake despite increased running speed when
testing O2 max (Fig. 2A);
the blood lactate concentration was above 6 mmol/l, and the respiratory
exchange ratio was above 1.05 (Table 2). We therefore suggest that
these criteria should be met in testing
O2 max in rats running on a treadmill,
as in human subjects (3). In a similar study by Fitzsimons
et al. (11), no leveling off of oxygen uptake was found in
female rats running at 20% (~11°) inclination. These differences
are probably due to differences in treadmill inclination, because we
did not find any true leveling off at 0, 15, 20, or 30° inclination
of the treadmill. It is conceivable that working at 30° or higher
inclination results in a longer muscle contraction-relaxation duty
cycle and sufficient intramuscular compression to obstruct local blood
flow, thereby limiting peripheral oxygen transport and peak oxygen
consumption. This view is supported by the fact that, compared with
other inclinations evaluated, a significantly higher lactate
concentration was observed during exercise at 30° inclination of the
treadmill (Table 2).
Relationship among oxygen uptake, HR, and power output.
HR was observed to increase linearly with power output (Fig.
2B), a typical feature of dynamic exercise with large muscle groups in rats (11) and humans (3). In many
situations, the most practical way to control the training intensity is
by monitoring HR. Obviously, the usefulness of such intensity scales
depends on HR obtained from a reliable test of maximal HR. From
regression analysis (Fig. 3A), it is apparent that maximal
HR is not reached at O2 max. This is a
normal observation (3), because the relationship between
HR and oxygen uptake becomes nonlinear at high exercise intensities. It
is thus not necessary to reach maximal HR to reach
O2 max. This probably explains why we
observed higher values of maximal HR compared with previous studies
(11, 24). There exists no established protocol for measurement of maximal HR, but to achieve it usually requires exercise
beyond the intensity at O2 max
(19). For practical reasons, we have chosen to modify a
model established by Ingjer (19). Figure 3A
shows that, with the present protocol, it is possible to estimate the
relative exercise intensity (in percentage of
O2 max) from HR measurements (measured
as percentage of maximal HR) with an accuracy of about ±5%.
Furthermore, the estimate of oxygen uptake from HR is possible with an
accuracy of ±6
ml · kg1 · min1 (Fig.
3B) using the present protocol. The usefulness of the former is obvious to control the relative exercise intensity by HR, whereas the latter could be used to estimate work economy. In the present study, a lowering of the HR by 25 beats/min at submaximal exercise intensities corresponds to a reduced oxygen uptake by ~5
ml · kg1 · min1.
Cardiovascular Effects of Aerobic Endurance Training
O2 max and HR response.
The present study demonstrates that intensity-controlled interval
running induces significantly larger training effects than previously
reported (11, 13, 20, 24, 34). It is conceivable that
these effects resulted from a carefully controlled level of exercise
intensity throughout the study. Differences in training response
reported in the literature are probably due to different training
regimens used, insufficient control of exercise intensity, or different
protocols for measuring O2 max. The
load required to produce a training effect increases as the performance is improved in the course of training (3). The training
load should, therefore, be set relative to the level of fitness of the
individual. This principle may explain why we observed a leveling off
after ~7 wk of endurance training (Fig. 4). It is possible that a
higher volume of training (e.g., 2 sessions per day) might have led to
further improvements in O2 max beyond 7 wk. Christensen (6) demonstrated, in humans, the need for
a gradual increase in training load with improved performance, in the
case of the effect on HR, as early as in 1931. He observed that regular endurance training at a given exercise rate gradually lowered the HR,
in line with results from the present study (Fig. 5B). Further training did not modify this HR response. After a period of
training at a higher load, a standard workload could then be performed
with even lower HR. The following general principle of training is
apparent in a number of parameters, among them O2 max: an adaptation to a given load
takes place and, to achieve further improvement, the absolute exercise
intensity has to be increased (3). In a study by
Fitzsimons et al. (11), 10 wk of treadmill training
in female rats reduced resting HR similarly to that observed after 4 wk
in the current study but less than after 7 and 13 wk. In the last 5 wk
of exercise, Fitzimons et al. (11) used a constant
absolute exercise intensity, which probably explains the similarities
and discrepancy in training response in these two studies. No change
was found in the maximal HR over the experimental period. This finding
is in agreement with a previous study (16) and confirms
that training does not affect maximal HR. The lower resting HR observed
in the endurance-trained rats may result from a reduced intrinsic HR,
enhanced vagal tone in response to a higher stroke volume, or both.
Reduced resting rate and submaximal HR are good coindicators of the
trained state (10, 16). No changes were observed in
basal metabolism, which is in accordance with previous studies on
training (16, 24).
Work economy.
Comparing steady-state O2 at fixed
absolute submaximal work intensities provides evidence of a different
aspect of physical conditioning than a standard
O2 max test. Our experiments demonstrated that running economy remained stable from 4 to 13 wk,
whereas O2 max increased substantially.
The amount of increase was similar to the 17% reported by Fitzsimons
et al. (11) after 10 wk of endurance training, which was probably
carried out at lower absolute intensities than those in the present
study (12). It is conceivable that training at lower
intensities may substantially improve work economy without changing
O2 max and that work economy, in many
cases, could be a more relevant measure to assess the effect of
specific training regimens. In some cases, improved work economy would,
in fact, imply increased work capacity in the face of unchanged
O2 max.
Oxygen pulse. Oxygen pulse, or oxygen uptake divided by HR, is the volume of oxygen transported by the blood and extracted by peripheral tissues for each heartbeat. This variable is useful to assess changes in stroke volume in response to training because it equals the product of stroke volume and the arterial-mixed venous oxygen difference. It has been shown that the upward displacement of the curve in response to training over time depends primarily on the stroke volume (31). In agreement with previous studies (31, 35), we have shown that training increased the oxygen pulse both at rest and during exercise (Fig. 5C and Table 3). Several factors may contribute to increased stroke volume in trained rats, including increased ventricular volumes because of hypertrophy, intrinsic or reflex bradycardia, and increased intrinsic myocardial contractility. Unpublished results from our laboratory indicate that cardiomyocytes isolated from trained rats have increased contractility and calcium sensitivity.
Respiratory exchange ratio.
In line with Musch et al. (24), we observed that training
lowers the respiratory exchange ratio at submaximal workloads in rats.
These findings are in agreement with observations in human subjects.
The greater the O2 max, the greater the percent contribution of fat to the energy metabolism at a given work
rate (9). As muscle glycogen stores are reduced, an
increasing percentage of substrate utilization must be taken from fat.
Individuals with better endurance capacity would be expected to
"spare" glycogen during moderate intensities, providing greater
reserves for fueling more intense exercise.
Ventricular weights and left ventricular cardiac myocyte dimensions. The increases in left ventricular weight in the present study are the largest ever reported in female rats after treadmill training. Our data also provide evidence that aerobic endurance training with sufficient training intensity leads to longitudinal myocyte growth. The cardiomyocyte elongation observed at 4 wk was similar to that observed after 20-30 wk of endurance training in previous studies (22, 23). After 7 and 13 wk, it was larger than in some studies (22, 23) but smaller than the 20% increase observed after 20 wk of treadmill running or swim training in young male and female rats, respectively (34). The differences could be age related or be due to the duration and/or intensity of the training regimen used.
Gender differences.
In both genders, the increase in
O2 max plateaued after 5-7 wk of
training. When properly normalized to body weight (in
ml · kg0.75 · min1),
O2 max and oxygen pulse were 15%
higher in males, which concurs with observations in humans (3,
32). [In sedentary rats,
O2 max appeared to drop when expressed
as
ml · kg1 · min1
but remained unchanged when expressed as
ml · kg0.75 · min1 (Fig.
4).] The discrepancy is probably because a large proportion of the
substantial increase of body weight in sedentary rats resulted from
increased fat content. Hence, the latter expression should be used when
oxygen uptake and derived measures are compared between individuals
with different body masses. Otherwise, the capacity of light
individuals will be overestimated at
O2 max and underestimated at submaximal
workloads, whereas the opposite will be the case for heavier individuals.
Conclusions.
The present training model mimics important human responses to
training with increased O2 max,
improved work economy, reduced HR, and myocardial hypertrophy. It could
be used in future studies on cellular, molecular, and integrative
mechanisms of cardiovascular adaptation to exercise, e.g., contractile
characteristics and calcium regulation in cardiac myocytes and
differences in signaling pathways between training-induced adaptive
myocyte enlargement and hypertrophy observed in heart failure.
Understanding the cellular mechanisms of training-induced amelioration
of myocardial function may help identify molecular targets for the
treatment and prevention of cardiovascular disease.
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ACKNOWLEDGEMENTS |
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We thank engineers Arnfinn Sira and Ketil Jensen for building the rat training equipment; Dr. A. O. Brubakk for assistance in the preparation of the training model; research fellow Marianne Berg and bioengineer Sissel Skarra for RT-PCR analyses.
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FOOTNOTES |
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U. Wisløff was the recipient of a research fellowship from the National Council on Cardiovascular Diseases. This work was also supported by grants from the Norwegian Research Council, Sintef Unimed, the Langfeldt Fund for Research in Physiology and Medical Biochemistry, the Blix Fund for the Promotion of Medical Science, the National Association for Lung and Heart Disease, and the Funds for Cardiovascular and Medical Research at Trondheim University Hospital.
Address for reprint requests and other correspondence: Ø. Ellingsen, Dept. of Physiology and Biomedical Engineering, Medical Technology Center, Norwegian Univ. of Science and Technology, Olav Kyrres gt. 3, N-7489 Trondheim, Norway (E-mail: Oyvind.Ellingsen{at}medisin.ntnu.no).
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 20 April 2000; accepted in final form 20 October 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIAL AND METHODS
RESULTS
DISCUSSION
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) and
sedentary controls (
) after 13 wk. Trained rats
significantly differed (P < 0.001) compared with
controls. Individual data are shown.