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1 Department of Physiology and Biomedical Engineering, Norwegian University of Science and Technology, N-7489 Trondheim; and 2 Department of Cardiology, St. Olavs Hospital HF, N-7006 Trondheim, Norway
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Whereas novel pathways of
pathological heart enlargement have been unveiled by thoracic aorta
constriction in genetically modified mice, the molecular mechanisms of
adaptive cardiac hypertrophy remain virtually unexplored and call for
an effective and well-characterized model of physiological mechanical
loading. Experimental procedures of maximal oxygen consumption
(
O2 max) and intensity-controlled treadmill running were established in 40 female and 36 male C57BL/6J mice. An inclination-dependent O2 max
with 0.98 test-retest correlation was found at 25° treadmill grade.
Running for 2 h/day, 5 days/wk, in intervals of 8 min at 85-90%
of O2 max and 2 min at 50% (adjusted
to weekly O2 max testing) increased
O2 max to a plateau 49% above
sedentary females and 29% in males. Running economy improved in both
sexes, and echocardiography indicated significantly increased left
ventricle posterior wall thickness. Ventricular weights
increased by 19-29 and 12-17% in females and males,
respectively, whereas cardiomyocyte dimensions increased by 20-32,
and 17-23% in females and males, respectively; skeletal muscle
mass increased by 12-18%. Thus the model mimics human responses
to exercise and can be used in future studies of molecular mechanisms
underlying these adaptations.
maximal oxygen uptake; work economy; respiratory exchange ratio; cardiomyocyte; allometric scaling
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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SEVERAL NOVEL SIGNALING
PATHWAYS of pathological cardiac hypertrophy have been unveiled
in the powerful model of mechanical overloading by thoracic aorta
constriction in genetically modified mice (8, 22). Thus
far, the molecular mechanisms of adaptive cardiac hypertrophy in
response to physiological stimuli remain virtually unexplored because
of a paucity of effective and well-controlled experimental models in
this species. Ideally, the outcome should mimic typical results of
exercise training in humans, e.g., increased maximal oxygen uptake
(O2 max) and work economy
(21). In healthy individuals, increased exercise capacity
is dependent on functional and structural adaptations in skeletal
muscle, blood vessels, and heart. Cardiac adaptation includes increased
ventricular chamber volumes and weights, cardiomyocyte hypertrophy,
increased cardiac output, and improved contractile function measured in isolated cardiomyocytes and in the intact heart (2, 3).
At present, there are few well-controlled endurance training studies in
mice. Training is usually carried out as voluntary exercise regimens,
with little control of exercise intensity and the individual's fitness
level. Voluntary wheel running is most frequently used.
O2 max has been shown to increase by 12-30% after a 7- to 12-wk period of free wheel running
(11, 40). The latter study also demonstrated a 6%
decreased respiratory exchange ratio (RER) at
O2 max in trained mice. Exercise capacity and adaptations have also been measured indirectly, e.g., as
maximal exercise duration and total distance run (26). A 4-wk regimen led to 15% increased cardiac mass as well as increased expression of hypertrophy markers, i.e., atrial and brain natriuretic peptides, by 74 and 52%, respectively (1). Myosin heavy
chain redistribution toward greater expression of type IIa and IId/x occurred, whereas skeletal muscle weights remained unchanged. Four
weeks of swimming led to cardiac hypertrophy, with a 10% increase in
heart weight and a 16% increase in heart-to-body weight ratio
(24). Although some studies have reported problems with both acute and chronic mice training, the large number of training studies in mice indicates the opposite. However, procedures for reliable exercise capacity measurements have been difficult to establish in mice (e.g., Refs. 11, 26).
In contrast, rat studies on training effects are numerous, with
well-defined protocols for exercise capacity evaluation,
intensity-controlled treadmill running, and robust cardiovascular
outcomes. Until recently, findings appeared somewhat contradictory.
Treadmill running with fixed exercise intensity induced only minor
increments in ventricular mass and cardiomyocyte dimensions (2,
3, 28, 29) or did not induce any effects (16, 18).
However, 10-20% improvements in
O2 max and work economy had been
demonstrated (16, 30). Because swim training had produced
up to 33% ventricular enlargement in rats, some studies concluded that
the mode of exercise is crucial for eliciting cardiac training
adaptations (16, 18). Even in rats, few studies had
accounted for the fact that the load intensity required to induce
physical conditioning increases as the performance improves during the
course of training (4). However, a recent study from our
laboratory demonstrated that intensity-controlled treadmill running
induced some of the largest and most consistent effects of exercise
training (42).
The purpose of the present study was to establish an experimental model
of intensity-controlled treadmill running in mice. The specific aims
were to 1) establish a valid and reliable treadmill protocol
for evaluating endurance capacity in mice; 2) establish a
standardized, long-term, intensity-controlled treadmill running protocol that is appropriately adjusted to the individual mouse endurance capacity by weekly O2 max
assessments; and 3) determine the effects of exercise
training on endurance capacity and cardiac adaptations, as assessed by
echocardiography and postmortem characteristics in male and female mice.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Study population and design.
A total of 40 female and 36 male adult C57BL/6J mice, 19-23 g,
7-8 wk old (Møllegaards Breeding Center, Lille Skensved,
Denmark), were included in the study. Animals were maintained in a
12:12-h light-dark cycle, 22.5 ± 1.4°C temperature, and
55.6 ± 4.0% relative humidity. The mice were fed a pellet rodent
diet and water ad libitum. Strewment was changed every third day. All
experimental protocols were performed during the mice dark cycle, and
the animals were rewarded with chocolate (Crispo, Nidar Bergene,
Norway) after each training or test session. Sedentary mice were given
the same amount of chocolate. None of the mice was excluded in the
study because they avoided treadmill running, and the same person
handled the mice during the study. The experimental protocol was
approved by the Norwegian Council for Animal Research, and the
experimental procedures conformed with the European Convention for the
Protection of Vertebrate Animals Used for Experimental and Other
Scientific Purposes and the Guiding Principles for Research
Involving Animals and Human Beings from the American Physiological
Society. The mice were assigned into groups as described in Table
1.
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Aerobic capacity.
Oxygen uptake (O2) in mice was tested
during treadmill running in a metabolic chamber. Ambient air was led
through the chamber at a rate of 0.5 l/min, and 200 ml/min samples of
gas were extracted to the paramagnetic oxygen analyzer (type 1155, Servomex) and the carbon dioxide analyzer (LAIR 12, M & C Instruments).
The gas analyzers have an accuracy of measurements of ±2% and were calibrated with standardized gas mixtures before every test session. The single-lane test treadmill was custom made and placed in the metabolic chamber; for training, mills with multiple lanes were used.
Stainless steel grids at the end of the lines provided an electrical
stimulus of 0.25 mA, 1 Hz, and 200-ms length, to keep the mice running,
and brushes avoided the mice from pinching feet between grid and
treadmill. Test-retest assessments of O2
and RER were performed during submaximal running at fixed standardized treadmill velocities at 25° (47%) inclination of the treadmill. After having been exposed to the equipment and treadmill running twice,
six mice of both sexes were assigned to test-retest procedures. Mice
were placed in the metabolic chamber for 10 min, and then they went
through a 10-min warm-up at 0.08 m/s before running for 5 min at four
different velocities (0.1, 0.14, 0.18, and 0.22 m/s). Each mouse ran
twice, with the velocity order low to high or high to low set randomly,
and performed both. With modifications, this method was adopted from
previous studies in rats (6, 42).
O2 max, six untrained female and male
mice were tested at five different inclinations (0, 15, 25, 35, and
45°), one test each day and the inclinations in random order, to
avoid possible conditioning biases. Each mouse had a regular 20-min
warm-up at 40-50% of O2 max before the O2 max protocol, which was
carried out by increasing speed by 0.03 m/s every 2 min. Because the
tests showed that middle inclinations (15-35°) resulted in
highest peak O2, these inclinations (15, 20, 25, 30, and 35°) were tested again after 8 wk of training in six
female and male mice, one test each day and the inclinations in random
order, to determine whether O2 max
occurred at similar grades.
O2 max was measured at the start of
every training week, and before and after the experimental training
period, whereas running economy was measured before and after. Before
O2 max testing, all mice went through a
regular warm-up before they ran at fixed submaximal velocities of 0.15, 0.20, and 0.25 m/s at 25° inclination, for 5 min at each level, to
determine the running economy. The treadmill velocity was then
increased by 0.03 m/s every second minute until the mice were unable
to, or refused to, run further. The criterion for reaching
O2 max was when
O2 leveled off despite increasing
running velocity. Another criterion for reaching
O2 max was RER above 1.0.
Training.
For the investigations of prolonged training adaptations, 28 female and
24 male mice were randomized into either treadmill running or sedentary
control groups. When O2 max remained unchanged for at least 3 consecutive wk, which occurred after 8 wk of
training, the mice were killed. Training mice exercised on
treadmills 2 h/day for 5 days/wk. At the start of every week, O2 max was measured as described and
workloads adjusted accordingly. In training mice, exercise intervals
alternated between 8 min at 85-90% of
O2 max and 2 min at 50-60%.
Before the first interval, each mouse performed a regular warm-up as described earlier. At the day when
O2 max was tested, trained mice
performed eight intervals after the test. In sedentary mice, treadmill
running skills were maintained by treadmill running for 15 min on a
flat treadmill at 0.15 m/s for 3 days/wk. This latter activity did not
seem to alter either O2 max or work
economy (Fig. 3).
Echocardiography. Echocardiography was performed in 16 female mice, after sedation with ketamine hydrochloride (100 mg/kg, Pfizer) and xylazine (5 mg/kg, Bayer) intraperitoneally, by using a GE Vingmed System FiVe ultrasound scanner with an epicardial probe at 10 MHz and 250 frames/s (GE Vingmed Ultrasound, Norway). After the mouse chest was shaved, the transducer was gently placed on it for recordings. Heart rate, systolic and diastolic left ventricular wall thickness, lumen diameters, and fractional shortening were calculated as the mean of 10 consecutive cardiac cycles in two-dimensional M-mode long-axis recordings following the recommendations of the American Society of Echocardiography (35). Mitral inflow deceleration time, peak velocity of early and late component of mitral inflow, and isovolumetric relaxation time were calculated as the mean of 10 consecutive cardiac cycles of pulsed wave Doppler spectra recordings.
Cardiac and skeletal muscle mass. After the training, mice were anestethized with diethyl ether and anticoagulated (0.1 ml heparin, 1,000 IU/ml; Novo Nordisk, Cophenhagen, Denmark). Hearts were rapidly removed, and left and right ventricles were carefully dissected and weighed. Extensor digitorum longus and soleus muscles from both hindlimbs were dissected out carefully and weighed after tendon removal.
Left ventricular myocytes. After the training, mice were anestethized and heparinized, and hearts were removed as described above. Hearts were then submerged in oxygenated perfusion buffer, cannulated via the aorta under a microscope, and connected to a standard Langendorff retrograde perfusion system adapted to mice. To balance variation of the left ventricle myocyte isolation method, one heart from both trained and sedentary group was taken each day. Left ventricular and septal myocytes were isolated by using a modified protocol from Christensen et al. (9). The heart was perfused at 2.2 ml/min for 10 min with a modified Joklik's minimum essential medium (Life Technologies) mixed in 2,000 ml deionized water containing (in mM) 1.2 MgSO4, 1.0 DL-carnitine (Sigma Chemical), and 23.8 NaHCO3. The buffer was equilibrated with 5% CO2-95% O2 for 30 min (37°C, pH 7.2). Subsequently, 150 U/ml collagenase type II (Worthington) and 0.1% (wt/vol) bovine serum albumin (Sigma Chemical) were added, and the heart was perfused until it became palpably flaccid, which usually occurred after 6-8 min. The heart was then cut down into the Joklik's medium containing 0.8% (wt/vol) bovine serum albumin (Sigma Chemical) and 0.75 mM CaCl2. The left ventricle was separated and minced and was shaken for 15-20 min in the collagenase type II and bovine serum albumin buffer (37°C, 5% CO2-95% O2, 100 rpm). The solution with the myocytes and unsolved tissue was then gently filtered through a nylon mesh (250 µm); added to HEPES buffer containing (in mM) 135 NaCl, 5 KCl, 1 MgCl2 · 6H2O, 1.2 CaCl2 · 2H2O, 10 HEPES, 8 C6H12 · H2O (37°C, pH 7.2, 5% CO2-95% O2); and centrifuged (600 rpm, 45 s, 21°C). The supernatant was then removed, and HEPES buffer was added. Cardiomyocytes were deposited on laminin-coated coverslips (10 mg/ml, Life Technologies) and placed in a cell chamber on an inverted microscope (Diaphot-TMD, Nikon) and measured for length and midpoint width.
Allometric scaling.
As demonstrated in Table 3, the body mass increased more in males than
in females. Changes in ventricular and skeletal muscle weights
and O2 may not be entirely due to
training regimens but also may be due to growth-related changes in body
mass. It was therefore necessary to normalize
O2 and cardiac and skeletal muscle
weights to the body dimensions (4). According to
dimensional analysis and empirical studies,
O2 should be expressed in relation to
body mass raised to the power of 0.75, over a wide range of body
weights (e.g., Ref. 41). Dividing for instance organ
weight by body weight is the usual approach, but this has previously been shown to be valid only if body weight is expressed as lean body
mass (5), because fat has very low metabolic activity (4). When lean body mass is undefined, ventricular mass
should be expressed in relation to body mass raised to the power of
0.78, which is demonstrated empirically as the best approximation
(5). Because no empirical studies relate the hindlimb
muscles of the mice to body weight, the reduced exponent was calculated
in the present training and sedentary control population by allometric equations to determine the relationship between body and extensor digitorum longus and soleus muscle mass. Skeletal muscle mass = a · mb, where a is
the mass coefficient, m is the body mass, and b
is the reduced exponent. The numerical value of b
can be obtained from the log-log plot of the experimental data because
the logarithmic expression is a straight line (e.g., log soleus
mass = log a + b · log
m). It was found that skeletal muscle mass should be
expressed to body mass raised to the power of 0.75. A detailed
introduction to allometric scaling is presented elsewhere
(4).
Statistics.
Data are expressed as means ± SD. The Friedman test and
appropriate procedures for multiple comparisons were used to determine changes in O2, RER, and body weights
throughout the experimental period, as well as differences in
O2 by using different inclinations of
the treadmill. The Mann-Whitney U-test was used to evaluate differences between groups and sexes. The relationship between O2 and speed was calculated by linear
regression analysis. P < 0.05 was considered
statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Test protocols.
The procedures for measuring O2 and RER
were found to be reproducible for measuring
O2 and RER during exercise. Measurements of O2 in both female and male mice
running at four submaximal velocities were similar on 2 different days
(Fig. 1). Test-retest correlation
O2 was 0.98, and the coefficient of
variation was 9.1%. Inclination of the treadmill affected the highest
O2 measured, as demonstrated in Table
2. This was evident in both trained and
untrained mice of both sexes. Peak O2
was found at a range of inclinations between 15 and 35°. RER reached
the highest values in the same range of inclinations, although in
untrained females the maximum value occurred at 25° (47%)
inclination (Table 2). Testing procedures for
O2 max were reliable and consistent with previous results. As shown in Fig.
2, O2
increased linearly with increasing running velocity, and reached a
plateau despite increased velocity, in both trained and untrained mice
of both sexes. Linear regression analysis was performed until
O2 leveled off for both sexes [i.e.,
for trained female mice, O2 = 110.3 · speed + 13.6 (r = 0.98, P < 0.001), and for sedentary controls, O2 = 49.2 · speed + 33.1 (r = 0.97, P < 0.001)]. The
respective linear regression for trained male mice was
O2 = 51.9 · speed + 36.7 (r = 0.99, P < 0.001), and for
their respective sedentary controls,
O2 = 29.3 · speed + 45.2 (r = 0.96, P < 0.001).
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Training effects.
After 6 wk of training, both female and male mice reached a plateau
49 ± 7 and 29 ± 5% above sedentary controls in female and
male mice, respectively. However,
O2 max appeared to increase
progressively in both sexes when it was not corrected for body mass. As
shown in Fig. 3, female mice had a higher
O2 max than males, except in baseline
recordings and in sedentary controls. This was evident both when
expressed as milliliters per kilogram per minute and expressed as
milliliters per kilogram raised to the power of 0.75 per minute but
not when expressed as milliliters per minute. Body mass
increased in all mice during the training regimen by 14 ± 3 and
17 ± 3% in trained and sedentary female mice, respectively, and
by 29 ± 5 and 34 ± 6% in male counterparts (all
P < 0.01; Table 3). Body
mass did not develop differently between sedentary and trained mice
within any sex, but increased significantly more in male mice than in
females. When properly scaled for body mass,
O2 max (expressed
ml · kg
0.75 · min1) in
female mice was 15% higher than in males mice after the training regimen. The maximal running speed when
O2 max was tested increased from
0.36 ± 0.03 to 0.63 ± 0.03 m/s in female mice during the
training regimen, whereas the respective increase in male mice was from
0.37 ± 0.02 to 0.65 ± 0.04 m/s.
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O2 at a given
running intensity, improved by 24.7 ± 3.4% in females and by
18.7 ± 4.6% in males after the training period (Fig.
4A). Training also reduced RER
during submaximal running by 8.7 ± 1.1% in females and 8.5 ± 1.0% in males. The decrease in RER was most marked at the highest
intensities (Fig. 4B). There was a trend (P = 0.14) toward a lower oxygen cost and RER in female mice during
identical submaximal running velocities (Fig. 4).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study documents robust and well-controlled protocols
for exercise training of mice of both sexes. Reliable
O2 max assessments were obtained in
treadmill running at 25° (47%) inclination, whereas peak
O2 measurements at grades below 15° or
above 35° underestimated aerobic exercise capacity. Within 6 wk,
intensity-controlled interval running at this inclination induced the
largest increments in O2 max,
myocardial weights, and cardiomyocyte dimensions reported in this
species. As discussed in Aerobic capacity after training,
allometric scaling significantly facilitated comparison across sexes
and varying body weights. We found that noninvasive evaluation
of cardiac dimensions by echocardiography was less sensitive in
detecting myocardial hypertrophy than postmortem chamber weights and
assessments of isolated cardiomyocyte length and width by video microscopy.
Test protocols.
The most common method for testing aerobic capacity in mice is
recording volume and velocity of voluntary wheel running (15, 17,
19, 34, 44). Others have estimated aerobic capacity by total
time of standardized incremental treadmill running (e.g., Ref.
26), O2 during swimming
(25), or by the cold-exposure method (e.g., Refs.
20, 25, 38). However, these
approaches have several problems. Seeherman et al. (38)
found that the cold-exposure method yielded 23% lower
O2 max than measurements during
treadmill running, whereas swimming differs from running because of
relatively inactive forelegs (24). Aerobic capacity may
further be underestimated if motivation is low.
O2 and RER demonstrated
reliable protocols. Similar values were obtained on separate days
during standardized running, which is in accordance with previous
studies in rats in our laboratory (42). A 5-min stage at
each intensity was chosen, because O2
leveled off after ~3 min (data not shown), as previously demonstrated
in rats (42) and humans (4).
O2 and RER were therefore
recorded during the last 2 min of each stage.
As reported in rats (42), we found an
inclination-dependent peak O2 between 15 and 35° in both trained and sedentary mice. In mice, angle seems to
be less crucial than in rats and humans, but RER indicated that
25° inclination yielded the highest cardiovascular load. A high load
is important because inappropriate treadmill inclination might
underestimate training-induced adaptations if a true
O2 max is not reached. A graded
treadmill recruits a larger muscle mass, lowers the cadence, and
induces RER values above 1.0. We suggest that flattening off of
O2 and RER above 1.0 may be used as
criteria for O2 max in mice. As also was reported previously in rats (6, 42),
O2 increased linearly with running
velocity. This linearity thus provides a tool to estimate
O2 from running velocity. However, the
linear regression should only be used if identical inclinations,
strains, and training states are compared.
O2 max in untrained mice has been
reported to range from ~80 to 260 ml · kg1 · min1, and RER at
O2 max from 0.91 to 1.28 (13, 14,
31, 32, 36, 38, 40). However, there are differences in these studies regarding test protocols, equipment, body masses, strains, age,
sex, and how accustomed the mice were to the methods. For instance, it
has been shown that mice strain (e.g., Refs. 12, 26), ambient temperature (e.g., Ref. 32) and
age (e.g., Ref. 36) affect
O2 max. On the other hand, the two
studies investigating O2 max and RER in
C57BL/6J, age and test protocol as the present study, found similar
results (12, 27).
Aerobic capacity after training.
The training regimen in the present study is probably the largest and
most efficient reported. Within 6 wk, O2
reached a plateau 50% above sedentary controls in female mice and 30%
above controls in males. Niebauer et al. (31) found that
O2 max increased 10% in C57BL/6J
females after treadmill running for 4 wk, 1 h twice each day, 6 days/wk, at an intensity of ~85% of O2 max. Increments of 5-6% in
C57BL/6J males (37) and 12% occurred in male Hsd:ICR
house mice (40) after 6 wk of treadmill running and
7-8 wk of voluntary wheel running, respectively. Differences in
training adaptations reported in other studies are probably due to
different training regimens and protocols and to insufficient control
of exercise intensity. However, comparison of the results in many
previous studies may be confounded by different methods for normalizing
O2 to body weight. As shown in Fig. 3,
allometric scaling greatly enhances comparison of
O2 in animals with different weights.
Reports of long-term running in mice have reported decreased (34,
40, 44) or unchanged (1, 19, 31, 33, 37, 39) body
mass, whereas swimming yielded an increase (24). In a
survey of 100 recent transgenic mice studies at PubMed, body mass
ranged between 17 and 74 g and age between 26 days and 12 mo.
O2 max is regarded as the best
denotation of aerobic capacity (4), work economy provides
a tool to investigate other aspects of aerobic capacity and chronic
conditioning. Endurance training at lower intensities may substantially
improve work economy, without increasing
O2 max. Improved work economy probably contributes to the large increase in maximal running velocity at
O2 max.
Cardiac structure and function. In the present study, ventricular weights increased more than previously reported in mice and about the same as in rats exercising for 7 wk with the same regimen (42). Other studies in mice report no change (31) or an increase between 10 and 15% in cardiac mass (1, 24), after 4 wk of training in C57BL/6J mice, treadmill, voluntary wheel, and swimming exercise, respectively. These studies lack a rigorous control of exercise intensity, and cardiovascular load seemed lower.
As far as we know, this is the first report of training-induced cardiomyocyte growth in mice. Both cell length and width increased, whereas only lengthening was observed in rats (29, 42). No differences in cardiomyocyte dimension between the sexes were found, even though males had greater ventricle mass, which may suggest a higher number of cardiomyocytes in males. Noninvasive assessment of hypertrophy by echocardiography was less sensitive than postmortem measurements. A modest increase in systolic left ventricular posterior wall thickness, and trends in systolic intraventricular septum thickness and diastolic left ventricle diameter were detected. Ultrasound M-mode or Doppler measurements detected no other changes. The lower sensitivity in echocardiography may result from insufficient temporal or spatial resolution. Echocardiography with a 15-MHz linear probe indicated that 49 animals would be required to detect 15% (power
0.8, 
of 0.05) differences in M mode
between two groups of CD-1 mice, hypertrophy and control
(10). Compensatory mechanisms in vivo at rest and negative
inotropic and chronotropic effects of anesthesia are other possible
causes. Echocardiography revealed bradycardia, as previously observed
in mice (7, 43).
Skeletal muscle. The weights of the hindlimb extensor digitorum longus and soleus muscles increased substantially. Males had larger extensor digitorum longus muscles, but soleus muscle weight was similar. Other studies report varying results: 20-24% increased (39) and unchanged (1, 19) skeletal muscle mass, and increased cross-sectional area (19, 33) and GATA-2 expression (hypertrophy marker), after 4-12 wk of training (19, 33). Interestingly, skeletal muscle growth occurs in mice in response to endurance training, contrary to observations in humans (4).
Conclusions.
In summary, the present study documents a procedure for reliable
testing of O2 max in mice. Graded
treadmill running seems to be a sensitive method to assess changes in
work capacity and work economy in response to exercise training and
probably also in disease states such as heart failure. The protocol for intensity-controlled interval treadmill running provides a well-defined model for exercise training that yields large and robust effects that
mimic central results in humans. We anticipate that future experiments
in this model will unveil novel molecular, cellular, and integrative
mechanisms of adaptation to exercise, e.g., differences in signaling
pathways between training-induced adaptive myocyte enlargement and
pathological hypertrophy observed in heart failure. Understanding the
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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The authors thank Arnfinn Sira and Ketil Jensen for building the mice testing and training equipment, Bjørn Angelsen and Hans Torp for help with echocardiography, and Jan Helgerud for advice on allometric scaling.
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FOOTNOTES |
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This work was supported by grants from the Norwegian Council on Cardiovascular Diseases, the EWS Foundation, the Torstein Erbo Foundation, and the Arild and Emilie Bachkes Foundation. O. J. Kemi is the recipient of a research fellowship from the Norwegian University of Science and Technology.
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 gate 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.
May 24, 2002;10.1152/japplphysiol.00231.2002
Received 18 March 2002; accepted in final form 17 May 2002.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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