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1 Department of Physiology and
Biomechanics, ABSTRACT Tanaka, T., Y. Ohira, M. Danda, H. Hatta, and I. Nishi.
Improved fatigue resistance not associated with maximum oxygen consumption in creatine-depleted rats. J. Appl.
Physiol. 82 (6): 1911-1917, 1997.
endurance capacity; high-energy phosphate contents; glycogen; mitochondrial enzymes
INTRODUCTION BOTH ENDURANCE WORK CAPACITY and maximal capacity of
oxygen consumption
( Depletion of creatine by feeding of the creatine analog
METHODS Animals
Practice runs on a treadmill were performed before each experiment to
familiarize the rats with running. But the running was performed only
twice in 2 wk to avoid any effects of training. The
Experiment I
Effects of
feeding of either creatine or its analog 
-guanidinopropionic acid
(-GPA) on endurance work capacity and oxygen consumption were
studied in rats. Resting high-energy phosphate contents in
hindlimb muscles were lower in the -GPA group and higher in the
creatine group than in controls. The glycogen contents in resting
hindlimb muscles of rats fed -GPA were significantly higher than
those in controls. The endurance run and swimming times to exhaustion
were significantly greater (32-70%) in the -GPA group than in
the control and creatine groups. However, there were no
beneficial effects on the maximum oxygen consumption (
O2 max) and oxygen
transport capacity of blood by the feeding of -GPA. None of these
parameters were significantly influenced by creatine supply. Both
maximum exercise time and
O2 max in the -GPA
group were not changed by normalization of glycogen levels. The
activities of mitochondrial enzymes in skeletal muscles were higher in
the -GPA group than in the controls. Thus endurance capacity is
improved if the respiratory capacity of muscles is increased, even when
the contents of high-energy phosphates in muscles are lower. Increased
endurance capacity was not directly associated with the elevated levels
of muscle glycogen, oxygen transport capacity of blood, or
O2 max.
O2 max) are improved
after intensive exercise training (8, 9, 12). This phenomenon is caused
by increased cardiac output, stroke volume, and arteriovenous oxygen
difference (9). The increased arteriovenous oxygen difference, which
reflects a greater oxygen extraction by muscles, may be influenced by
the improved respiratory capacity of muscles (13, 14, 18, 26). Severe
iron-deficiency anemia, on the other hand, decreases both endurance
capacity and O2 max (7,
22). However, Davies et al. (7) reported that an elevation of
hemoglobin after a transfusion of red blood cells in iron-deficient and
anemic rats caused an increase in
O2 max but
not in endurance capacity. It is suggested that the
O2 max and endurance
capacity may be influenced differently by oxygen transport capacity of
blood and oxygen utilization capacity in tissues, respectively.
-guanidinopropionic acid (-GPA) decreases the high-energy
phosphate contents in muscles (10, 11, 23, 27-29). However, the
mitochondrial respiratory capacity of these muscles is improved (10,
24, 29, 30) and fatigue resistance of the fast-twitch muscle extensor digitorum longus is increased in response to chronic depletion of
creatine (33). A significantly elevated glycogen content in muscles is
also induced by the feeding of -GPA (21, 29, 31). These findings
suggest that chronic creatine depletion may affect endurance capacity
positively. However, it is not known whether feeding of -GPA in rats
influences O2 max.
Therefore, the present study was performed to investigate the possible
mechanism responsible for the improved endurance capacity in
-GPA-fed rats.
-GPA, and creatine groups. Rats were housed
individually in stainless steel cages and were pair fed. Control rats
were fed a commercial powdered food (CE-2, Nihon CLEA, Tokyo, Japan),
and the same food containing either 1% -GPA or 1% creatine was fed
to the other groups. The amount of food supplied, which was completely
eaten within ~12 h, was gradually increased in accordance with
growth. From week 4 to the end of the
experiment, each rat was fed a 20-g diet (0.2 g -GPA or creatine) daily. Water was supplied ad libitum. Temperature and humidity in the
animal room with a 12:12-h light-dark cycle were maintained at
~23°C and ~55%, respectively.
O2 max and endurance
capacity in treadmill running or swimming were determined. These
measurements were done in different groups of rats to avoid any effects
of frequent changes in diet, because the same parameters were
determined in the same rat twice both before and after an adjustment of
muscle glycogen levels with a 2-day interval.
Fig. 1.
Schema for experiment I. Days for
measurement of phosphorus compounds by
31P-nuclear magnetic resonance
spectroscopy (NMR) and oxygen consumption (O2) are indicated by arrows.
-GPA, -guanidinopropionic acid; No. 1 and No. 2, 1st and 2nd set
of treadmill runs, respectively.
[View Larger Version of this Image (11K GIF file)]
Fig. 2.
Examples of 31P-NMR spectra
(A),
Pi/phosphocreatine (PCr)
ratio (B), and
PCr/(PCr+Pi) ratio
(C). Values are means ± SE for 6 rats in each group. -GPAP, phosphorylated -GPA; ppm, parts per million. *** P < 0.001 vs.
control. 
P < 0.001 vs. creatine group.
[View Larger Version of this Image (27K GIF file)]
O2 max.
Three days after the NMR analysis, the oxygen consumption
(O2) and carbon dioxide
production (CO2) at rest
and during an exhaustive treadmill run were measured as reported
previously (5, 22). Briefly, a bottomless Plexiglas metabolic chamber (7.5 × 29 × 12 cm) was placed over a treadmill belt. An
electrified grid with variable voltage was set in the rear wall of the
chamber. Belt-chamber clearance was ~2 mm at the front, and the
bottom edges of the chamber were in contact with the belt along the
sides and back. This allows for entrance of ambient air into the
chamber and unidirectional flow past the animal. Tygon tubing was
attached to the air outlet placed on the ceiling. The air was pumped
out, and the fractions of oxygen and carbon dioxide were measured by mass spectrometry. The flow rate was 5.42 l/min.
O2 and
CO2 were measured
30-40 min after the values reached stable levels. In
a previous study from our laboratory (24), the resting
O2 was monitored
continuously for ~3 h and stable values reached after ~30 min were
used for the data. Therefore, the resting
O2 and
CO2 were monitored for
30-40 min, and stable levels reached at the end of resting period
were used. Then, an exhaustive treadmill run was performed, and the
measurements were made throughout the exercise. The data
were stored in computer and recorded on paper continuously. The
inclination of treadmill was kept constant at 10° from 0 to 6 min,
but the speed was increased every 2 min (30, 40, and 50 m/min).
The inclinations were 20° from 6 to 8 min and 30° from 8 to 10 min with a constant speed at 50 m/min. Then, the speed was increased to
60 m/min (30° inclination) and maintained until the end of
exercise. The end point for every test was decided by a rat's
inability to run at the speed.
Because feeding of -GPA causes an elevation of glycogen content in
muscles (21, 29, 31), the same measurement
of O2 was repeated again
after an adjustment of glycogen level. After the first treadmill run,
three sets of exhaustive swimming, with 30-min intervals between sets,
were performed to deplete glycogen in hindlimb muscles.
After the swimming, the rats in the -GPA group were fed lard for 2 days to inhibit an elevation of glycogen level. Rats in the other
groups were supplied the original control or creatine diet for 2 days.
One group of six rats that were fed the control diet and did not
perform the exhaustive swimming was also fed lard. In a pilot study,
the glycogen contents of resting soleus in the three groups were
determined (25) to examine the validity of the method for adjustment of
muscle glycogen.
Measurements in blood and muscles.
After the second treadmill run, each group of rats was fed the original
diet. One week after the recovery from the second treadmill run, rats
were anesthetized with an intraperitoneal injection of pentobarbital
sodium and ~2 ml of resting blood were withdrawn into a
heparin-coated syringe from the jugular vein. The concentration of
hemoglobin, red blood cell counts, and hematocrit were analyzed by
using an automatic blood analyzer (MEK-4500, Nihon Technicon). Heart
and soleus muscles were dissected out, and the wet weights were
determined. Soleus muscles were then homogenized in 175 mM KCl buffer
containing 10 mM tris(hydroxymethyl) aminomethane · HCl and 2 mM EDTA (pH 7.2) by using a
Polytron, with the homogenizing tube kept in ice water. The activity of -hydroxyacyl-CoA dehydrogenase was measured spectrophotometrically (4).
Experiment II
Endurance capacity at a submaximal intensity. Endurance exercise capacity was determined in six rats from each of the three groups. In the first group, an exhaustive treadmill run at 20 m/min and 0° inclination was performed. The exercise was terminated when a rat could not maintain the treadmill speed. Manipulation of muscle glycogen as in experiment I was done, and the exhaustive run time at the same work rate was measured 2 days later. In the second group, swimming was performed in a pool with a 55-cm diameter and 50-cm depth. The water temperature was adjusted to ~30°C. The fur was shampooed to avoid the buoyancy effects of air bubbles. A weight equivalent to 2.5% of body weight was attached by using a rubber band around the waist of each rat. Six rats (2 rats from each group) swam at the same time. Exhaustion was defined as the point when the rat could not swim up to the water surface for 10 s. The same exercise was repeated 2 days later after an adjustment of glycogen level in hindlimb muscles.Experiment III
Measurement of glycogen and high-energy phosphates. Effects of-GPA feeding and/or manipulation with swimming
and lard feeding on glycogen were determined in additional hindlimb muscles of control and -GPA groups to investigate why endurance capacity is increased. In 12 control and 12 -GPA-fed rats, the levels of glycogen (25), as well as ATP (16) and PCr (15), in soleus,
plantaris, and the lateral portion of gastrocnemius from the left limb
were measured. These muscles in resting rats, anesthetized with
pentobarbital sodium, were clamped with a pair of aluminum tongs cooled
in liquid nitrogen and stored at 
80°C until analyzed. The
samples were pulverized under liquid nitrogen and homogenized before
the assay, as in a previous study from our laboratory
(20). Such measurements were performed both with and
without adjustment of glycogen levels by swimming and dietary manipulation (n = 6 in each group).
Measurements in blood and muscles.
In the rats without manipulation of muscle glycogen, the weight of
soleus and heart and hematologic profiles were also measured as in
experiment I. Furthermore, activities
of citrate synthase (32) and -hydroxyacyl-CoA dehydrogenase were
assayed spectrophotometrically in the right soleus, plantaris, and red
and white portions of the gastrocnemius.
Statistics
All data are presented as means ± SE. Statistical significance was examined by analysis of variance and Scheffé's or Student's t-test for paired comparison. Differences were considered significant at the 0.05 level of confidence.RESULTS
High-Energy Phosphates
Decreased peak heights of PCr and ATP and an appearance of a new peak for phosphorylated-GPA were noted in the NMR spectra in the calf
muscles of rats fed -GPA (Fig.
2A), similar to those reported in a
previous study from our laboratory (23). These findings
were supported by the results of the biochemical determinations (Table
1). The levels of high-energy phosphates
were not altered by lowering muscle glycogen content. The heights of
PCr and ATP spectra tended to be elevated in rats fed creatine. The
Pi/PCr ratio was
significantly elevated by -GPA feeding (Fig.
2B; P < 0.001). This is due to a greater reduction in PCr than in
Pi. The rate of ATP synthesis
estimated as 1/(1 + 0.6 × PCr/Pi) (6) was significantly
elevated (data not shown). In contrast, a significant reduction of the
Pi/PCr ratio was seen in
the group fed creatine (P < 0.001).
The PCr/(PCr+Pi) ratio, which indicates the relative content of PCr,
was decreased significantly by the feeding of -GPA (Fig.
2C; P < 0.001). But it was increased by creatine supplementation (P < 0.001), as was indicated by the
elevated peak height of PCr in the NMR spectrum.
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The contents of ATP and PCr, determined biochemically, in soleus,
plantaris, and lateral gastrocnemius were significantly lowered in
response to -GPA feeding by ~31-40 and ~88-93%,
respectively (Table 1). The magnitudes of the decreases were not
different between slow and fast muscles. These levels were not
influenced by lowering muscle glycogen content.
Glycogen
The glycogen content of resting soleus was approximately 68% higher in-GPA than in control rats (Table 2;
P < 0.001). The elevation of
glycogen level was even greater in fast-twitch plantaris (92%;
P < 0.001) and the lateral
gastrocnemius (102%; P < 0.001). The glycogen levels in the soleus tended to decrease insignificantly after creatine supplementation. After 2 days of lard feeding after three sets of exhaustive swimming, the glycogen in the -GPA group was lowered (~50% in soleus, ~41% in plantaris, and ~38% in
the lateral gastrocnemius; P < 0.001).
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Mitochondrial Enzymes
The activities of citrate synthase in the soleus, plantaris, and red and white portions of gastrocnemius were elevated by 20, 40, 27, and 40% in response to chronic feeding of-GPA
(P < 0.05 to 0.001).
Those of -hydroxyacyl-CoA dehydrogenase were increased by 94, 46, 40, and 26% (P < 0.05 to 0.001),
respectively. The activity of -hydroxyacyl CoA
dehydrogenase in the soleus was even decreased after the diet was
supplemented with creatine (~47%; P < 0.01).
O2 and Work Capacity
O2 obtained by Adams et al.
(2) were identical to those of controls, those levels in both milliliters per minute (data not shown) and milliliters per minute per
kilogram body weight (Table 3) were
significantly higher in rats fed -GPA than in other groups. Similar
results were also obtained in a previous study from our laboratory
(24). Enhanced metabolic rate in creatine-depleted rats
may be related to the stimulated rate of ATP synthesis and an increased
growth of brown adipose tissue (35). The resting
O2 was not influenced
significantly by the feeding of creatine, although the mean values
tended to be less than in the control-diet group
(P > 0.05). Nor was the resting
O2 affected by changing the
glycogen content in muscle. The
O2 max was not
significantly influenced by the feeding of either -GPA or creatine
or by changing the glycogen content in muscle. Lard feeding in the
control group did not induce any significant effects on
O2 max (data not
shown). The durations of both the treadmill run
(P < 0.001) and swimming
(P < 0.01) at submaximal intensities were significantly improved by -GPA feeding (Fig. 3). The increased endurance capacities were
not affected by normalization of muscle glycogen levels in the -GPA
group. The maximum exercise time to exhaustion was not affected by the
feeding of creatine. The content of glycogen in the control group
(Table 2) and ATP and PCr in both the control and -GPA groups (Table
1) recovered completely within 2 days after an exhaustive exercise.
Thus it appears that a 2-day recovery interval between two bouts of
exhaustive exercise is sufficient.
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P < 0.05, P < 0.01, and
P < 0.001 vs.
creatine group.
Characteristics of Oxygen Transport and Utilization
The body weight of the-GPA group was lower than that in the
control-diet (P < 0.01) and
creatine-diet groups (Table 3; P < 0.05). The absolute weight of the soleus in the -GPA group was
significantly less than in other groups (Table
4; P < 0.001). The muscle weight relative to body weight in the -GPA group
was also lower than in other groups (P < 0.001). The reduced gain of muscle weight, normalized by body
weight, was not statistically significant in general when adult rats
were fed -GPA (1, 3). However, significantly less weight gain in the
plantaris, medial gastrocnemius, tibialis anterior, and extensor
digitorum longus compared with the control-diet group was seen when
-GPA feeding was initiated at weaning (1). The mean
weight of the soleus was also less than in controls but not
significantly so. Further, an insignificant trend of
reduced gain of muscle weight was reported elsewhere (17, 30). Such
discrepancy might be caused by the number of animals (5 rats in Ref.
30) and/or duration of -GPA feeding (35 days in Ref. 17).
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Hemoglobin concentration, red blood cell counts, and hematocrit were
identical in the two sets of measurements performed both without
manipulation of glycogen and 1 wk after the manipulation. Thus the data
were combined (Table 4). These values in the -GPA group tended to be
subnormal. The heart weight in absolute value also tended to be
decreased by the feeding of -GPA (P > 0.05). These values were not affected by supplementation of
creatine.
DISCUSSION
The endurance capacities at a submaximal work intensity were increased
in rats fed -GPA chronically (Fig. 3), although the high-energy
phosphate contents in muscles are lowered even at rest (10, 11, 23, 27-29; Table 1, Fig. 2). The present study was performed to
investigate the mechanism responsible for the improved endurance
capacity in rats fed -GPA. Increased mitochondrial respiratory
capacity (10, 24, 29, 30) and glycogen content (21, 29, 31) in skeletal
muscles of -GPA rats are possible factors that could explain the
increase in endurance capacity. The
O2 max was measured
during two sets of exhaustive treadmill runs both with and without
adjustment of muscle glycogen levels. The capacities of oxygen
transport by blood and oxygen utilization by muscles were also
evaluated as possible factors.
Significantly greater endurance in a treadmill run to exhaustion was
seen in rats fed -GPA. The lower body weight noted in the -GPA
group may have given them an advantage in the treadmill run. Therefore,
we also measured endurance capacity by using a swimming exercise test.
Because body fat content is less in -GPA than in control rats (24),
swimming may be disadvantageous for -GPA-fed rats in terms of the
buoyancy effect of fat. But an increased endurance capacity in swimming
with weight equivalent to 2.5% of body weight was observed in
-GPA-fed rats. Thus the lower body weight may not be the factor for
the improved endurance capacity in running.
Adams et al. (2) reported that -GPA feeding in rats tended to reduce
heart rates, peak left ventricular blood pressure, and estimated
cardiac O2 during exercise.
Further, the distribution of V1
isomyosin in the left ventricle was decreased and that of V2 isomyosin was increased by
-GPA feeding. These results suggest that one of the factors that
increase the endurance capacity in response to -GPA feeding might be
an improved cardiac function. However, it is also reported that the
speed-related contractile properties, measured both in vitro and in
situ, were shifted toward those of slow-type muscles and that fatigue
resistance was improved in soleus (34) and extensor digitorum longus
(33) of -GPA- fed rats, suggesting that an increased function of
skeletal muscles, besides cardiac muscle, plays an important role in
the improvement of work performance.
Decreased high-energy phosphate contents were noted in the hindlimb
muscles of -GPA group, as was reported previously (10, 11, 23,
27-29). However, the estimated rate of ATP synthesis was elevated.
This estimation is strongly supported by the increased O2 at rest (Table
3). Furthermore, an increased mitochondrial respiratory
capacity was also suggested by the pronounced increase of mitochondrial
enzyme activities, as was also reported elsewhere (10, 24, 29, 30).
Significant shifts of myosin heavy chain and light chain isoforms from
fast to slow type were also found (1-3, 19, 28). These data
indicate that endurance capacity remains high if the respiratory
capacity and/or the rate of ATP synthesis is improved,
even when the high-energy phosphate contents in muscles are low.
Interestingly, the increased endurance capacity was not associated with
an elevation of O2 max,
although these parameters are generally altered in parallel in response
to physical training (8, 9, 12) and/or iron-deficiency
anemia (7, 22). Unaltered O2
during treadmill run at a submaximal steady-state intensity was also
found in creatine-depleted rats (2). Nor was the
O2 max
influenced by changing the preexercise glycogen content in
muscle. The
O2 max may be closely
associated with cardiac output and/or blood hemoglobin levels,
as was reported previously (7, 9, 22), but not necessarily with the
respiratory capacity of muscles, as the present results show.
Although the glycogen content in resting muscles of -GPA-fed rats
was higher than in controls, as was reported elsewhere (21, 29, 31),
the improved endurance capacity was not affected by lowering the
preexercise level of glycogen. However, exercise-related glycogen
depletion may be less in the -GPA group than in controls because of
the increased glucose uptake, suggested by elevated GLUT-4 glucose
transporter expression (29) and mitochondrial energy metabolism. A
glycogen sparing effect was seen in electrically stimulated muscles of
-GPA-fed rats (Y. Ohira and J. O. Holloszy, unpublished
observations). Hemoglobin concentration, red blood cell counts,
hematocrit levels, and heart weight, which were measured to evaluate
the oxygen transport capacity of blood, tended to be less in -GPA
than other groups; thus, the improvement of endurance capacity in
-GPA-fed rats was not caused by an increased oxygen transport
capacity of blood.
Supplementation of creatine tended to induce opposite responses from
-GPA feeding generally, although the hemoglobin concentration and
heart weight remained normal. High-energy phosphate contents in resting
hindlimb muscles were higher than normal. But both O2 max and exercise
time to exhaustion were similar to those in the control-diet group.
Possible reasons for such normal work performance even with greater
high-energy phosphate contents might be the poor mitochondrial
respiratory capacity suggested by lower activity of -hydroxyacyl-CoA
dehydrogenase (P < 0.01)
and lower glycogen levels (P > 0.05).
In conclusion, the endurance running and swimming times to exhaustion
in -GPA-fed rats were significantly greater than in control and
creatine groups. The -GPA feeding did not increase O2 max, hemoglobin, red
blood cell counts, hematocrit, or heart weight. The activities of
mitochondrial enzymes in skeletal muscles were higher in the -GPA
group. It is suggested that endurance capacity is improved if the
respiratory capacity of muscles is increased even when the contents of
high-energy phosphates are lower. Increased endurance capacity was not
directly associated with the levels of muscle glycogen, oxygen
transport capacity of blood, or
O2 max.
ACKNOWLEDGEMENTS
The authors are grateful to Dr. J. O. Holloszy (Washington University School of Medicine, St. Louis, MO) for advice.
FOOTNOTES
Address for reprint requests: Y. Ohira, Dept. of Physiology and Biomechecanics, National Institute of Fitness and Sports, Kanoya City, Kagoshima Pref. 891-23, Japan.
Received 19 September 1996; accepted in final form 12 February 1997.
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