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1 Laboratory of Neurochemistry,
Faculty of Integrated Human Studies, Kyoto University, Kyoto
606-01, Japan; 2 Brain
Research Institute, There have been no systematic comparisons of
skeletal muscle adaptations in response to voluntary wheel running
under controlled loading conditions. To accomplish this, a voluntary
running wheel for rats and mice was developed in which a known load can
be controlled and monitored electronically. Five-week-old male
Sprague-Dawley rats (10 rats/group) were assigned randomly to either a
1) sedentary control group
(Control); 2) voluntary exercised
with no load (Run-No-Load) group; or
3) voluntary exercised with
additional load (Run-Load) group for 8 wk. The load for the Run-Load
group was progressively increased to reach ~60% of body weight
during the last week of training. The proportions of fast glycolytic
(FG), fast oxidative glycolytic (FOG), or slow oxidative (SO) fibers in
the plantaris were similar in all groups. The absolute and relative
plantaris weights were greater in the Run-Load group compared with the
Control and Run-No-Load groups. The mean fiber cross-sectional areas of FG, FOG, and SO fibers were 20, 25, and 15% greater in the Run-Load than in Control rats. In addition, these fiber types were 16, 21, and
12% larger in Run-Load than in Run-No-Load rats. The muscle weights
and mean cross-sectional areas of each fiber type were highly
correlated with the average running distances and total work performed
in the Run-Load, but not the Run-No-Load, group. The slope of the
relationship between fiber size and running distance and total work
performed was significant for each fiber type but was higher for FG and
FOG fibers compared with SO fibers. These data show that the load on a
rat running voluntarily can determine the magnitude of a hypertrophic
response and the population of motor units that are recruited to
perform at a given loading condition.
fiber cross-sectional area; fiber type distribution; running wheel; skeletal muscle loading
EXERCISE TRAINING IN RATS results in a large number of
adaptations in the contractile, morphological, and metabolic properties of skeletal muscle that are specific to the type and amount of exercise. In general, skeletal muscles of rats that are trained by
using a relatively low-intensity and long-duration type of work show
endurance-related adaptations, including increased percentages of
oxidative fibers, higher oxidative capacities, higher myoglobin levels,
higher mitochondrial levels, and increased capillarization (1, 6). In
contrast, training in which a strength or power type activity is used
(relatively high intensity and short duration) results in fewer
apparent metabolic adaptations but elicits muscle fiber hypertrophy (1,
25). However, many of the procedures used to train rats, such as
running on a motorized treadmill, forced swimming with added weights,
and weight lifting, provide little quantitative information on overload
parameters that can be interpreted with respect to the "size
principle" of recruitment of muscles during normal movements.
Furthermore, most of the training paradigms involve physical and
psychological stressors, i.e., electrical shock, loud sounds, air
blasts, and food deprivation and reward to keep the rats exercising at
a constant level. In addition, the exercise training is often performed
during daytime hours when rats are not normally active. Because of
these inherent problems with forced-exercise protocols, it is difficult
to distinguish between the contribution of the exercise training alone
vs. the training plus the associated physical and psychological
stresses to the muscle adaptations.
Rats are a highly active species and will run spontaneously in running
wheels at their own pace if given the opportunity (12, 13, 17, 22, 24).
These studies indicate that rats spontaneously run distances greater
than normally performed during typical treadmill exercise-training
regimens. Chronic voluntary wheel running results primarily in
"aerobic" adaptations in the skeletal muscles (10, 17, 23), but
some hypertrophy (12-20%) has been reported in the predominantly
slow soleus muscle of young male (15) and female (13) rats. The
plantaris muscle, a predominantly fast agonist of the soleus, appears
to hypertrophy in female (13), but not in male (15-17), rats in
response to voluntary running. In these studies, the total distance run
is usually recorded, but the running rates and loads are unknown, and,
therefore, these adaptations cannot be interpreted with respect to use
or recruitment patterns.
We have developed a running wheel that allows the imposition of a known
load during the voluntary running activity. The purpose of the present
study was to determine the effects of 8 wk of voluntary wheel running,
with and without an additional load, on the plantaris muscle weight and
fiber type composition and size of male rats. The plantaris muscle was
studied because it is a primary ankle extensor and thus is activated
during the running task (8) and because it has a mixture of fiber types
and thus allows for the determination of fiber type-specific effects
(2). In addition, although the plantaris is responsive to some
conditions of chronic increased or decreased loading (18, 19), it
appears to be unresponsive to unloaded wheel running in the male rat
(15-17). We hypothesized that the high-intensity activation
associated with increased loading during voluntary running would
heavily recruit the fast plantaris muscle and that the level of
hypertrophy in a fiber type would reflect the recruitment patterns of
each motor unit type and their sensitivity to the level of loading during the recruitment. The results show that muscle fiber size is much
more sensitive to load and total work performed than the total amount
of recruitment or activity and that the fast fibers are considerably
more responsive to the added loads than are the slow fibers.
Experimental animals. Thirty male
Sprague-Dawley rats (5 wk old; initial body weight, 115 ± 6 g) were
used in this 8-wk study. The rats were assigned randomly and equally
into three groups: 1) a
cage-confined sedentary control group (Control);
2) a voluntary running group with
free access to a rotating wheel (Run-No-Load); and
3) a voluntary running group with
free access to a rotating wheel plus additional loading, as described
below (Run-Load). All rats were individually housed in similar cages,
except that there was no rotating wheel in the Control cages (see
below). Food and water were provided ad libitum. The rats were kept in a controlled environment of a fixed 12:12-h light-dark cycle (lights off from 1900 to 0700), with the room temperature maintained at 22 ± 2°C. Body weight was recorded weekly. All procedures were approved by the University Committee for the Care and Use of Animals for Research Purposes and followed the Guidelines of the National Institutes of Health for the Care and Use of Laboratory Animals.
Running-wheel apparatus and protocol.
The running-wheel apparatus includes a standard rat plastic cage (30 × 40 × 20 cm) and a running wheel (diameter, 31.8 cm; width, 10 cm) attached vertically to a freely rotating shaft
inserted into a metal controller box that is supported on a metal base
(Fig. 1). The wheel rotates on the shaft
whenever the rat walks or runs in either direction in the wheel, and
the number of revolutions and load on the wheel are continuously
recorded. A transducer in the controller box (Fig.
1A) connected to the wheel
produces an electronic signal for each revolution of the wheel. This
signal then is sent to, and subsequently stored by, a computer via a
sequencer (Fig. 1B), which is
equipped to continuously monitor the number of signals from up to 20 wheels simultaneously. The time interval for data collection is set by
a time-mark generator (from 3 s to 24 h), and the number of wheel
revolutions during this interval is recorded as a computer text file.
The load attached to the wheel can be changed arbitrarily (see below),
and the rats have free access to the wheel.
ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References
METHODS
Top
Abstract
Introduction
Methods
Results
Discussion
References
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Fig. 1.
Loaded running-wheel apparatus: control box
(A) and data-sequence system
(B).
a, Calibrated current value of load
added to a wheel; b, load-adjustment
knob; c, wheel-revolution counter;
d, switch for no-load (free) or load
condition; e, output signal to the
sequencer; f, power switch;
g, running wheel (diameter, 31.8 cm
and width, 10.0 cm); h, plastic cage
(30.0 × 40.0 × 20.0 cm);
i, drinking bottle;
j, food box;
k, output to any computer via
RS232C; l, input for signals from
the control box; m, power switch. Note
that the sequencer can simultaneously collect signals from 20 different
cages.
The load on the wheel is adjusted by varying the current load from a
control panel (Fig.
1A,b).
The load on the wheel is calibrated by hanging known weights on one of
the bars on the wheel until the wheel is displaced. The range in
loading on the wheel is from 0 to 350 g, and the relationship between
the calibrated value of the load added to a wheel and the actual
current load on the wheel is linear and highly correlated
(r = 0.995). The regression line for
this relationship is y = 0.86x 
9.5, where
x is the current load on the wheel
and y is the calibrated value in
Fig. 1A,a. Therefore, when the
current load on the wheel is set on 100 g, the calibrated value is
calculated as follows: 76.5 = 0.86 (100) 9.5. The load
necessary to overcome the inertia of the wheel at "no load" was
4.5 g: therefore, the force used to calculate work in the no-load
condition was 4.5 g (see below).
In the present study, the rats were allowed to run voluntarily in the wheel for 12 h each day during the dark cycle. The rats in the Run-Load group were exercised with no load for the first week, and then the load was progressively increased: weeks 2 and 3 at 120 g; weeks 4 and 5 at 140 g; week 6 at 160 g; week 7 at 190 g; and week 8 at 220 g. Work was calculated and expressed relative to body weight as follows
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Tissue preparation. At the end of the
8-wk training period, the rats were anesthetized with pentobarbital
sodium (50 mg/kg ip). The plantaris muscles on the right side were
removed, cleaned of excess fat and connective tissue, and wet weighed.
The muscles were placed on cork, stretched to approximate their in vivo
length, and immediately frozen in isopentane cooled in liquid nitrogen. Serial transverse sections, 10 µm thick, from the midbelly region of
each muscle were cut in a cryostat at 20°C. The sections
were air-dried and stained for myosin adenosine triphosphatase
following alkaline preincubation, succinate dehydrogenase, and
-glycerophosphate dehydrogenase. The muscle fibers were classified
as fast glycolytic (FG), fast oxidative glycolytic (FOG), or slow
oxidative (SO), as described previously (14). Between 400 and 450 fibers were sampled consistently from a midregion of the muscle cross
section. The cross-sectional area of each fiber on the muscle
transverse section was measured by using a computer image-processing
system.
Statistical procedures. All statistical analyses were performed by using Statview. One-way ANOVA was used to determine overall differences, and a post hoc Bonferroni adjustment was used to determine individual group differences. Pearson product correlations were used to determine the relationship between running distance and muscle weight or fiber cross-sectional area by fiber type. The 0.05 probability level was established for statistical significance.
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Body and muscle weights. At the end of the study, the mean body weight was 9 and 5% lower in the Run-Load group than in the Control and Run-No-Load groups (Table 1). Mean absolute plantaris muscle weight was 19 and 17% greater in the Run-Load group compared with the Control and Run-No-Load groups. When differences in body weights were considered, these differences were 31 and 24%, respectively.
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Fiber type distribution and cross-sectional areas. There were no differences in the fiber type distribution of the plantaris muscle among the three groups (Table 2). Compared with the Control and Run-No-Load groups, the mean cross-sectional areas of the FG, FOG, and SO fibers were 20 and 16%, 25 and 21%, and 15 and 12% greater in the Run-Load group, respectively (Table 3). There were no differences in the mean fiber cross-sectional areas of any fiber type between the Control and Run-No-Load groups.
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Relationships between running distance and muscle weight or fiber cross-sectional area. The average daily voluntary running distance in the Run-No-Load group increased almost threefold during the 8-wk exercise period (Fig. 2). The Run-Load rats showed three response patterns for running distance: two rats showed a response similar to that observed in the Run-No-Load group (high-distance subgroup); six rats ran a similar distance as the Run-No-Load rats during the first week and then maintained a relatively constant distance each week throughout the study (moderate-distance subgroup); and two rats ran ~50% less than the Run-No-Load group during the first week and maintained this relatively low level of running distance throughout the study (low-distance subgroup).
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Plantaris muscle weights were positively correlated (r = 0.88) with running distance in the Run-Load group, but not (r = 0.16) in the Run-No-Load group (Fig. 3). Furthermore, the cross-sectional area of each fiber type was positively and significantly correlated with running distance in the Run-Load group, but not in the Run-No-Load group (Fig. 4). The regression equations and correlations for each fiber type in the Run-Load group were as follows: FG = 0.312x + 3,707, r = 0.88; FOG: y = 0.267x + 3,567, r = 0.88; SO: y = 0.116x + 3,275, r = 0.57. All slopes for the relationship between fiber size and running distance were significantly different from zero for the Run-Load, but not the Run-No-Load, groups. In addition, the slope for this relationship in the Run-Load group was 169% (P < 0.05) and 130% (P = 0.07) higher in FG and FOG compared with SO fibers.
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Relationships between work and muscle weight or fiber
cross-sectional area. During the 8-wk period, the
amount of work for the Run-No-Load group increased only from ~250 to
~400 N · m · kg body
wt
1 · day1
(Fig. 5). In contrast, the
amount of work in the low-, moderate-, and high- distance subgroups for
the Run-Load group increased from ~250 (no load added during
week 1) to ~2,500, 7,500, and 12,000 N · m · kg body
wt1 · day1
during weeks 6-8. Therefore, the
work for these Run-Load subgroups was ~6-, 20-, and 30-fold greater
than for the Run-No-Load group during the final 3 wk of the study.
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Plantaris muscle weights were positively correlated
(r = 0.85) with the amount of work
performed in the Run-Load group, but not in the Run-No-Load group
(r = 0.17) (Fig.
6). However, it should be noted that the
data points for the Run-No-Load group were distributed evenly around
the extended regression line for the Run-Load data (see dashed line in
Fig. 6). The cross-sectional area of each fiber type was positively
correlated with the amount of work performed in the Run-Load group (FG,
r = 0.85; FOG,
r = 0.86; SO,
r = 0.54), but not in the Run-No-Load
group (FG, r = 0.03; FOG,
r = 0.41; SO,
r = 0.25) (Fig.
7). The regression equations for each fiber
type in the Run-Load group were as follows: FG = 0.074x + 3,694; FOG:
y = 0.063x + 3,557; SO:
y = 0.027x + 3,272. All slopes for the
relationship between fiber size and work were significantly different
from zero for the Run-Load, but not for the Run-No-Load, group. In
addition, the slope for this relationship in the Run-Load group was
174% (P < 0.05) and 133%
(P = 0.09) higher in FG and FOG
compared with SO fibers. It also should be noted that the points for
the FG fibers of the Run-No-Load group were distributed around the
extended regression line for the Run-Load data, whereas the points for
the FOG and SO fibers all fell below the line. Thus it appears that the
FG, but not the FOG or SO, fibers showed a linear response across the
no-load and load conditions.
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The primary finding of the present study was that the plantaris muscle of male rats hypertrophied in response to loaded, but not to unloaded, voluntary wheel running. The lack of a hypertrophic response of the plantaris muscle in the Run-No-Load rats is consistent with previous results (15-17). Our interpretation of the present results is that the increment in load placed on the Run-Load rats was sufficient to incrementally recruit more motor units in the plantaris muscle at a higher frequency to accomplish the task. This interpretation is supported by the significant increase in the cross-sectional area in each fiber type in the Run-Load rats. Furthermore, the largest hypertrophy occurred in the rats that ran at the highest loads and was greatest in the fibers that would be recruited the least theoretically, i.e., the FG fibers. These data indicate that the responsiveness to loading differed among the fiber types, i.e., FG > FOG > SO.
Advantages of voluntary vs. forced exercise. Although forced treadmill running, swim training, or weighttraining are useful models for studying skeletal muscle plasticity in rats, these regimens undoubtedly include stress to the animals, and thus it is not obvious whether the observed physiological changes are due to stress, exercise, or a combination of the two. A less stressful model for rats (28) and mice (26) is a training regimen involving voluntary running exercise as used in the present study. The rats run voluntarily during their normal active hours, i.e., at night, and no stressor is used to force them to run. Running occurs in the same cage in which the rats are housed; therefore, the environment is not changed for running and nonrunning conditions. In addition, trainers are not necessary, and the rats can voluntarily exercise 7 days/wk. All of these conditions provide a more controlled and physiological environment and, thereby, facilitate the interpretation of the observed adaptations relative to the adaptation-inducing event, i.e., voluntary running.
Muscle mass and fiber size adaptations. The effects of voluntary running on extensor muscle mass and fiber size in male rats appear to be highly variable. For example, Ishihara et al. (7) showed no change in the absolute weights of the soleus or plantaris muscles of 4-wk-old male Wistar rats exercised for 45 days, although the weights relative to body weight were increased for both muscles. In addition, only the FOG fibers in the superficial (away from the bone) region of the plantaris hypertrophied. In contrast, Rodnick et al. (15-17) showed an increase in soleus, but not in plantaris, weight in young male Sprague-Dawley rats after 6 wk of voluntary running. The soleus hypertrophy ranged from 13 to 20% and was not correlated with running distance. These data are consistent with the recruitment of the soleus but not the plantaris during unloaded voluntary running. The major advantages of the load-controlled voluntary running wheel are that it provides a means of modulating the workload according to the appropriate experimental conditions and also provides a means of quantifying the work performed. The present data indicate that, through the use of this wheel, hypertrophy can be induced in the plantaris muscle by voluntary running in male rats if the rats are provided access to wheels with added resistance to rotation.
Comparison with other high-resistance exercise models. The present means of inducing muscle hypertrophy has several advantages over other methods of producing hypertrophy (11, 25). In the present study, the presence of hypertrophy in all fiber types in Run-Load rats suggests that all types of motor units in this region of the plantaris were recruited during loaded running. In addition, the mean cross-sectional area of each fiber type was positively related with running distance and total work performed in the Run-Load group. Also, the voluntary loaded running described in the present study allows the rat to exercise freely during its entire active (awake) period without being monitored closely by a trainer. Gonyea and Ericson (4, 5) operantly trained cats to lift weights with their forelimbs against progressively increasing resistances for a food reward. The flexor carpi radialis muscles of the trained limb were larger than those of the nontrained limb (16%) and those of body weight-matched controls (44%) (4). They also found that all fiber types were ~10% larger in the trained compared with nontrained muscles, indicating that the muscle was heavily recruited during the task. Klitgaard (9) operantly trained rats for a food reward to lift (via plantar flexion) a weight bar resting on their shoulders. Training resulted in marked increases in the weights and maximum tension capability of both the soleus and plantaris muscles. Although these training procedures were successful in producing a modest amount of muscle hypertrophy without the use of behaviorally aversive techniques, both involved some form of food deprivation. Roy et al. (21) trained rats to respond to a light stimulus (to avoid a mild shock through a grid floor) by standing in such a way as to touch a bar lowered from the top of a weight-lifting chamber. The rats were made to lift loads of up to 300% body weight by having weights attached to a belt around the abdomen. The relative weights of the soleus and adductor longus, a predominantly slow adductor of the thigh, were 11 and 14% larger in the weight-lifting compared with control rats. All of the above procedures used in rats required considerable technical assistance. Other procedures that have been used to produce work-induced muscle hypertrophy in rats have included electrical stimulation of specific regions of the brain (3) or skeletal muscles (27) or a synergist removal (20), but each of these included invasive procedures that may have resulted in conditions that differ significantly from the voluntarily performed work in vivo in the awake animal.
Summary. An exercise model for small rodents in which the resistance (workload) of a voluntary running wheel can be controlled and monitored has been presented. This training regime avoids a variety of stressful stimuli associated with imposing an exercise regimen on rats, particularly when performing high-resistance training. Because low-volume voluntary running under loaded conditions results in muscle hypertrophy, this training modality appears to be a valuable tool to study the mechanisms associated with the prevention of muscle atrophy and how these and other adaptations relate to the population of motor units that must be recruited to accomplish a motor task.
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ACKNOWLEDGEMENTS |
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The authors thank Jung Kim for assistance in producing the figures and for preparing the manuscript for publication.
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FOOTNOTES |
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This study was supported in part by the Grant-in-Aid for Scientific Research 08680112 from the Ministry of Education, Science, and Culture of Japan.
Address for reprint requests: R. R. Roy, Brain Research Institute, UCLA School of Medicine, Center for the Health Sciences, 10833 Le Conte Ave., Los Angeles, CA 90095-1761 (E-mail: rrr{at}ucla.edu).
Received 19 December 1997; accepted in final form 19 February 1998.
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D. W. Russ and R. M. Lovering Influence of activation frequency on cellular signalling pathways during fatiguing contractions in rat skeletal muscle Exp Physiol, November 1, 2006; 91(6): 957 - 966. [Abstract] [Full Text] [PDF]
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M. Ishido, K. Kami, and M. Masuhara In vivo expression patterns of MyoD, p21, and Rb proteins in myonuclei and satellite cells of denervated rat skeletal muscle Am J Physiol Cell Physiol, August 1, 2004; 287(2): C484 - C493. [Abstract] [Full Text] [PDF]
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) and in Run-Load groups that had a relatively
high (
, n = 2), moderate (
,
n = 6), or low (
,
n = 2) running distance. Bars indicate
SE. See text for detailed group description.
