Medicine & Science in Sports & Exercise:
BASIC SCIENCES: Original Investigations
Training Effects in Mice after Long-Term Voluntary Exercise
DAVIDSON, SARA R.1; BURNETT, MARGARET2; HOFFMAN-GOETZ, LAURIE1
1Department of Health Studies and Gerontology and 2Department of Kinesiology, Faculty of Applied Health Studies, University of Waterloo, Waterloo, Ontario, CANADA
Address for correspondence: Laurie Hoffman-Goetz, PhD, MPH, Department of Health Studies and Gerontology, Faculty of Applied Health Studies and Gerontology, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, N2L 3G1 Canada; E-mail: email@example.com.
Submitted for publication April 2005.
Accepted for publication August 2005.
Background: Mice are an important animal model in exercise studies on the immune system, cancer, and aging. There is limited research about the training effects of long-term voluntary exercise in this species.
Purpose: To describe the training effects in mice given long-term aerobic voluntary exercise.
Methods: Female C57BL/6 mice were randomly assigned to 1) individual cages with in-cage running wheels with 24-h access (WR; N = 31), or 2) individual cages without running wheels for 16 wk (NR; N = 20). Run-to-exhaustion (RTE) times, V̇O2peak, speed at V̇O2peak, and citrate synthase (CS), succinate dehydrogenase (SDH), and phosphofructokinase (PFK) activity in the soleus, plantaris, and red and white gastrocnemius were assessed.
Results: Final body weight and speed at V̇O2peak did not differ by training condition. WR mice had significantly longer RTE times (P < 0.001) and higher V̇O2peak (P < 0.05) compared with NR mice. Higher CS and SDH activities were found in WR compared with NR mice for soleus (P < 0.01), red gastrocnemius (P < 0.01), and plantaris (P < 0.01) muscles. PFK activity was higher in WR mice in white gastrocnemius compared with NR mice (P < 0.01).
Conclusions: Voluntary running wheel activity for 16 wk in female C57BL/6 mice resulted in longer run times to exhaustion, higher V̇O2peak, and higher SDH and CS activities in oxidative muscles. These findings suggest that wheel running in female C57BL/6 mice: 1) produces a measurable aerobic training effect and 2) is an effective exercise modality for long-term training studies.
Mice are frequently used as an animal model to study the effects of exercise on a variety of physiological processes including immune responses (13), aging (28), and carcinogenesis (30). The exercise modality used is often in the form of long-term training and typically involves forced activity such as treadmill running (4). However, forced activity protocols activate the hypothalamic-pituitary-adrenal (HPA) axis and the "stress" response with a concomitant elevation in plasma corticosterone levels, catecholamines, heart rate and blood pressure (21). Thus, results of studies employing forced exercise models may be confounded by chronic activation of the stress response. In contrast, voluntary exercise, such as wheel running, tends not to be associated with activation of the stress response (8) and, therefore, has been proposed as a training protocol to circumvent this problem.
A significant limitation in the literature on voluntary exercise paradigms involving mice is that few studies document physiological and biochemical indices indicative of training effects. V̇O2 uptake, V̇CO2 production, respiratory exchange ratio (RER), and citrate synthase activity in soleus muscle have been reported, but the duration of the voluntary exercise was relatively short (8 wk) (19). Concurrent changes in performance measures (such as V̇O2peak) and in skeletal enzyme activity in mice as a result of voluntary wheel exercise have not been systematically assessed.
The purpose of this study was to describe the performance and biochemical training effects of mice given access to running wheels for 4 months compared with mice not given access to running wheels. The physiological performance measures included run-to-exhaustion (RTE) times, V̇O2peak and speed at V̇O2peak. The skeletal muscle enzyme measures included citrate synthase (CS), succinate dehydrogenase (SDH) and phosphofructokinase (PFK) activity in the soleus, plantaris, and red and white gastrocnemius. Due to the nature of wheel running as an aerobic endurance activity, we hypothesized that there would be longer RTE times, and higher V̇O2peak, and CS and SDH activities in the soleus, red gastrocnemius, and plantaris in wheel-run mice compared with nonrun mice.
Female C57BL/6 mice, age 4-6 wk and weighing 16.9 ± 0.2 g, were obtained from Harlan Sprague Dawley (Indianapolis, IN), acclimated to our vivarium for 1 wk, and then randomly assigned to one of two groups: 1) individual cages (29.5 × 18.5 × 12.5 cm) with in-cage running wheels allowing 24 h access (WR; N = 31) and with supplemental toys for enrichment (i.e., plastic tubes, nesting materials) or 2) individual cages without running wheels (NR; N = 20) and with supplemental toys. The mice were housed for 16 wk in a humidity (65%) and temperature (21 ± 1°C) controlled room, maintained on a 12-h reversed light-dark cycle and provided with tap water and food (Laboratory Rodent Chow, PMI Foods, Richmond, IN) ad libitum. The guidelines for experimental procedures established by the Canadian Council on Animal Care were followed and all protocols with live animals were approved by the university animal care committee.
Wheel Running Activity
Activity of mice on the running wheels (23.0 cm in diameter) was monitored by a magnetic switch affixed to each wheel, which recorded the number of completed revolutions; data were captured by an automated computer monitoring system and software (Vital View Application software, Mini Mitter Company, Sunriver, OR). Physical activity was recorded continuously as wheel revolutions per 15-min interval, converted to kilometers and summed by week for analysis. Free open-field locomotor activity of mice within cages was not measured. Exercise performance measures and skeletal muscle enzyme activities were obtained for a randomly selected subset of mice from each of the WR (N = 10) and NR (N = 10) groups.
Run to exhaustion (RTE).
Two weeks before sacrifice, mice were acclimated once to run on a small rodent treadmill (Omni-max metabolic small rodent treadmill, Omni Tech Electronics, Columbus, OH) (5-min warm-up followed by 15-20 min at 28 m·min−1). One day after acclimation to the treadmill, mice were run during the dark cycle until they reached volitional exhaustion using a modification of the protocol of Campisi et al. (2). In brief, for the first 5 min, the speed of the treadmill was gradually increased to 28 m·min−1, and thereafter, the mice ran at 28 m·min−1 until exhaustion. To encourage the mice to run, an electric shock grid at the base of the treadmill was activated to deliver a 0.2-mA pulse. This delivered an uncomfortable shock but did not injure or harm the mouse. Volitional fatigue or exhaustion was defined as the refusal to run after 10 consecutive tail shocks.
One week before sacrifice, mice were placed in the metabolic treadmill over a 10-min period to measure resting V̇O2. Thereafter, mice were run on the treadmill with the speed increasing by 2 m·min−1 every 90 s (22) until exhaustion was reached. Volitional exhaustion was defined as above at which time V̇O2peak was measured.
Mice were sacrificed by sodium pentobarbital (0.6-0.8 cm3 per mouse, i.p.) overdose. Muscle samples from WR and NR mice were obtained for soleus (SOL), plantaris (PLANT), and red (RG) and white gastrocnemius muscle (WG), which were isolated, flash frozen in liquid nitrogen, and stored at −90°C until assessed for enzyme activity.
Muscle enzyme activity.
All muscles were cut into 5- to 10-mg segments, homogenized in homogenizing buffer (glycerol (50%), sodium phosphate buffer (20 mM), 2-mercaptoethanol (5 mM), ethylendiaminetetraacetic acid (EDTA, 0.5 mM), BSA (10%)) to yield a 50:1 dilution and assayed for succinate dehydrogenase (SDH), citrate synthase (CS), and phosphofructokinase (PFK) activities. An aliquot of each muscle homogenate was sonicated (with a 3-mm tip, 2 s on, 5 s off, for a total of 20 s at 60 Hz; Vibra Cell, Sonics and Materials, Danbury, CT) and subsequently analyzed for PFK and SDH activity on the same day (3). The remaining homogenate was stored at −90°C for CS and protein analysis.
Muscle homogenates were diluted in diluting medium (imidazole-HCl (20 mM), BSA (0.02%)) to yield a 1:150 dilution. Twenty-five microliters of the diluted samples were aliquoted and placed in a 37°C water bath for 10 min, then 100 μL of SDH reagent (phosphate buffer (0.03 M), sodium succinate (115 mM), phosphate (0.0015%), and BSA (10%)) were added. Thirty minutes later, 200 μL of 1 N NaOH were added, the samples were removed from the water bath, and 100 μL of bromobenzene were added, followed by centrifugation for 3 min at 15,000 × g. Twenty-five microliters of supernatant were aliquoted, 1 mL of dilute reagent (hydrazine (100 mM) EDTA (4 mM), and NAD (0.4 mM)) was added, and the fluorescence of NAD+ was measured fluorometrically. Ten microliters of dilute MDH-fumarase reagent (hydrazine, EDTA, NAD, fumarase (700 U·mL−1), malate dehydrogenase (6000 U·mL−1)) were added, and the samples were incubated in the dark for 2 h at room temperature (RT) and read fluorometrically.
Muscle homogenates were diluted in PFK diluting medium (Tris-HCl (50 mM), K2HPO4 (10 mM), 2-mercaptoethanol (5 mM), EDTA (0.5 mM), BSA (0.02%)) to yield a 1:15,000 dilution. Five microliters of the diluted sample were aliquoted and 100 μL of reagent 1 (Tris-HCl (50 mM), ATP (1 mM), fructose-6-phosphate (1 mM), K2HPO4 (10 mM), MgCL2 (2 mM), NADH (200 μM), 2-mercaptoethanol (1 mM), BSA (0.05%), aldolase (0.09 U·mL−1), glycerol-3-phosphate dehydrogenase/triosphosphate isomerase (GDH:TIM)) were added. After 1 h at RT, this reaction was stopped by adding 10 μL of 0.75 N HCl and left for 10 min at RT. One milliliter of 6 N NaOH (10 mM imidazole) was then added, the samples were incubated for 20 min at 60°C, and the fluorescence of NAD+ was measured fluorometrically.
Muscle homogenates were diluted to yield a 1:2500 dilution. Ten microliters of the diluted sample were aliquoted, 100 μL of reagent 1 (Tris-HCl (50 nM), acetyl CoA (0.4 mM), oxaloacetate (0.5 mM) and BSA (0.25%)) added, and samples incubated at RT for 1 h. Ten microliters of 0.75 N NaOH were added, the samples incubated at RT for 10 min, 1 mL of reagent 2 was added (Tris-HCl (100 mM), ZnCl2 (100 μM), BSA (0.01%), NADH (30 μM), citrate lyase (0.003 U·mL−1), malate dehydrogenase (3 U·mL−1)) and incubated at RT for 20 min. Sixty microliters of 1 N HCl were added, the samples were incubated at RT for 10 min, and 100-μL aliquots of the solution were added to 1 mL 6 N NaOH (10 mM Imidazole). Samples were incubated at 60°C for 20 min, and the fluorescence of NAD+ was measured fluorometrically.
The concentration of protein in muscle homogenates was determined using Lowry method (18). All enzymes are expressed as moles per hour per kilogram of protein.
Data were analyzed using SPSS v12.0 software, and values are reported as group means ± SEM. Running wheel data were analyzed with a repeated measures ANOVA, and all other dependent variables were analyzed with a one-way ANOVA (for data that were normally distributed) or with a Mann-Whitney U test (for data that were not normally distributed). A threshold of significance of α = 0.05 was accepted as being different from chance alone. Unless otherwise indicated, there were 10 mice in each of the WR and NR groups used for analysis of performance measures and muscle enzyme activities.
There were no significant differences in final body weight between WR (24.6 ± 0.7 g) and NR (26.2 ± 0.9 g) mice at sacrifice.
Average running distance.
Figure 1 shows the average running distances of female C57BL/6 mice for 16 wk. Mice ran on average 2.21 ± 0.49 km·d−1 for a total of 364.72 ± 28.83 km over the 16-wk period. At week 1, average running distance was 14.0 ± 2.0 km. Running distance varied significantly over time (F1,30 = 4.37, P < 0.05) and each weekly time point was significantly higher than week 1 (all P values < 0.05).
FIGURE 1-Average run...Image Tools
Exercise performance measures.
There was a significant difference in RTE times between NR and WR groups (Mann-Whitney U statistic = 0.00, P < 0.001), with WR mice having almost double the time to exhaustion during treadmill challenge. Initial analysis of V̇O2peak between NR and WR groups indicated no difference between groups. This lack of difference was the result of one animal in the NR group with a V̇O2peak of 91 mL·kg−1·min−1, which was significantly higher than values for WR mice and resulted in a large standard deviation for the NR group. When this outlier was removed, there was a significant difference in V̇O2peak (∼10%) in WR mice compared with NR mice (F1,17 = 4.417, P < 0.05), but no significant difference in the speed at which V̇O2peak was elicited (Table 1).
Skeletal muscle enzyme activity.
Table 2 shows theskeletal muscle enzyme activity from SOL, RG, WG, and PLANT of female C57BL/6 mice. For SOL, there was significantly greater activity of CS (F1,18 = 5.051, P < 0.05) (∼18%) and SDH (F1,18 = 8.836, P < 0.01) (∼23%) in the SOL from WR compared with NR mice. In contrast, PFK activity did not differ by training group. For RG, there was significantly greater CS (F1,18 = 4.994, P < 0.05) (∼26%) and SDH (F1,18 = 16.107, P < 0.01) (∼61%) activity in the RG from WR relative to NR mice. As with the SOL, no difference in PFK activity was found by training group for RG. For PLANT, WR mice had higher CS (∼16%) (F1,18 = 13.074, P < 0.01) and SDH (Mann-Whitney U Statistic = 1, P < 0.01) activity (∼56%) in the PLANT muscle compared with NR mice. No significant differences were found for PFK activity between the two groups. For WG, no significant difference was found in CS activity in the WG by training group. However, the activity of SDH, an oxidative enzyme (F1,18 = 16.107, P < 0.01) and of PFK,a glycolytic enzyme (Mann-Whitney U Statistic = 3, P<0.01) differed significantly as a function of training group, with activity higher in WR (∼87%) compared with NR mice.
The main findings of this paper are that beginning at ages 5-7 wk, female mice that were given 16 wk of access to in-cage running wheels had physiological performance and skeletal muscle enzyme changes suggestive of a training effect. These changes included longer treadmill run times to exhaustion, and higher V̇O2peak, oxidative enzyme activity in the SOL, RG and PLANT, and glycolytic enzyme activity in the WG. This study is unique in its comprehensive characterization of skeletal muscle biochemistry and performance characteristics for mice given long-term voluntary training. Nonetheless, the data are specific to adult (6 months old) female C57BL/6 mice, and additional studies will be needed to determine whether performance and skeletal muscle enzyme changes occur in other strains, in both genders, and at different ages.
During the 16 wk of the study, WR female mice accumulated an average daily running distance of 2.21 ± 0.49 km·d−1, a weekly distance of 22.8 ± 1.8 km·wk−1, and a total running distance of 364.72 ± 28.83 km. These running distances are similar to those found by Mehl et al. (20) involving female C57BL/6 mice, but lower than those found by Valentinuzzi et al. (28) involving male C57BL/6. Wheel running distance is variable and dependent on many factors including gender, strain, and age (6). The results presented here indicate that the maximal average running distance in female C57BL/6 mice occurred at week 12. Others have reported peak running distance for mice and rats to occur at weeks 3-4 (9,25), week 5 (23), week 6 (17), and week 8 (1,29). The peak and plateau in distances on running wheels also reflect strain and gender contributions. Finally, there were no significant differences in final body weights between the WR and NR mice. This result was not unexpected, because female rodents increase their food intake in proportion to their energy expenditure (26), whereas males decrease their food intake (11).
WR mice had approximately 10% higher V̇O2peak values than NR mice indicating that wheel running is able to invoke a change in aerobic function. Increases in V̇O2peak after wheel running have been observed after 8 (17), 10 (29), and 12 wk (23) of voluntary wheel exposure in rodents. Similar increases in V̇O2peak (∼14%) have been observed after 12 wk of treadmill training (16). Nonetheless, the actual V̇O2peak values for mice in the present study were lower than those reported by Fueger et al. (7). The reasons for this difference are not known. Because mice in the two studies differed by substrain (6J vs 6), backcrossing (Ukko 1 backcrossed onto C57BL/6J for 5 generations vs no backcrossing across strains), age (4 vs 6 months), and gender (mixed vs females only), V̇O2peak may have differed as a result; it is also possible that in the present study mice were running at submaximal rather than maximal exertion, which would result in lower V̇O2peak. WR mice ran nearly twice as long in the RTE as NR mice, providing further evidence that wheel running invokes changes to aerobic capacity. Other studies report significantly longer RTE times in rats following 8 wk of wheel access (2,17,23). Similarly, 13 wk of treadmill training significantly increased RTE times (5).
CS and SDH are widely used as metabolic markers for muscle oxidative capacity (9,29), and PFK and hexokinase for muscle glycolytic capacity (9,10). The SOL, RG, PLANT, and WG were selected for evaluation because of their involvement in wheel locomotion and differences in fiber type and metabolic capacity: SOL (Type I, oxidative), RG (Type II, oxidative), PLANT (Type II, oxidative, glycolytic), and WG (Type II, glycolytic). Significantly increased CS activity in the WR group was found in the SOL (18%), RG (26%), and PLANT (16%) muscles. SDH activity was also higher in the WR group for the SOL (23%), RG (38%), and PLANT (56%) muscles. Increased activity of these oxidative enzymes is consistent with the hypothesis that voluntary wheel running is an endurance exercise, and leads to an upregulation of oxidative enzyme activity in oxidative muscle. Our results agree with previous studies in rats showing increased CS activity in SOL between 4 and 8 wk (9,15) and PLANT between 2 and 12 wk of voluntary wheel exposure (9,10,25). Increased SDH activity in rat SOL (29) and rat red vastus lateralis (Type II oxidative, glycolytic) (1) occur after 4 wk of voluntary wheel exposure, results similar to enzymatic changes occurring with treadmill training (5,26,27).
No significant increase in CS activity was found in WG of WR mice that were given 16 wk of running. This was expected because WG is predominantly a glycolytic muscle, and no increase in rat CS activity for other glycolytic muscles (e.g., white head of tricep brachii) have been reported after voluntary wheel exposure (25).
In contrast, Podolin et al. (24) found no significant differences in rat CS activity in the soleus following 8 wk of wheel exposure. Bagby et al. (1) also reported no significant change in SDH in rat soleus after 7 or 16 wk of wheel exposure. Differences in wheel running speed may contribute to these divergent results, because higher speeds require muscles with a higher percentage of Type II fibers than Type I fibers (1).
Unexpectedly, we found an increase of SDH activity in the WG. However, increased oxidative enzymes (CS) in other glycolytic muscles, such as the epitrochlearis, have been observed after 2-3 wk of wheel exposure in rats (12). The physiological reasons for increased oxidative enzyme activity (SDH or CS) in muscle that is primarily Type II, glycolytic are not clear from our data. However, there is some evidence for fiber type change in rat extensor digitorum longus from Type II glycolytic to Type II oxidative and Type I in female rats given 45 d of voluntary exercise (15).
PFK activity in WG was nearly twice as high in the WR compared with the NR group; however, no significant difference in PFK activity occurred in the SOL, RG, or PLANT muscles of WR mice. Our finding of increased PFK activity in WG, the finding by Kriketos et al. (15) of increased hexokinase (another glycolytic enzyme) in the extensor digitorum longus, and by Hokama et al. (12) of increased hexokinase in epitrochlearis suggest that voluntary running involves both glycolytic and oxidative muscles. No significant difference between WR and NR mice were found for PFK activity in the SOL, RG, and the PLANT muscles. Increases in hexokinase activity have been found in the SOL after 4 but not 8 wk of voluntary exercise and in the PLANT after 4 and 8 wk of voluntary exercise (9). The activity of hexokinase in the SOL may be upregulated shortly after the initiation of exercise, but this effect is not persistent. This may also explain why no significant increases in PFK activity in the SOL were found after 16 wk in the mice. However, serial measurements of PFK in SOL over the training period would be necessary to confirm whether up- and then downregulation of this enzyme occurred.
The observed increases in skeletal muscle oxidative enzyme activity and performance measures in WR mice suggest that long-term exposure to running wheels is a form of aerobic endurance training. However, an alternate explanation is that mice without running wheels are deconditioned rather than WR mice being trained animals (23). Mice are naturally active animals, and removing their access to activity by using standard caging without wheels may make them artificially inactive. However, it is common practice in exercise studies involving rodents to include a sedentary control group. Further research investigating differences in performance measures and skeletal enzyme activity between mice allowed free-range locomotion, voluntary wheel access, or treadmill training is required to clarify the differences in these parameters as a result of the different types of activity. Detraining has been found to quickly decrease exercise-induced improvements in cardiac adaptations (14); therefore, removing physical activity can result in lower parameter values compared with animals with regular access to exercise. Nonetheless, one strength of voluntary wheel running is that this exercise mode is more representative of human physical activity, which involves voluntary rather than forced activity.
In conclusion, access to voluntary running wheels for 16 wk in adult female C57BL/6 mice resulted in longer run times to exhaustion and higher V̇O2peak, oxidative enzyme activity in oxidative muscles, and glycolytic enzyme activity in glycolytic muscle. Taken together, our results suggest that 4 months of voluntary wheel running in this mouse strain produces an aerobic training effect. The magnitude of this aerobic training effect needs to be evaluated against other exercise modalities, such as treadmill running. Nonetheless, a recent study shows that training elicited by voluntary wheel running may be equivalent to treadmill training: CS activity in gastrocnemius was higher in wheel-trained ApcMin/+ male mice than treadmill-trained male mice, and both exercise modes resulted in higher CS activity than untrained controls (20). Given that wheel running is a voluntary activity that does not activate the HPA axis and the stress response, it constitutes an effective exercise modality for long-term studies in mice.
This research was supported by a grant from the NSERC Canada to LH-G. The authors thank J. Guan and E. Bombardier for technical assistance.
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