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Loss of desmin leads to impaired voluntary wheel running and treadmill exercise performance

¹Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado 80309-0347; and ²Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030

Submitted 24 April 2003 ; accepted in final form 29 June 2003

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION DISCLOSURES ACKNOWLEDGMENTS REFERENCES

 
We examined voluntary wheel running and forced treadmill running exercise performance of wild-type mice and mice null for the desmin gene. When given access to a cage wheel, desmin null mice spent less time running and ran less far than wild-type mice. Wild-type mice showed a significant training effect with prolonged voluntary wheel running, as evidenced by an increase in mean running speed across the 3-wk exercise period, whereas desmin null mice did not. Desmin null mice also performed less well in acute treadmill stress and endurance tests compared with wild-type mice. We also evaluated serum creatine kinase (CK) activity in wild-type and desmin null mice in response to running. Voluntary running did not result in elevated CK activity in either wild-type or desmin null mice, whereas downhill treadmill running caused significant increases in serum CK activity in both wild-type and desmin null mice. However, the increase in serum CK was significantly less in desmin null mice than in wild-type mice. These results suggest that the lack of desmin adversely affects the ability of mice to engage in both chronic and acute bouts of endurance running exercise but that this decrement in performance is not associated with an increase in serum CK activity.

intermediate filaments; serum creatine kinase; dystrophy; skeletal muscle; muscle damage

Studies using null and transgenic animals have shown that the absence of a gene product or expression of a mutant structural protein can have varying effects on exercise performance. For example, mice null for either the IIb or IId/x myosin heavy chain (MHC) do not run as long, as far, or as fast as wild-type mice in a voluntary exercise paradigm (11). Similarly, mice carrying a mutation in the cardiac -MHC gene show impaired treadmill exercise performance (7). Mice null for type XV collagen, which is a major component of the muscle basal lamina, show a greater susceptibility to exercise-induced muscle damage than their wild-type littermates, as assessed by histological evidence of muscle damage in cross sections (6). In addition, mdx mice, which lack the dystrophin gene product, also run less far than wild-type controls in a voluntary freewheel model, and they display greater muscle membrane damage than wild-type mice as assayed by serum creatine kinase (CK) activity (4, 5, 12). Together, these studies support the hypothesis that both the extracellular matrix and intracellular structural proteins are necessary for normal exercise function in mice.

To date, there have been few studies examining the consequences of a loss in desmin expression on muscle function in intact animals. Milner et al. (21) found that involuntary swimming exercise results in 50% mortality of desmin null mice, although they did not report the cause of death. Moreover, performance parameters were not assessed in that study. Grip task studies reveal that the limbs of desmin null mice are weaker and fatigue more easily than wild-type mice (17). Although it is clear that the absence of desmin affects acute muscle function, it is not clear to what degree exercise performance might be impaired over time in desmin null mice relative to wild-type mice or whether desmin null mice can adapt to a prolonged exercise stimulus.

In the present study, we used both voluntary wheel and forced treadmill running exercise protocols to determine the extent to which the absence of desmin affects exercise performance. In addition, we examined the levels of serum CK activity in wild-type and desmin null mice after voluntary wheel running and downhill treadmill running. We hypothesized that the lack of desmin would result in both a decrease in endurance exercise performance and an increase in serum CK activity in desmin null mice compared with wild-type littermates. Our data demonstrate that both voluntary and forced running performance are adversely affected in desmin null mice but that this decrement is not accompanied by elevated serum CK activity.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION DISCLOSURES ACKNOWLEDGMENTS REFERENCES

 
Mice and genotyping. The generation of desmin null mice has been previously described (20). Wild-type 129 mice were obtained from Jackson Laboratories and bred with desmin null mice. Breedings of heterozygous mice were set up to produce wild-type, heterozygous, and desmin null mice. A PCR protocol was used to screen for desmin null mice by using genomic DNA isolated from tail snips. The following oligonucleotides were used: primer 5'-TGATGTCAGGAGGGCTACA and primer 3'-TGGATACTTTCTCGGCAG) to detect the wild-type allele and 5' primer TGATGTCAGGAGGGCTACA and 3' primer CGTCTATCAGGTTGTCACG to detect the null allele. The mdx mice were obtained from a colony maintained at the University of Colorado.

Voluntary and forced exercise protocols. All protocols used in this study were conducted with the approval of the Institutional Animal Care and Use Committee at the University of Colorado, Boulder. Male mice at age 3 mo (27.3 ± 0.7 and 22.1 ± 0.5 g average body weight for wild-type and desmin null, respectively) were used for all studies except the CK assay performed on 6- to 8-wk-old males. Wild-type and desmin null mice were placed in cages with running wheels attached to bicycle computers as described by Allen et al. (1). Distance and time run were recorded daily for 3 wk for each animal, and average speed was calculated from distance and time.

The treadmill stress and endurance tests were performed according to a previously described protocol (15). For both tests, mice were acclimated to the treadmill before running by placing them on an unmoving treadmill for 10 min, then at 5 m/min for 10 min, and at 10 m/min for 10 min on succeeding days for 3 days before testing. For the stress test, the treadmill was set at a 7° incline and an initial speed of 20 m/min, and the speed was increased 1.5 m/min every 2 min. Mice were run until they could not maintain sufficient speed to remain off the shock grid, and the maximum speed they attained was recorded. For the endurance test, the treadmill was also initially set at a 7° incline and a speed of 20 m/min. The test ran for 30 min, and the time at which mice failed to keep running was recorded. In addition, an optical counter placed at the back of the treadmill recorded the number of times the optical beam was broken per minute (beam breaks/min) by the mouse during the duration of the test. Each test was performed three times with 2 days of rest between each test, and the results were averaged for each mouse.

To examine the effects of downhill running on serum CK activity, mice were run on a treadmill at a 16° decline at 10 m/min for 5 min as previously described (26). These conditions were previously shown to produce eccentric damage to the gastrocnemius muscle in mdx mice (26).

CK assay. Blood was drawn for CK assays on the day before acclimatization (3 days before the run), 1 h after treadmill running, and the following day, when they were killed. The first two blood samples were obtained by tail bleeds, and the final blood sample was taken from the chest cavity after excising the heart on the day after the run. After incubation at room temperature for 30 min to allow for clotting, blood was microcentrifuged at 14,000 rpm for 10 min, and the supernatant (plasma) was removed and stored at -70°C until use. The CK assay was performed by using a commercially available kit (Sigma Chemical, St. Louis, MO). Values are reported as international units.

Statistical procedures. Data are reported as means ± SE for all experiments. Differences between groups were evaluated by using the one-way ANOVA test with Fisher's post hoc test. For analysis of wheel running data, repeated-measures ANOVA was used. A value of P < 0.05 was taken as statistically significant.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION DISCLOSURES ACKNOWLEDGMENTS REFERENCES

 
Voluntary exercise performance. Voluntary exercise performance was categorized on the basis of the average amount of time the mouse ran per day over a 3-wk period. Three categories were chosen to represent low, intermediate, and high running: <1h,1-3h,and >3h average running per day. As shown in Fig. 1, 65% (11 of 17) of desmin null mice ran <1 h/day, compared with 33% (3 of 9) of wild-type mice; 11% (2 of 17) of desmin null mice ran >3 h/day, while 33% (3 of 9) wild-type mice ran >3 h/day. Thus desmin null mice did not run to the same extent as wild-type mice.

View larger version (14K): [in this window] [in a new window]   Fig. 1. Average time run per day for wild-type mice compared with desmin null mice. Three-month-old male mice were placed in a cage containing a cage wheel for 3 wk, and the time run per day was recorded and averaged per mouse across the 3-wk exercise period. Each symbol represents the daily average for 1 mouse (n = 9 for wild-type mice, n = 17 for desmin null mice). Three categories were chosen to better organize the data: <1 h/day, 1-3 h/day and >3 h/day. Sixty-five percent (11 of 17) of desmin null mice ran <1 h/day, compared with 33% (3 of 9) of wild-type mice. Two desmin null mice (12%) ran >3 h/day, whereas 33% (3 of 9) wild-type mice ran >3 h/day. *Significantly different from wild-type mice, P < 0.05.

Examination of the patterns of time, distance, and speed run over the 3-wk period revealed that desmin null mice were lower for all parameters measured. Desmin null mice spent less time running and ran less distance throughout the entire duration of the voluntary exercise period compared with wild-type mice (Fig. 2, A and B). After an initial dramatic decrease in time run for both genotypes after the first day of exercise, average time remained largely steady, decreasing slightly for both genotypes throughout the rest of the exercise period (Fig. 2A). In contrast, the average distance run by the wild-type mice increased across the training period and was significantly greater than that for the null mice, which did not show any increase (Fig. 2B). As a consequence of the increase in mean distance run and the slight decrease in average time run, average speed increased steadily for wild-type (from 0.71 to 1.23 km/h, a 73% increase) mice over the 21-day course of the study. Desmin null mice displayed a significantly lower increase in average speed (from 0.64 to 0.77 km/h, a 20% increase) over the course of the experiment compared with wild-type mice (Fig. 2C).

View larger version (23K): [in this window] [in a new window]   Fig. 2. Time, distance and speed run across the exercise period for wild-type and desmin null mice. A: average time run for wild-type and desmin null mice. Desmin null mice ran less than wild-type mice. B: average distance run for wild-type and desmin null mice. Desmin null mice ran less distance than wild-type mice. C: average speed run for wild-type and desmin null mice. Average speed increased significantly from day 1 to day 21 for wild-type mice but increased minimally in desmin null mice. Values are means ± SE; n = 9 wild-type mice and n = 17 desmin null mice. *All time points after this significantly different from wild-type mice, P < 0.05.

Treadmill exercise performance. Desmin null mice also performed less well than wild-type mice in endurance and stress treadmill exercise tests (Fig. 3). For the endurance test, treadmill-acclimated mice were forced to run at 20 m/min until they could no longer maintain sufficient speed. Most desmin null mice (5 of 6) failed to maintain running for more than 12 min, whereas the majority of wild-type mice (8 of 13) were able to run for 25 min and 2 mice were able to complete the full 30 min in all three runs (Fig. 3B). In addition, desmin null mice failed to keep pace with the treadmill as well as wild-type mice, as indicated by their increased beam breaks per minute (Fig. 3A). Similarly, desmin null mice were unable to achieve the maximum speeds achieved by wild-type mice in the treadmill stress test (Fig. 3C) and failed at lower speeds compared with wild-type mice (Fig. 3D).

View larger version (26K): [in this window] [in a new window]   Fig. 3. Involuntary exercise in wild-type and desmin null mice. A: average number of beam breaks per minute for wild-type and desmin null mice. Desmin null mice had significantly more beam breaks per minute in the endurance treadmill test than wild-type mice. B: number of mice that could endure a speed of 20 m/min for a given length of time was plotted as the average of 3 runs against time in the endurance test. C: mean maximum treadmill speed achieved for wild-type and desmin null mice. Maximum speed achieved was significantly lower in desmin null mice compared with wild-type mice. D: 3 runs of the test were averaged for each mouse, and the average maximum speed achieved was plotted. Desmin null mice failed at a lower maximal speed compared with wild-type mice. Values in A and C are means ± SE; n = 15 wild-type mice and n = 8 desmin null mice. *Significantly different from wild-type mice, P < 0.05.

Serum CK activity and wheel running. We examined serum CK activity to determine whether exercise-induced intracellular enzyme efflux differed between wild-type and desmin null mice. Neither wild-type nor desmin null mice demonstrated elevated serum CK activity before exercise (Fig. 4A). Moreover, voluntary wheel running exercise did not result in increased serum CK activity in wild-type or desmin null mice, but CK activity was elevated in voluntarily running mdx mice (Fig. 4), which served as a positive control. Therefore, it seems that muscle membrane damage is unlikely to be a factor in the impaired voluntary exercise performance of desmin null mice compared with wild-type mice at this age.

View larger version (16K): [in this window] [in a new window]   Fig. 4. Serum creatine kinase (CK) levels in exercised mice. A: serum CK levels 3 days before and 1 day after voluntary wheel running exercise for 3-mo-old male wild type, desmin null, and mdx mice. Values are means ± SE; n = 5 wild-type mice, n = 7 desmin null mice, and n = 8 mdx mice. Wild-type and desmin null mice did not show any elevation of serum CK activity after voluntary wheel running exercise. Serum CK activity for mdx mice both pre- and postexercise was significantly different between desmin null and wild-type mice, P < 0.05. *Serum CK activity was significantly elevated postexercise compared with pre-exercise for mdx mice, P < 0.05. B: serum CK levels in international units (IU) for wild-type and desmin null mice 3 days before and1hand 1 day after downhill treadmill running. Values are means ± SE. Both genotypes demonstrated an increase in serum CK levels 1 day after downhill treadmill running; however, the increase was significantly greater in wild-type mice than in desmin null mice. The lack of desmin is associated with elevated serum CK levels after downhill treadmill running. *Significantly different from pretreadmill, P < 0.05. Significantly different from wild-type mice, P < 0.05. C: average beam breaks per minute during the downhill treadmill running test, demonstrating the lack of a difference between wild-type and desmin null mice in the ability to engage in the downhill running paradigm. Values are means ± SE; n = 5 wild-type mice and n = 7 desmin null mice for both B and C.

Serum CK activity and downhill treadmill running. We employed a downhill treadmill protocol to further assess the role of desmin in protecting muscle from CK efflux. This protocol has been shown to produce increased serum CK activity in mdx mice (26). Serum CK activity for wild-type and desmin null mice was not significantly different 3 days before or 1 h after downhill running exercise, but serum CK activity at 1 day after exercise was significantly elevated in both groups of mice (Fig. 4B). However, serum CK activity in desmin null mice was significantly lower compared with wild-type mice (Fig. 4B). There was no significant difference between wild-type and null mice in the ability to tolerate the downhill running (Fig. 4C).

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION DISCLOSURES ACKNOWLEDGMENTS REFERENCES

 
Desmin is a muscle-specific intermediate filament protein believed to play roles in protecting muscle from mechanical perturbations and in maintaining sarcomeric organization. Because desmin is expressed in cardiac, smooth, and skeletal muscle cells, and all of these systems (cardiac, vascular, and musculoskeletal) are critical to meeting the increased work demands of endurance exercise, we hypothesized that desmin null mice would demonstrate decreased exercise performance compared with wild-type mice. Our results demonstrate that the loss of desmin results in impairments in both voluntary and forced running exercise in mice as measured by running distance, time, and speed, but because we did not measure other indexes of exercise performance, such as oxygen uptake or muscle contractile properties (24, 27), it is not possible to extrapolate to other forms of endurance or resistance exercise at this time.

The absence of desmin resulted in a significant impairment in voluntary running exercise behavior. Fewer desmin null mice engaged in voluntary running exercise compared with wild-type mice, and time, distance, and speed run were also decreased in desmin null mice compared with wild-type mice (Fig. 2). Our results are thus consistent with previous studies on MHC 2b and 2d/x null mice, which also showed a decrement in voluntary wheel running ability compared with wild-type mice (11). Similarly, mdx mice will run voluntarily despite greater muscle damage compared with wild-type mice, but they run less far than wild-type mice (4, 5, 12). Together, these data suggest that optimal running ability depends on the appropriate expression of proteins related to force generation and transmission.

Desmin null mice also showed impaired performance in two forced treadmill exercise tests. Desmin null mice were not able to tolerate the stress test as well as wild-type mice, reaching maximal running speeds that were significantly lower than those of wild-type mice. In addition, desmin null mice were also less able to respond to a prolonged exercise test in which speed was held constant; only one desmin null mouse of six (16.7%) was able to run more than 12 min, but most (61%) of the wild-type mice were able to complete at least 25 min of the endurance exercise test (Fig. 3B). Desmin null mice also had more beam breaks per minute than wild-type mice, indicating that they were unable to maintain the appropriate running speed. Together, these data demonstrate that desmin null mice are unable to respond as well to an acute, intense exercise challenge compared with wild-type mice.

Previously, our laboratory showed that, in wild-type mice, average voluntary running speed increased over time and could be used as an indicator of adaptation to exercise (1, 15). This increase in average speed over time likely represents physiological adaptations in response to exercise training, along with improvements in running efficiency by the mice as they become acclimated to wheel running. In the present study, wild-type mice showed increased running speed across the 3 wk of voluntary wheel running, whereas desmin null showed minimal changes in average speed over the course of the experiment (Fig. 2C). These data demonstrate that exercise performance in desmin null mice is less adaptable to voluntary exercise training than that of wild-type mice.

In the present study, we measured serum CK activity to determine whether increased susceptibility to muscle membrane damage contributes to the impaired voluntary exercise performance of the desmin null mice. Serum CK activity is commonly used as an assay for muscle membrane damage after downhill running (4). Although studies on both rodents and humans have suggested that serum CK activity may not be directly quantitatively associated with muscle damage (13, 14), to date there have been few quantitative studies on the relationship between serum CK levels and muscle damage in inbred mouse strains. It should also be recognized that other forms of muscle damage can exist that do not result in elevated serum CK activity and that the results from the present study do not address these other forms of muscle damage.

Neither wild-type nor desmin null mice undergoing voluntary wheel running exercise at 3 mo of age revealed any evidence of elevated serum CK activity (Fig. 4A). Therefore, muscle membrane damage as assessed by serum CK levels does not appear to play a major role in the impaired voluntary exercise performance of desmin null mice. The lack of elevated CK activity in wild-type mice also suggests that muscle membrane damage does not occur in response to voluntary running in normal mice either. The mdx mice were used as a control for elevated serum CK activity, and they displayed a significant postexercise increase in serum CK activity compared with wild-type and desmin null mice, consistent with previous reports demonstrating increased muscle damage in mdx mice after voluntary exercise (4, 5, 12). The results suggest that normal wheel running is sufficient to induce elevated serum CK activity in the absence of dystrophin but not desmin. Indeed, using downhill treadmill running to induce eccentric contractions, we observed that desmin null mice had significantly less serum CK activity compared with wild-type mice (Fig. 4B). Together, both the voluntary wheel running and the downhill treadmill running data suggest that the absence of desmin results in an impairment of aerobic running exercise performance that is not associated with an increase in serum CK activity. One alternate possibility is that the loss of desmin affects cardiac or skeletal muscle mitochondrial function, which in turn adversely affects aerobic exercise performance. Consistent with this hypothesis are recent studies suggesting that desmin null mice have reduced mitochondrial function (19, 20).

In conclusion, in the present study we report that the absence of desmin results in impairment of both voluntary and involuntary exercise performance in the absence of elevated serum CK activity. These studies suggest that normal desmin levels are a necessary component of exercise performance and raise the possibility that mutations in the desmin gene may affect performance in humans as well. These studies also suggest that the role of desmin filaments in lateral force transmission and/or organization of myofibrillar and organellar localization (2) may be more critical during exercise than its role in protection from mechanical insults.

	DISCLOSURES

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION DISCLOSURES ACKNOWLEDGMENTS REFERENCES

 
These studies were supported by National Heart, Lung, and Blood Institute Grant HL-56510 (to L. A. Leinwand).

	ACKNOWLEDGMENTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION DISCLOSURES ACKNOWLEDGMENTS REFERENCES

 
The authors thank Gail Ackerman for help with breeding and maintaining the desmin null mice; Margaret Isenhart for supplying mdx mice; and Brooke Harrison, Dr. Steve Luckey, Gail Ackerman, and Dr. Steve Langer for assistance in the exercise protocols.

	FOOTNOTES

 

Address for reprint requests and other correspondence: L. A. Leinwand, Dept. of Molecular, Cellular, and Developmental Biology, Univ. of Colorado, Campus Box 347, Boulder, CO 80309-0347 (E-mail: leinwand{at}ataqdog.colorado.edu).

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.

	REFERENCES

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION DISCLOSURES ACKNOWLEDGMENTS REFERENCES

 

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