Endurance-training-induced in respiratory muscles

cellular adaptations

SCOTT K. POWERS, JOHN LAWLER, DAVID CRISWELL, STEPHEN DODD, STEPHEN GRINTON, GREG BAGBY, AND HAROLD SILVERMAN Center for Exercise Science, Departments of Exercise and Sport Science and Physiology, University Florida, Gainesville, Florida 32611; Department of Zoology and Physiology and Applied Physiology Laboratory, Louisiana State University, Baton Rouge 70803; and Department of Physiology, Louisiana State University Medical Center, New Orleans, Louisiana 70112

POWERS, SCOTT K., JOHN LAWLER, DAVID CRISWELL, STEPHEN DODD, STEPHEN GRINTON, GREG BAGBY, AND HAROLD SILVERMAN. Endurance-training-induced cellular adaptations muscles. J. Appl. Physiol. 68(5): 2114-2118, in respiratory 1990.-Controversy exists concerning the adaptability of mammalian respiratory muscles in response to endurance training. We examined the effects of 8 wk of progressive treadmill exercise (45 min/day 5 days/wk) on the biochemical adaptations of rat diaphragm and intercostal muscles. Female Sprague-Dawley rats were randomly assigned to a sedentary control (n = 10) or an exercise-training group (n = 10). Endurance training resulted in an enhanced oxidative capacity in the anterior costal diaphragm as evidenced by a 29% increase (P < 0.05) in the activity of succinate dehydrogenase (SDH) in trained animals compared with controls (4.15 t 0.13 vs. 3.21 t 0.17 ~rnoLg-lo min-‘). Similarly, SDH activity in the intercostal muscles was 32% greater (P < 0.05) in the trained animals than in the untrained animals (1.72 & 0.11 vs. 1.30 & 0.06 pm01 . g-’ smin-l). In contrast, the crural region of the diaphragm showed no significant increase (P > 0.05) in oxidative capacity as a result of the training program (3.28 & 0.12 vs. 3.13 & 0.18). Furth ermore, training did not alter (P > 0.05) lactate dehydrogenase activity in the intercostals or in the crural or the costal diaphragm. These data demonstrate that the oxidative capacity of the costal diaphragm and the intercostal muscles can be enhanced by increasing respiratory loads via regular endurance exercise. We speculate that the lack of metabolic adaptation in the crural region of the diaphragm was not due to limited plasticity of the fibers in this area but to failure of the exercise-training program to provide the appropriate stimulus for cellular adaptation. diaphragm; muscle

rat skeletal fiber types

muscle;

exercise;

oxidative

capacity;

OF RESPIRATORY MUSCLES to adapt to changing functional demands could have many important clinical implications. This is particularly important for the diaphragm because it is the only skeletal muscle that can be considered essential for life. Thus it is surprising that the adaptive strategies of the diaphragm to increased metabolic demand have only recently been investigated. It is well established that regular aerobic exercise increases the oxidative capacity of locomotor muscles in both rats and humans (15, 16, 17); however, the effects of endurance training on diaphragm biochemTHE ABILITY

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ical adaptability remain unclear (10, 12, 14, 18, 24, 26). To date, most investigations of diaphragmatic plasticity have focused on the costal region of the diaphragm alone (10, 14, 18, 26) or the entire diaphragm (i.e., costal and crural regions together (12). This seems unfortunate because recent evidence suggests that physiological and metabolic differences exist between the costal and crural regions of the diaphragm (7,8,25,28). Hence, it appears that studies designed to investigate biochemical adaptations in the diaphragm should analyze the crural and costal regions independently. In addition, there is evidence that the intercostal muscles assist diaphragmatic function by stabilizing and lifting the rib cage during both quiet and heavy ventilatory efforts (23). Therefore studies assessing respiratory muscle adaptation to endurance training should consider not only the two regions of the diaphragm but the intercostals as well. To our knowledge, there are no published reports of the effects of endurance training on the crural and costal regions of the diaphragm along with the intercostal muscles. Therefore we tested the hypothesis that regular endurance exercise would enhance the oxidative capacity of respiratory muscles by examining the effects of 8 wk of progressive exercise training on selected glycolytic and oxidative enzyme changes in the costal and crural diaphragm and the intercostal muscles. METHODS Animals and trainingprotocol. These experiments were approved by the University Committee for Use of Animals in Research and followed the guidelines established by the American Physiological Society. Twenty female Sprague-Dawley rats (120 days old) were fed rat chow and water ad libitum and were maintained on a 12-h light-dark photoperiod. Rats were selected for their willingness to run and were randomly assigned to an exercise-training or sedentary control group. The training group ran on a treadmill 5 days/wk for 8 wk; each training session began and ended with a 5min “warmup” and “cool-down” at 21 m/min (0% grade). On day 1 (week 1) of training the animals began exercising at 30 m/min (15 min, 0% grade), and the duration of exercise was increased by 5 min/day until the animals reached 35 min of training (excluding the warm-up and cool-down

0 1990 the American

Physiological

Society

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CELLULAR

ADAPTATION

IN RESPIRATORY

periods). Beginning in week 2 the animals began exercising on a “hard-easy” cycle: Monday, Wednesday, and Friday were the hard days, and Tuesday and Thursday were the easy days. The training protocol for week 2 consisted of 35 min of treadmill exercise (30 m/min, 2.5% grade) on the hard days and 35 min of running at 30 m/min (0% grade) on easy days. Thereafter the treadmill speed remained constant, but the percent grade was increased by 2.5%/wk on the hard days and the work rate on the easy days remained unchanged. The exercise intensity (30 m/min, 17.5% grade) during the last week of training has been shown to elicit -90% of maximal O2 uptake 6% maxp 5- to 6-fold increase in alveolar ventilation) in untrained rats (11). Electric shocks were used to motivate the animals to run during weeks 1 and 2 of training and were discontinued during weelz 3. Biochemical assays. Within 24-48 h after the last training session, animals were anesthetized with pentobarbital sodium (50 mg/kg ip), and the anterior costal and crural regions of the diaphragm and the intercostal and plantaris muscles were removed. Excised muscles were quickly dissected free of fat and tendon in ice-cold rat Ringer solution and minced before homogenization. Homogenization included a 15-s treatment with a UltraTurrax T25 tissue homogenizer (IKA Works, Cincinnati, OH) followed by 15 passes of the homogenate in a tightfitting Potter-Elvehjem homogenizer. Then the homogenates were centrifuged (3°C) for 10 min at 700 g. We have demonstrated previously that this homogenization technique is proficient in cellular and mitochondrial disruption in the rat diaphragm (20). The supernatant was decanted and assayed for protein concentration and succinate dehydrogenase (SDH, E.C. 1.3.99.1) and lactate dehydrogenase (LDH, E.C. 1.1.1.27) activity. Tissue samples used to determine SDH activity were homogenized in cold 100 mM phosphate buffer with 0.05% bovine serum albumin (BSA, l:20 wt/vol, pH 7.4), and tissue for LDH was homogenized in cold 100 mM tris(hydroxymethyl)aminomethane buffer with 0.05% BSA (1:20 wt/vol, pH 7.4). SDH activity in all muscle samples was determined using the technique described by Singer (30). LDH activity was determined using a modification of the procedure described by Bergmeyer et al. (3). Briefly the principle of operation for this assay is that the reduction of pyrivate results in an equimolar amount of NADH being oxidized to NAD. The oxidation of NADH results in a decrease in the amount of absorbance at a wavelength of 340 nm, and the rate of decrease in absorbance is directly proportional to LDH activity in the sample. The reaction cocktail contained a final concentration of 0.118 mM NADH, 54 mM phosphate buffer (pH 7.4), and 0.831 mM pyruvate. All enzyme assays were performed in triplicate at 25OC. The intra-assay coefficients of variation for SDH and LDH were 4.9 and 6.5%) respectively. Protein concentration was measured in duplicate by the technique of Layne (21). The intraassay coefficient of variation of protein analysis was F;s?z Data analysis. Differences between control and exercise-trained groups were determined by Student’s test after application of the correction for multiple tests UWV

/Vb

t

t

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suggested by Dunn (9). Significance was established at P c 0.05. RESULTS

Body weights, diaphragm weights, and the ratio of diaphragm weight to body weight did not differ between the control and training group at the conclusion of the endurance-training program (Table 1). SDH and LDH activities in the diaphragm, intercostals, and plantaris from trained and control animals are shown in Fig. 1. SDH was measured as a marker of oxidative capacity because it is tightly bound to the inner cristae membrane of mitochondria (27), and increases in SDH activity reflect an overall enhancement of tissue oxidative capac1. Body weight, diaphragm weight, and the ratio of diaphragm weight to body weight in trained TABLE

and sedentav animaZs Body Wt,

Group

Diaphragm Wt/ Body Wt,

Diaphragm Wt,

g

g

mdg

Trained 354.5t26.2 1.18t0.09 3.32k0.28 Control 362.1t32.2 1.19*0.13 3.2820.25 Values are means k SD of 10 rats/group. No significant difference between groups in any variable (P > 0.05).

SDH

Activity

*

Costal B 800

1

600

-

400

-

A

fI 7 *

tD .

Intcrcostals LDH

Plantaris

Activity

.-E E . L” 2 h .‘= i .e a’

0

Conuol

f7J Tmncd

200

-

= P 2 0-t

Costal

Intercostals

Plantaris

1. SDH and LDH activities in costal and crural diaphragm, intercostals, and plantaris muscle in trained and control animals. v a1ues are means k SE. * Significant differences between experimental groups (P c 0.05). FIG.

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ity (26,27). LDH was measured as a marker of glycolytic capacity. Although it is acknowledged that phosphofructokinase is often considered the best marker of maximal glycolytic flux in a tissue, LDH activity correlates reasonably well with glycolytic potential of muscle (26, 27). SDH activity was significantly higher (29%) in the costal region of the diaphragm in the trained animals than in the controls, indicating that exercise training increased the oxidative capacity of the costal region of the diaphragm (Fig. 1). Although SDH activity tended to be higher in the crural region of the diaphragm in the trained animals than in the controls, the difference was not significant. Similarly, no differences in LDH activity existed between experimental groups in the crural or costal region, which implies that the glycolytic capacity of the diaphragm was unaltered by the training program. Figure 1 also shows LDH and SDH activities for the intercostal and plantaris muscles in the control and trained groups. Training resulted in a significant improvement in the oxidative capacity of the intercostal muscles of the trained animals as evidenced by a 32% increase in SDH activity. Note that this SDH activity represents the composite of both the internal and external intercostals because the two muscles were not separated before homogenization. LDH activity in the intercostals was not significantly different between experimental groups. In the plantaris muscles, SDH activities were significantly higher in the trained than in the sedentary animals, and LDH activities did not differ between experimental groups. Muscle protein concentrations for both experimental groups are shown in Fig. 2. Note that tissue protein concentrations were measured in the crural and costal regions of the diaphragm only. Small but significant increases in total protein concentrations were observed in the trained animals in both the crural and costal regions of the diaphragm compared with the control animals. DISCUSSION

To our knowledge, this is the first investigation of the differential metabolic effects of endurance training on

IN RESPIRATORY

MUSCLES

the muscles primarily responsible for respiratory movement. The crural and costal regions of the diaphragm and the intercostal muscles were analyzed independently to determine whether different metabolic responses to t raining occur. The results indicate that exercise training causes significant increases in the oxidative capacities of th e intercostal muscles and the costal diaphragm and no change in the oxidative capacity of the crural diaphragm. The 29% increase in SDH activity in the costal diaphragm as a result of endurance training is quantitatively similar to data reported by Ianuzzo et al. (18) but is approximately threefold greater than the training-induced SDH alterations reported by Moore and Gollnick (26) in the rat costal diaphragm. Furthermore these findings differ from the data of Fregosi et al. (l2), Metzger and Fitts (24), and Green et al. (14), who found no significant improvement in the oxidative capacity in the rat diaphragm after training. A possible explanation of the conflicting results between studies may be as follows. It seems likely that the training-induced changes in diaphragmatic SDH activity in the present study exceeded the improvement reported by Moore and Gollnick (26) because of differences in exercise-training protocols. Although the results of the two studies are qualitatively similar, the progressive increases in work rates employed in the current study were severalfold more intense than those in the exercise regimen utilized by Moore and Gollnick (26). Hence, we postulate that the metabolic challenge to the costal diaphragm of our training program was greater than that of Moore and Gollnick (26) and therefore mediated a comparatively higher oxidative adaptation in the costal diaphragm. The explanation for the divergent findings between the present &a and th ose of Fregosi et al. (12) is not completely clear. Fregosi et al. (12) used a training intensity that exceeded the work rates employed by Moore and Gollnick (26) but was less than the intensity utilized in the present experiments. Yet they found no increase in diaphragm oxidative capacity. One possible explanation for the findings of Fregosi et al. (11) is that they did not divide the diaphragm into separate metabolic regions (i.e., crural

zoo-

* .

loo-

0

Control

a

T&cd

FIG. 2. Protein concentrations in crural and costal diaphragm in control and trained groups (means k SE). * Significantly higher in trained than in control animals for both regions of diaphragm (P < 0.05).

.

0 -

Costa1

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CELLULAR

ADAPTATION

vs. costal) for biochemical analysis but rather assayed the entire diaphragm. This may be important because the crural region has been shown to differ from the costal groups in both fiber type and oxidative capacity (25,28), suggesting that these two regions of the diaphragm do not have identical responsibilities. Therefore, because the crural region constitutes ~33% of the total diaphragm weight in the rat (28), the combination of the costal and crural regions into one single biochemical analysis might mask metabolic changes that occur in the costal region alone as a result of training. Data from the present study support this argument (Fig. 1). Furthermore, Metzger and Fitts (24) recently reported that 6 wk of high-intensity interval training did not significantly alter the activity of the Krebs cycle enzyme citrate synthase in the costal region of the diaphragm. These findings are difficult to explain in light of the present findings and those of Moore and Gollnick (26) and Ianuzzo et al. (18), which clearly demonstrate an enhanced oxidative capacity in the costal diaphragm after endurance training. One obvious difference between the work of Metzger and Fitts (24) and the aforementioned studies is the training protocol. In the current study and the investigation of Moore and Gollnick (26) and Ianuzzo et al. (18) a continuous-exercise-training protocol was used, whereas Metzger and Fitts (24) used high-intensity interval training. Whether the differences in training protocols can explain the divergent findings requires further study. In addition, a report by Green et al. (14) demonstrated no significant improvement in oxidative capacity in the rat diaphragm after an extreme training program (continuous exercise 240 min/day at 80% VOW max).At present, we cannot explain why animals exposed to this level of training failed to demonstrate oxidative improvements in the costal diaphragm. However, an extreme training regimen such as this might result in a chronic elevation of blood corticosteroids, which could negatively impact protein synthesis in muscle. This hypothesis warrants further investigation. To summarize the published reports on the effects of endurance training on the costal diaphragm, the present study and the work of others (18,26) clearly demonstrate that the metabolic properties of the costal diaphragm can be modified by changes in functional demands. The conflicting reports in the literature are likely due to differences in training protocols between studies and the failure in some studies to independently analyze the costal and crural regions of the diaphragm. Furthermore, although it is clear that the costal diaphragm responds to training, the optimal training method to increase diaphragmatic oxidative capacity and the limits of plasticity have yet to be determined. Only one published report has examined the effect of regular muscular exercise on the crural diaphragm in rodents (24), and only two published studies have reported the effects of a chronically elevated metabolic load on the biochemical properties of the crural diaphragm (1, 19). Metzger and Fitts (24) observed no significant alterations in the crural diaphragm after interval training. In contrast, Akabas et al. (1) demonstrated that 3 wk of chronic inspiratory flow resistance

IN RESPIRATORY

MUSCLES

2117

in sheep resulted in significant increases in citrate synthase and cytochrome oxidase activities in this muscle. Similar findings in rodents have been reported by Keens et al. (19). Therefore it appears that under conditions of a chronic elevated metabolic load the crural diaphragm is plastic and is subject to metabolic alterations similar to other skeletal muscles. The explanation for the failure to observe a metabolic change in the crural diaphragm in the present study (or any exercise study to date) may be that the intensity of the exercise-training program does not provide a metabolic overload for the crural diaphragm. Although there is growing evidence that the crural and the costal diaphragm may have different ventilatory responsibilities (6-8), little information is currently available concerning the pattern of motor unit recruitment in these regions during exercise. Furthermore, work by Metzger et al. (25) suggests that the shortening velocity is lower (in vitro) in the crural than in the costal diaphragm at physiological temperatures. If this is true in vivo, the energy requirement might be lower in the crural than in the costal diaphragm during repetitive contractions. This finding, coupled with the fact that the crural diaphragm already has a high oxidative capacity, could be a factor in the failure of this region to demonstrate metabolic change in response to endurance training. Additional experiments to expand our understanding of the type(s) of ventilatory loads required to mediate metabolic alterations in the crural diaphragm seem warranted. Another interesting aspect of the present study was that in the intercostal muscles the SDH activity was 32% higher in the trained animals than in the sedentary animals. This training-induced increase in the oxidative capacity of the intercostals differs from the findings of Moore and Gollnick (26), who reported no improvement in the oxidative capacity of the intercostals in rats after 26 wk of treadmill exercise. Again this difference may be related to the marked difference in exercise intensity employed in these studies. It seems possible that the moderate-intensity-training program employed by Moore and Gollnick (26) may not have provided the necessary stimulus for cellular metabolic adaptation. This argument is supported by the observation that high ventilatory rates are required to significantly increase blood flow to the intercostals during exercise (29). Additional support for the notion that these muscles are plastic and can undergo large increases in oxidative capacity in response to metabolic overload can be found in work by Keens et al. (19), who demonstrated that a chronic ventilatory muscle load induced by tracheal stenosis in rats results in a significant increase in SDH activity in the intercostal muscles. Respiratory muscle fatigue has been observed in a number of clinical situations and may contribute to respiratory failure (10,31). Improvement in the oxidative capacity and thereby respiratory muscle function that would result from regular exercise or “specific” ventilatory muscle training suggests that this practice might be a useful therapeutic modality in patients who are predisposed to respiratory muscle fatigue. Similar conclusions have been reached by Akabas et al. (1). However, before

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respiratory muscle training can be practically employed in pulmonary rehabilitation programs, much information is needed to answer pragmatic questions such as the type, duration, and intensity of exercise that will optimize metabolic alte rations in respiratory muscles. Furthermore, in patients with chronic obstructive lung disease, additi .onal compl icating factors such as malnutrition, hypercapnia, and hypoxia may also be present. In addition, obstructive and resistive lung diseases may produce metabolic alterations in respiratory muscles and render further adaptation i.mpossible. Addition .a1 stu *dies are required to evaluate the impact of the above factors, individually or in combination, on respiratory muscles engaged in- training studies (1). In summary, these data clearly demonstrate that regular exercise training results in a significant increase in the oxidative capacity of the costal diaphragm as well as the intercostal muscles of rats with no significant improvement in the oxidative capacity of the crural diaphragm. We speculate that the lack of metabolic adaptation in the crural region of the diaphragm was not due to limited plasticity of the fibers in this area but to failure of the exercise-training p rogram to provide the appropriate stimulus for cellular adaptation. The magnitude of the oxidative increase in the costal diaphragm and the intercostals is comparable to the changes observed in locomotor muscles after endurance training. These findings in the rat are consistent with the observation that training can increase the endurance of respiratory muscles in humans (2, 5, 22). The result of an increase in oxidative capacity in respiratory muscles would be an enhanced capacity for fat utilization and a reduction in the depletion of muscle glycogen stores (13, 16, 17, 27). These metabolic alterations could have important implications in delaying fatigue during intense and prolonged ventilatory requirements. Therefore, improving our understanding of the cellular adaptation of respiratory muscles may lead to important clinical benefits in the man .gement of patients with lung disease or other disorders that might cause respiratory muscle weakness. The authors thank Dan Ayers for technical assistance. Address for reprint requests: S. K. Powers, Center for Exercise Science, Room 27-FLG, University of Florida, Gainesville, FL 32611. Received 4 August 1989; accepted in final form 16 November

1989.

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Endurance-training-induced cellular adaptations in respiratory muscles.

Controversy exists concerning the adaptability of mammalian respiratory muscles in response to endurance training. We examined the effects of 8 wk of ...
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