Abstract
Patients with COPD have derangements in respiratory mechanics that may cause them to stop exercising before the exercising limb muscles reach their functional limits. However, because lung disease makes activity unpleasant, patients with chronic obstructive pulmonary disease (COPD) often adapt a sedentary lifestyle leading to progressive deconditioning. Deconditioning will lead to progressive deterioration in limb muscle function, which could adversely affect exercise capacity. The purpose of this study was to determine whether fatigue of the quadriceps muscle occurs after high intensity cycle exercise to the limits of tolerance in patients with moderate to severe COPD. Nineteen male patients with COPD (FEV1 1.54 ± 0.12 L; 42 ± 3% predicted) exercised at 60 to 70% of their predetermined maximal work capacity until exhaustion. The femoral nerve was supramaximally stimulated with a figure-of-eight magnetic coil, and quadriceps twitch force (TwQ) was measured before and at 10, 30, and 60 min postexercise. Patients exercised at 53.7 ± 4.1 watts for 10.4 ± 1.4 min. Peak V˙ o 2 was 1.24 ± 0.08 L/min (51.3 ± 3.6% predicted). TwQ fell significantly postexercise; 79.2 ± 5.4% of baseline value at 10 min postexercise (p < 0.005), 75.7 ± 4.8% at 30 min postexercise (p < 0.001), and 84.0 ± 5.0% at 60 min postexercise (p < 0.005). Acceptable M-waves from the quadriceps muscle (not obscured by stimulus artifact) were obtained in six subjects. M-wave amplitude was unchanged from baseline at all times postexercise indicating that the fall in TwQ was due to contractile fatigue and not to transmission failure. In conclusion, contractile fatigue of the quadriceps muscle occurs after high intensity cycle exercise to the limits of tolerance in patients with COPD.
Patients with COPD have derangements in respiratory mechanics that may cause them to stop exercising before the exercising limb muscles reach their functional limits. However, because activity is associated with dyspnea in such patients, they often adopt a sedentary lifestyle resulting in significant deconditioning (1). Deconditioning may predispose the exercising limb muscles to fatigue at work loads that would not ordinarily result in fatigue. Furthermore, deconditioning will lead to progressive deterioration in limb muscle function, which could adversely affect exercise capacity. Peripheral muscle weakness is commonly observed in patients with COPD (2-4). Recent studies have shown that quadriceps strength correlates with exercise capacity independent of pulmonary function (2– 4). Furthermore, many patients with COPD stop exercise primarily because of the subjective complaint of leg fatigue (5) before they become “ventilatory-limited” (5). We hypothesized that despite their ventilatory limitations, patients with COPD would develop contractile fatigue of the exercising muscle after a bout of intense exercise. Recently, Polkey and colleagues (6) have shown that fatigue of the quadriceps muscle can be detected with serial measurements of quadriceps twitch force (TwQ) during magnetic stimulation of the femoral nerve. Accordingly, we measured TwQ before and after high intensity cycle exercise to the limits of tolerance in a group of patients with COPD to determine whether quadriceps fatigue could be detected.
Nineteen male patients with COPD 61.3 ± 2.0 yr of age volunteered for the study. Their height and weight were 1.77 ± 0.01 m and 84.5 ± 2.8 kg, respectively. The diagnosis of COPD was made by a clinical course consistent with chronic bronchitis and/or emphysema, a long history of cigarette smoking (62.6 ± 7.3 pack-years), and pulmonary function testing revealing irreversible airflow obstruction (FEV1 ⩽ 65% predicted, FEV1/FVC ratio ⩽ 65%). All patients were receiving inhaled bronchodilators. None of the patients were receiving oral prednisone. One patient was receiving supplemental oxygen and the studies were performed while the patient received oxygen. All patients were clinically stable and none had clinical evidence of exercise-limiting cardiovascular or neuromuscular disease. None of the patients was involved in a pulmonary rehab program. Seventeen of the patients were quite sedentary. One patient was a daily walker and another patient was physically quite active. The study was approved by the appropriate institutional review boards, and written informed consent was obtained from all subjects.
All patients first underwent an incremental exercise test and pulmonary function testing. On a subsequent day, the patients performed constant load exercise to exhaustion. Quadriceps twitch force, maximum voluntary contraction force, and lactate levels were obtained before and after exercise in all patients. In six of the patients, quadriceps M-waves were obtained before and after exercise. In five of the patients, superimposed twitches were obtained during the maximum voluntary contractions to determine the degree of voluntary activation. In thirteen of the patients, a stimulus output-quadriceps twitch force curve was obtained to determine if femoral nerve stimulation was supramaximal. Seven of the patients performed an additional constant load exercise study to exhaustion on a subsequent day. On this day, adductor pollicis twitch force was measured before and after exercise.
Spirometry was performed according to ATS recommendations (PK Morgan, Chatham, Kent, UK) (7). Lung volumes were measured by body plethysmography (PK Morgan). Single-breath diffusing capacity for carbon monoxide and the maximal voluntary ventilation in 12 s were also measured (PK Morgan). Predicted normal values were those of Crapo and colleagues (8-10) and Kory and coworkers (11). Pulmonary function is shown in Table 1.
| Actual | Predicted (%) | Range (%) | ||||
|---|---|---|---|---|---|---|
| FEV1, L | 1.54 ± 0.12 | 42 ± 3 | (16–65) | |||
| FVC, L | 3.12 ± 0.16 | 66 ± 3 | (45–91) | |||
| FEV1/FVC | 49 ± 3 | (28–65) | ||||
| RV, L | 4.70 ± 0.28 | 209 ± 12 | (116–322) | |||
| TLC, L | 7.96 ± 0.25 | 114 ± 4 | (96–141) | |||
| Dlco , ml/min/mm Hg | 14.54 ± 1.43 | 52 ± 5 | (29–96) |
An incremental symptom-limited exercise test was performed to determine each subject's maximal work capacity. After a 3-min acclimatization period and 2 min of unloaded cycling, the work load was increased by 10 to 15 W every minute until the subject could no longer continue. The last work load for which a subject was able to complete the full minute of cycling was designated Wpeak.
Several days after the incremental exercise test, constant work load exercise was performed on an electronically braked cycle ergometer (CPE-2000; Medgraphics, St. Paul, MN) at 60 to 70% of Wpeak to volitional exhaustion. The subjects were again allowed 3 min to acclimatize to the breathing circuit, they then exercised for 1 min of unloaded cycling and 2 min at 10 W (warm-up period) before initiating exercise at 60 to 70% of Wmax.
Expired gas was analyzed for O2 and CO2 by a zirconium electrochemical cell O2 analyzer and an infrared CO2 analyzer, respectively. Flow was measured with a pneumotachograph (preVent Pneumotach; Medgraphics). A microprocessor calculated breath-by-breath values of O2 uptake, CO2 production, and minute ventilation and its components (respiratory rate and tidal volume), and the results were averaged every 30 s. The pneumotachograph and gas analyzers were calibrated before each exercise test. The pneumotachograph was calibrated with a 3-L volume calibration syringe at widely varying flow rates. The gas analyzers were calibrated with two test gases of known composition (room air and 12.0% O2, 5.0% CO2). The one patient who was receiving oxygen breathed from a 200-L reservoir bag containing 35% O2. Thirty minutes of quiet breathing were recorded prior to exercise to allow equilibration to take place. Immediately after exercise was discontinued, the patients were asked why they stopped; whether it was due to shortness of breath, leg discomfort, chest pain, lightheadedness, or other symptoms. If patients chose more than one symptom we asked them to choose the symptom that they felt was most responsible for their stopping exercise.
Subjects were studied supine on a bed with the knee flexed at 90 degrees and the leg passively stabilized to prevent lateral motion. A nonelastic ankle strap attached to a force transducer (Model 3167; Lebow Products, Troy, MI) and amplifier (Model 7530; Lebow Products) measured quadriceps strength. Care was taken to ensure that the knee remained flexed at 90 degrees, the ankle strap and transducer were parallel to the floor, and that the ankle strap position remained constant throughout the experiment. M-waves were recorded with surface electrodes placed over the belly of the rectus femoris. In the majority of subjects, magnetic stimulation of the femoral nerve elicited a large shock artifact that obscured the M-wave. However, with repositioning of the surface electrodes and ground, M-waves were obtained before and after exercise in six subjects.
Subjects rested in the bed for 20 min before the start of the study to ensure that getting to the laboratory did not inadvertently potentiate the twitch. The femoral nerve was stimulated with a magnetic stimulator (Magstim 200; Magstim Co. Ltd., Whitland, Dyfed, Wales) using a 45-mm figure-of-eight coil (6). Stimulation of the magnetic coil induces a monophasic electrical current that progressively declines to zero over 0.1 ms. The coil was initially placed in the femoral triangle just lateral to the femoral artery and repositioned systematically to determine the best location for subsequent stimulations. The position that resulted in the largest quadriceps twitch response was marked and used for the remainder of the study. A minimum of eight twitches were obtained before and 10, 30, and 60 min postexercise. All twitches were obtained at 100% of stimulator output. Twitch force and quadriceps EMG were digitized and stored on disk using Windaq software (Dataq Instruments Inc., Akron, OH) at a sampling rate of 1,000 Hz. To determine whether femoral nerve stimulation was supramaximal, a stimulus output-force curve was obtained in 13 subjects at the beginning of the protocol. At least five twitches were obtained at 50, 60, 70, 75, 80, 85, 90, 95, and 100% of power output. The subjects then rested for 15 min and the measurements at 100% power output were repeated (the repeat measurements at 100% power output were used as our baseline measurements).
At least five maximum voluntary contractions (MVC) were obtained before and 30 min after exercise. In five subjects, MVC were also obtained 10 and 60 min postexercise. The MVC maneuvers were always performed after the unpotentiated twitch measurements. To determine the degree to which our subjects could voluntarily activate their quadriceps muscle, twitches were obtained during the MVC maneuvers (twitch interpolation) in five subjects. Superimposed twitches were compared with twitches obtained with the leg relaxed, 5 s after the MVC maneuver (resting potentiated twitch) to determine the percent activation during the MVC maneuver (100-superimposed twitch/ resting potentiated twitch X 100) (12).
To ensure that changes in TwQ were specific to the exercising muscle and not a nonspecific generalized effect of exercise, a nonexercising muscle, the adductor pollicis was also studied in seven subjects (on a separate day) as previously described (13). Briefly, transcutaneous ulnar nerve stimulation was performed with a bipolar stimulating electrode (Dantec 13L36; Allendale, NJ) placed over the ulnar nerve at the wrist. M-waves were obtained by placing surface electrodes over the muscle belly. Constant current square-wave impulses 0.1ms in duration were delivered and current was progressively increased until no further increase in M-wave amplitude was seen. To ensure that stimulus intensity remained maximal, current was increased by an additional 20 to 50% throughout the experimental study. Twitch force was measured with a force transducer connected to the thumb via a metal chain with terminal loop. The coil was placed over the interphalangeal joint of the thumb and the hand was secured in supination with the thumb abducted and the interphalangeal joint fully extended. A minimum of eight twitches were obtained before and 10, 30, and 60 min after exercise.
A Teflon catheter was inserted into a vein in the dorsum of the hand. To arterialize the blood, the dorsum of the hand was heated until skin temperature exceeded 42° C for at least 2 min prior to sampling. To clear catheter and tubing dead space, the first 2 ml of blood were discarded. Blood samples were obtained before and 5, 15, and 30 min after exercise.
Changes in variables over time were analyzed by repeated-measures analysis of variance and paired t test with Bonferroni correction. Data are expressed as the mean ± SE. For each individual subject, a fall in twitch force of > 15% postexercise was considered potentially indicative of fatigue. In our laboratory, the average within-subject, between-trial coefficient of variation for TwQ is 8% (14, 15). We reasoned that any difference from baseline that was twice the average between-trial variability was unlikely to be due to chance alone. Correlations between continuous variables were made using simple linear and stepwise multiple regression.
TwQ at different power outputs is shown in Figure 1. TwQ progressively increased with increasing power output up to a power output of 90%. TwQ at 90 and 95% power output were not significantly different from TwQ at 100% power output. TwQ reached 95% of the force obtained at 100% power output in eight of 13 subjects at 90% power output and 12 of 13 subjects at 95% power output, suggesting that a plateau in force does occur in most subjects at the higher power outputs.
Fig. 1. Quadriceps twitch force (TwQ) during magnetic stimulation of the femoral nerve at different power outputs (expressed as a percentage of the force generated at 100% power output) (n = 13, mean ± SE). Asterisk indicates significant difference from 100% power output. TwQ progressively increased with increasing power output up to a power output of 90%.
[More] [Minimize]TwQ before and after exercise is shown in Figure 2. At baseline, TwQ averaged 8.42 ± 0.76 kg. TwQ fell significantly postexercise (to a minimum of 75.7 ± 4.8% of the baseline value at 30 min postexercise) and remained significantly decreased at 1 h postexercise. Quadriceps M-wave amplitude was not significantly different from baseline at any time postexercise in the six subjects in whom it could be measured. A representative example is shown in Figure 3. In the six subjects with quadriceps M-waves, TwQ also fell significantly postexercise (78.9 ± 3.8% at 30 min postexercise, p < 0.005). The fall in TwQ postexercise was not significantly different at any time postexercise in the subjects with quadriceps M-waves (78.9 ± 3.8% at 30 min postexercise, n = 6) compared with the subjects without quadriceps M-waves (74.4 ± 5.3% at 30 min postexercise, n = 13). TwQ in each subject before and 10 min after exercise is shown in Figure 4. TwQ fell by > 15% postexercise in 11 of the 19 subjects.
Fig. 2. Quadriceps twitch force (TwQ) before and 10, 30, and 60 min after exercise (n = 19, mean ± SE). Asterisk indicates significant difference from baseline value. TwQ fell significantly postexercise and remained significantly decreased 60 min postexercise.
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Fig. 3. Compound motor action potential (M-wave) and twitch force from the quadriceps muscle before and after exercise in a representative patient. The preexercise data has been shifted slightly to the left to show the data more clearly. Twitch force fell significantly postexercise, whereas M-wave amplitude and shape remained unchanged.
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Fig. 4. Quadriceps twitch force (TwQ) before and 10 min after exercise in each patient (n = 19). Patients who displayed at least a 15% reduction in TwQ postexercise potentially indicative of contractile fatigue of the quadriceps muscles are represented by the closed circles, and patients who did not meet this criteria are represented by the open circles. TwQ fell by > 15% postexercise in 11 of the 19 patients.
[More] [Minimize]MVC decreased from 53.6 ± 5.4 kg to 48.2 ± 5.1 kg (p < 0.01) at 30 min postexercise. Twitches superimposed upon the MVC maneuver in the fresh state (baseline) averaged 19.2 ± 5.8% of the resting potentiated twitch, indicating that subjects were not able to fully activate their quadriceps muscle during the MVC maneuver. On average, subjects achieved 80.8 ± 5.8% of full activation (range, 65 to 98%) during the MVC maneuver (at baseline in the fresh state). No significant differences were observed in the degree of activation of the quadriceps muscle at any time postexercise compared with baseline (i.e., subjects achieved the same degree of activation of the quadriceps muscle in the fatigued state as they did in the fresh state). In the five patients who had MVC measurements obtained at 10, 30, and 60 min postexercise, MVC was 46.8 ± 7.2 kg at baseline and decreased to 43.0 ± 7.5 kg at 10 min postexercise, 43.4 ± 7.5 kg at 30 min postexercise and 42.8 ± 8.5 kg at 60 min postexercise. Potentiated twitches were 64.5 ± 23.5% larger than unpotentiated twitches.
TwAP was not significantly different from baseline at any time postexercise. In individual subjects, a fall in TwAP of > 15% was observed in one subject at 10 min postexercise (a rise in TwAP of > 15% was also observed in one subject) (Figure 5). At 30 min postexercise, none of the subjects demonstrated a > 15% fall in TwAP.
Fig. 5. Adductor pollicis twitch force (TwAP) before and 10 min postexercise in each patient (n = 7). Patients who displayed at least a 15% reduction in TwAP postexercise are represented by the closed circles, and patients who did not meet this criteria are represented by the open circles. The solid line represents the mean value at 10 min postexercise. TwAP fell by > 15% 10 min postexercise in only one patient.
[More] [Minimize]Subjects exercised at 53.7 ± 4.1 W (67.6 ± 1.9% of Wpeak) for 10.4 ± 1.4 min. Peak V˙o 2 was 1.24 ± 0.08 L/min (51.3 ± 3.6% of predicted). Peak V˙o 2 during constant work load exercise averaged 98.0 ± 3.2% of the peak V˙o 2 obtained during the maximal incremental exercise test. Maximal heart rate was 132 ± 4 beats/min (83 ± 2% of the predicted maximum). Peak ventilation during exercise was 48.5 ± 3.4 L/min; 82.2 ± 3.5% of the 12 s MVV. Lactate measurements before and after exercise are shown in Figure 6. Lactate levels increased from 1.4 ± 0.1 at baseline to 4.7 ± 0.5 mmol/L at 5 min postexercise (p < 0.001). Shortness of breath was the primary limiting symptom in seven of the patients, whereas leg discomfort was the primary limiting symptom in 12 of the patients.
Fig. 6. Lactate levels before and 5, 15, and 30 min after exercise (n = 19). Asterisk indicates significant difference from baseline. Lactate levels increased significantly postexercise.
[More] [Minimize]No significant differences were observed between the fatiguers and the nonfatiguers in their pulmonary function (FEV1, residual volume), exercise endurance time, work load, peak exercise V˙o 2 (percent predicted), peak heart rate (percent predicted), peak exercise ventilation as a percentage of the 12 s MVV, increase in serum lactate levels postexercise or baseline quadriceps strength (MVC or TwQ). Of the 19 subjects, nine had a FEV1 < 40% predicted, i.e., had severe obstructive disease. Five of these subjects (56%) demonstrated a ⩾ 15% fall in TwQ postexercise. Of the 19 subjects, 10 had milder disease and six (60%) of these subjects had a ⩾ 15% fall in TwQ postexercise. The fall in TwQ postexercise was not significantly different between the patients who were limited by shortness of breath (22.1 ± 9.8%, n = 7), compared with the patients who were limited by leg discomfort (20.0 ± 6.6%, n = 12). Of the seven patients limited by shortness of breath, three demonstrated a > 15% fall in TwQ, whereas in the 12 patients limited by leg fatigue, eight demonstrated a > 15% fall in TwQ postexercise (χ2 = 2.06, p > 0.10).
TwQ and MVC at baseline were significantly correlated (r = 0.78, p < 0.001). MVC at baseline correlated with FEV1, percent predicted, r = 0.78, p < 0.005 and peak exercise V˙o 2 (obtained during the maximal incremental exercise test), percent predicted, r = 0.82, p < 0.0001. TwQ at baseline also correlated with FEV1, percent predicted, r = 0.66, p < 0.003 and peak (incremental exercise) V˙o 2, percent predicted, r = 0.79, p < 0.0001. FEV1, percent predicted also correlated with peak (incremental exercise) V˙o 2 (r = 0.75, p = 0.0004). Stepwise backward linear regression revealed that FEV1 and TwQ were independent predictors of peak V˙o 2. The addition of FEV1 to the regression model improved the variation in peak V˙o 2 predicted by the model from 63% (TwQ alone) to 72% (TwQ + FEV1). The fall in TwQ postexercise did not correlate with the increase in lactate postexercise (r = 0.20), exercise endurance time (r = 0.30), or peak exercise V˙e as a percentage of the 12 s MVV (r = −0.15), FEV1 (r = 0.20), residual volume (r = 0.23), or peak exercise heart rate (r = 0.28). A weak correlation was observed between the fall in TwQ postexercise and peak exercise V˙o 2 (during the constant load exercise) (r = 0.51, p < 0.05).
Magnetic stimulation was used in this study to detect overt contractile fatigue of the quadriceps. In our laboratory, magnetic stimulation of the femoral nerve is highly reproducible (14, 15). The within-subject between-trial (within a single day) coefficient of variation is 8.0 ± 0.9% (14, 15). Magnetic stimulation of the femoral nerve has been successfully employed to detect contractile fatigue of the quadriceps muscle in several prior studies (6, 14, 15). Magnetic stimulation of the femoral nerve is technically much easier to apply and better tolerated (less painful) than transcutaneous electrical stimulation, which we felt would be highly advantageous for this particular study when measurements had to be performed repeatedly at precise time intervals in elderly patients with respiratory disease.
The usual method for determining that maximal stimulation is maintained over time (no change in M-wave amplitude) is problematic during magnetic stimulation because the M-wave is often obscured by a large stimulus artifact. We were able to obtain satisfactory M-waves in six of the 19 subjects. M-wave amplitude was unchanged from baseline at all times postexercise in every subject. (Figure 3). TwQ was significantly decreased postexercise in this subgroup and the amount by which TwQ fell postexercise was similar to that of the other patients (78.9 ± 3.8% compared with 74.4 ± 5.3%). In this subgroup of patients, contractile fatigue of the quadriceps was definitively demonstrated and there was no evidence of transmission fatigue. Transmission fatigue is a reversible, exertion-induced impairment in the transmission of neural impulses through nerves or across neuromuscular junctions. With transmission fatigue, M-wave amplitude and twitch force both decrease because the electrical impulse is not getting through to the muscle. With contractile fatigue, M-wave amplitude remains unchanged, whereas twitch force decreases (failure of excitation-contraction coupling). Technically, stimulation was performed in exactly the same manner as in the other subjects and no twitches were deleted because of a low M-wave amplitude. It appears from this and prior studies that minor changes in coil position do not lead to significant changes in M-wave amplitude or TwQ. It also appears that marking the coil position on the skin and placing the coil in precisely this position with repeated measurements leads to reproducible measurements of TwQ and M-wave amplitude. Similar observations have been made with regard to magnetic stimulation of the phrenic nerves, which has been more extensively studied (16, 17). Thus, we feel that in the subjects in whom M-waves could not be obtained, the fall in TwQ postexercise is real and reflects contractile fatigue of the quadriceps muscle.
Polkey and colleagues (6) have shown, and we have confirmed (14), that supramaximal stimulation of the femoral nerves can be achieved by magnetic stimulation at the higher power outputs of the stimulator in young healthy subjects. Patients with COPD are elderly with increases in adipose tissue and abdominal girth and a reduction in skeletal muscle mass, which could make it more difficult to achieve maximal stimulation. We examined the stimulus output-force relationship in 13 patients with COPD. TwQ appeared to plateau at the highest power outputs in 12 of the 13 subjects.
Magnetic stimulation provides a more diffuse stimulus than does transcutaneous electrical stimulation. The question arises as to whether magnetic stimulation was specific to the quadriceps muscles. The only motor nerve remotely near the femoral nerve is the obturator, which supplies the adductor group of muscles. When EMG electrodes were placed over the adductor muscles, no M-waves were seen (n = 5) (also see Reference 6). There was no physical evidence of any movement of the leg other than knee extension. Furthermore, no EMG activity was observed from the hamstring muscles (quadriceps antagonists) during magnetic stimulation of the femoral nerve. Thus, magnetic stimulation of the femoral nerve appears to be specific for the quadriceps muscle.
Twitch force can also be affected by changes in leg position or twitch potentiation (18). We were careful to keep the leg in a standard position before and after exercise. The coefficient of variation for repeated TwQ measurements in our laboratory (with the patient being disconnected from the measuring apparatus and sitting in a chair before being reconnected) is 8.0 ± 0.9% (14, 15). The subject kept his leg relaxed for at least 10 min before unpotentiated twitches were obtained (20 min for measurements at baseline and at 30 and 60 min postexercise). Thus, neither changes in leg position or twitch potentiation could have significantly affected our results.
Our patients were not able or were unwilling to fully activate their quadriceps muscle during the MVC maneuvers. Young healthy subjects are usually able to fully activate this muscle during maximal voluntary efforts (19). Our patients performed the MVC maneuver while lying supine (to facilitate stimulation of the femoral nerve). This is a somewhat awkward position to perform a quadriceps MVC maneuver and may account in part for the submaximal efforts. Importantly, there was no significant change in the degree of activation of the quadriceps muscle during the MVC maneuvers postexercise.
TwQ fell significantly after high intensity cycle exercise to the limits of tolerance in a group of patients with moderate to severe COPD. As discussed above, the fall in TwQ is indicative of contractile fatigue of the quadriceps muscle. Fatigue was specific to the exercising muscles since twitch force measured in a nonexercising skeletal muscle, adductor pollicis did not change after exercise.
The fall in TwQ did not correlate with the increase in serum lactate levels post exercise (r = 0.20). At first glance, this result might seem surprising. However, changes in twitch force are indicative of changes in the force produced at low frequencies of stimulation, i.e., low frequency fatigue. Low frequency fatigue is thought to be due to impairment in excitation-contraction coupling. In a seminal study, Vollestad and colleagues (19) showed that fatigue can occur in the absence of changes in muscle metabolites (measured from muscle biopsy specimens). In that study, subjects performed intermittent submaximal contractions of the quadriceps muscle to task failure (inability to maintain the target force). Task failure occurred at 70 ± 25 min and changes in muscle metabolites (including lactate accumulation) were present at this time. However, during the first 30 min of the protocol, no changes could be detected in muscle metabolites while force had fallen by 40%. Thus, fatigue can occur independent of changes in muscle metabolites as was observed in our study.
At 30 min postexercise, TwQ fell by approximately 25%, whereas the MVC fell by only 10%. The decrease in TwQ postexercise reflects low frequency fatigue. Edwards and colleagues (20) showed many years ago that low frequency fatigue of the quadriceps muscle occurs after high intensity leg exercise in healthy subjects. The fall in force at low frequencies of stimulation greatly exceeded the fall in force at high frequencies (20). The MVC maneuver is a relatively high frequency maneuver and will not be as sensitive as the twitch in detecting low frequency fatigue.
Our patients had considerable limitations in exercise capacity. Their peak V˙o 2 was only 51.3 ± 3.6% of predicted. Exercise limitation was presumably due to the patient's underlying lung disease. Patients might have been expected to stop exercise “early” (because of their ventilatory limitations) prior to stressing the exercising limb muscles. However, in our study the majority of patients with COPD developed contractile fatigue of the quadriceps muscle postexercise. Thus, the exercise performed was clearly sufficient to stress the exercising limb muscles. It would be of interest to determine if a similar intensity of exercise (approximately 50% of predicted maximum) would result in contractile fatigue of the quadriceps muscles in healthy elderly subjects. Patients with COPD usually reduce their level of activity because of dyspnea with exertion leading to progressive deconditioning (1). In turn, deconditioning may cause the muscles to fatigue at levels of exertion that would normally be insufficient to induce fatigue.
Even though our patients had moderate to severe COPD, 12 of the 19 patients stated that they stopped exercise primarily because of leg discomfort. Interestingly, no difference in the degree of exercise-induced quadriceps fatigue was observed between the patients who stopped exercise primarily because of shortness of breath and the patients who stopped exercise primarily because of leg discomfort. However, many of our patients complained of both shortness of breath and leg discomfort. They then chose the symptom that they felt was most responsible for their stopping exercise, but it is likely that both symptoms played some role in exercise termination. Hamilton and colleagues (21) showed in a large group of subjects (both normal and those with cardiopulmonary disease, including COPD) that 50% of subjects stop exercise because of both leg discomfort and shortness of breath. As mentioned above, we asked our patients to choose only one limiting symptom, which may have influenced our results. Nevertheless, our results suggest that patients who stop exercise because of shortness of breath may still develop contractile fatigue of the quadriceps muscle. Conversely, patients who stop exercise because of leg discomfort will not always develop contractile fatigue of the quadriceps muscle.
In our study, TwQ fell to 75.7 ± 4.8% of the baseline value at 30 min postexercise (p < 0.001). In preliminary studies, we have measured the degree of quadriceps fatigue induced by a similar exercise protocol in young (n = 13) and in elderly (n = 10) healthy subjects (14, 22). TwQ fell to 54.8 ± 4.2% of the baseline value postexercise in the young healthy subjects and to 64.0 ± 6.3% in the elderly healthy subjects. The fall in TwQ postexercise in our patients with COPD was significantly less than that observed in the young healthy subjects (p < 0.005) but not in the older healthy subjects. Thus, the degree of exercise induced quadriceps fatigue was not significantly different between patients with COPD and healthy elderly subjects even though our patients with COPD exercised at significantly lower work loads (53.7 ± 4.1 versus 75.4 ± 6.0 W, p = 0.01), suggesting that the quadriceps muscle is more fatiguable in patients with COPD. Muscle biopsies performed in patients with COPD have shown a reduction in mitochondrial enzyme activities and in the proportion of type 1 fibers in the quadriceps muscle consistent with a reduced oxidative capacity (23). Furthermore, patients with COPD had a significant reduction in quadriceps endurance time compared with control subjects when asked to perform a simple endurance test to exhaustion (24). Given this reduction in oxidative and endurance properties, it is not surprising that the quadriceps muscle appears to be more fatiguable in patients with COPD. Interestingly, the degree of exercise-induced quadriceps fatigue did not correlate with the FEV1, whereas exercise capacity (peak V˙o 2) did. Thus, patients with more severe COPD had greater reductions in exercise capacity, but despite performing less work they developed similar degrees of quadriceps fatigue. As outlined above, these results could be explained by patients with COPD progressively reducing their activity as their disease worsens, leading to greater deconditioning, which in turn increases muscle fatiguability.
Peripheral muscle weakness is commonly observed in patients with COPD (2-4). In our patients, quadriceps MVC was 53.6 ± 5.4 kg and TwQ was 8.4 ± 0.8 kg. These values are lower than those seen in young healthy subjects, but they are not significantly less than those observed in a group of healthy but sedentary elderly men (22). The majority of our patients with COPD had moderate disease, and presumably if we had studied more patients with severe disease, we would have seen greater peripheral muscle weakness (quadriceps strength correlated with FEV1 in our study).
Measurements of quadriceps strength (TwQ and MVC) were strongly correlated with exercise capacity (peak V˙o 2). Similar observations have been made by others (2-4). In contrast, this association was not seen in young and elderly healthy subjects (14, 22). To determine whether there is a causal relationship between quadriceps strength and exercise capacity, it would be useful to strengthen this muscle and see if improvements in muscle strength lead to commensurate improvements in exercise capacity. To date, interventions that have increased muscle mass and strength during an endurance exercise training program such as growth hormone administration (25) or resistance training (26) have not led to additional improvements in exercise capacity beyond that seen with a standard endurance exercise program.
In conclusion, significant contractile fatigue of the quadriceps muscle occurs in patients with COPD after constant work load cycle exercise to the limits of tolerance.
Supported by the American Heart Association Western New York Affiliate.
| 1. | Casaburi, R. 1993. Exercise training in chronic obstructive lung disease. In R. Casaburi and T. L. Petty, editors. Principles and Practice of Pulmonary Rehabilitation. W. B. Saunders, Philadelphia. 204–224. |
| 2. | Gosselink R., Troosters T., Decramer M.Peripheral muscle weakness contributes to exercise limitation in COPD. Am. J. Respir. Crit. Care Med.1531996976980 |
| 3. | Hamilton A. L., Killian K. J., Summers E., Jones N. L.Muscle strength, symptom intensity and exercise capacity in patients with cardiorespiratory disorders. Am. J. Respir. Crit. Care Med.152199520212031 |
| 4. | Bernard S., LeBlanc P., Whittom F., Carrier G., Jobin J., Belleau R., Maltais F.Peripheral muscle weakness in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med.1581998629634 |
| 5. | Killian K. J., LeBlanc P., Martin D. H., Summers E., Jones N. L., Campbell E. J. M.Exercise capacity and ventilatory, circulatory, and symptom limitation in patients with chronic airflow limitation. Am. Rev. Respir. Dis.1461992935940 |
| 6. | Polkey M. I., Kyroussis D., Hamnegard C. H., Mills G. H., Green M., Moxham J.Quadriceps strength and fatigue assessed by magnetic stimulation of the femoral nerve in man. Muscle Nerve191996549555 |
| 7. | American Thoracic SocietyStandardization of spirometry: 1994 update. Am. J. Respir. Crit. Care Med.152199511071136 |
| 8. | Crapo R. O., Morris A. H., Gardner R. M.Reference spirometric values using techniques and equipment that meets ATS recommendations. Am. Rev. Respir. Dis.1231981659664 |
| 9. | Crapo R. O., Morris A. H.Standardized single breath normal values for carbon monoxide diffusing capacity. Am. Rev. Respir. Dis.1231981185189 |
| 10. | Crapo R. O., Morris A. H., Clayton P. D., Nixon C. R.Lung volumes in healthy nonsmoking adults. Bull. Eur. Physiopathol. Respir.181982419425 |
| 11. | Kory R. C., Callahan R., Borsen H. G., Syner J. C.The Veterans Administration-Army cooperative study of pulmonary function: I. Clinical spirometry in normal men. Am. J. Med.301961243258 |
| 12. | Bellemare F., Bigland-Ritchie B.Central components of diaphragmatic fatigue assessed by phrenic nerve stimulation. J. Appl. Physiol.62198713071316 |
| 13. | Mador M. J., Dahuja M.Mechanisms for diaphragmatic fatigue following high intensity leg exercise. Am. J. Respir. Crit. Care Med.154199614841489 |
| 14. | Mador M. J., Kufel T. J., Pineda L.Quadriceps fatigue following cycle exercise to exhaustion (abstract). Am. J. Respir. Crit. Care Med.1571998A96 |
| 15. | Kufel T. J., Pineda L., Mador M. J.Comparison of potentiated and unpotentiated twitches as an index of contracile fatigue (abstract). Am. J. Respir. Crit. Care Med.1571998A215 |
| 16. | Mador M. J., Rodis A., Magalang U. J., Ameen K.Comparison of cervical magnetic and transcutaneous phrenic nerve stimulation before and after threshold loading. Am. J. Respir. Crit. Care Med.1541996448453 |
| 17. | Mador M. J., Rodis A., Diaz J.Diaphragmatic fatigue following voluntary hyperpnea. Am. J. Respir. Crit. Care Med.15419966367 |
| 18. | Mador M. J., Magalang U. J., Kufel T. J.Twitch potentiation following voluntary diaphragmatic contraction. Am. J. Respir. Crit. Care Med.1491994739743 |
| 19. | Vollestad N. K., Sejersted O. M., Bahr R., Woods J. J., Bigland-Ritchie B.Motor drive and metabolic responses during repeated submaximal contractions in humans. J. Appl. Physiol.64198814211427 |
| 20. | Edwards R. H. T., Hill D. K., Jones D. A., Merton P. A.Fatigue of long duration in human skeletal muscle after exercise. J. Physiol. (Lond.)2721977769778 |
| 21. | Hamilton A. L., Killian K. J., Summers E., Jones N. L.Symptom intensity and subjective limitation to exercise in patients with cardiorespiratory disorders. Chest110199612551263 |
| 22. | Pineda L. A., Kufel T. J., Mador M. J.Quadriceps fatigue following exhaustive cycle exercise in the healthy elderly (abstract). Am. J. Respir. Crit. Care Med.1591999A411 |
| 23. | Maltais F., Simard A. A., Simard C., Jobin J., Desgagnes P., Leblanc P.Oxidative capacity of the skeletal muscle and lactic acid kinetics during exercise in normal subjects and in patients with COPD. Am. J. Respir. Crit. Care Med.1531996288293 |
| 24. | Serres I., Gautlier V., Varray A., Prefaut C.Impaired skeletal muscle endurance related to physical inactivity and altered lung function in COPD patients. Chest1131998900905 |
| 25. | Casaburi R., Carithers E., Tosolini J., Phillips J., Bhasin S.Randomized placebo controlled trial of growth hormone in severe COPD patients undergoing endurance exercise training (abstract). Am. J. Respir. Crit. Care Med.1551997A498 |
| 26. | Bernard, S., F. Whittom, P. LeBlanc., J. Jobin, R. Belleau, C. Berube, G. Carrier, and F. Maltais. 1999. Aerobic and strength training in patients with chronic obstructive pulmonary disease (abstract). Am. J. Respir. Crit. Care Med. 159:A257:896–901. |
