American Journal of Respiratory and Critical Care Medicine

When freed from central cardiorespiratory limitations, healthy human skeletal muscle has exhibited a significant metabolic reserve. We studied the existence of this reserve in 10 severely compromised (FEV1 = 0.97 ± SE 0.01) patients with chronic obstructive pulmonary disease (COPD). To manipulate O2 supply and O2 demand in locomotor and respiratory muscles, subjects performed both maximal conventional two-legged cycle ergometry (large muscle mass) and single-leg knee extensor exercise (KE, small muscle mass) while breathing room air (RA), 100% O2, and 79% helium + 21% O2 (HeO2). With each gas mixture, peak ventilation, peak heart rate, and perceived breathlessness were lower in KE than cycle exercise (p < 0.05). Arterial O2 saturation and maximal work capacity increased in both exercise modalities while subjects breathed 100% O2 (work: + 10% bike, + 25% KE, p < 0.05). HeO2 increased maximal work capacity on the cycle ( + 14%, p < 0.05) but had no effect on KE. HeO2 resulted in the greatest maximum minute ventilation in both bike and KE (p < 0.05) but had no effect on arterial O2 saturation. Thus, a skeletal muscle metabolic reserve in these patients with COPD is evidenced by: (1) greater muscle mass specific work in KE; (2) greater work rates with higher fraction of inspired oxygen (Fi O2 ); (3) an even greater effect of Fi O2 during KE (i.e., when the lungs are less challenged); and (4) the positive effect of HeO2 on bicycle work rate. This skeletal muscle metabolic reserve suggests that reduced whole body exercise capacity in COPD is the result of central restraints rather than peripheral skeletal muscle dysfunction, while the beneficial effect of 100% O2 (with no change in maximum ventilation) suggests that the respiratory system is not the sole constraint to oxygen consumption.

Mounting evidence suggests that a deficit in skeletal muscle metabolism may accompany the prominent lung pathology of chronic obstructive pulmonary disease (COPD) (1-3). Understanding the contribution of skeletal muscle dysfunction in COPD is important not only because of its effect on the general functional state of patients both before and after lung transplant (4), but because such a myopathy may also manifest itself in the respiratory muscles, thereby compounding respiratory problems (5).

Single-leg knee extensor exercise allows the opportunity to study skeletal muscle in a functionally “isolated” situation, where central cardiorespiratory limitations have less influence on muscle function (6). In such a scenario normal healthy subjects have previously demonstrated twice the maximum mitochondrial metabolic rate recorded than when central limitations were a dominant factor (7, 8). This can be interpreted as evidence of a large skeletal muscle metabolic capacity, not usually taxed during whole body exercise. This reserve is also evident when skeletal muscle maximum oxygen consumption (V˙o 2max) increases due to increased O2 delivery while breathing 100% O2 (7). Additionally, it has previously been demonstrated that in healthy subjects a reduction in the work of breathing allows a greater leg muscle blood flow at maximal cycle exercise, affording the potential to perform more work if a metabolic reserve exists (9).

The existence of a skeletal muscle metabolic reserve in patients with COPD during whole body exercise has never been documented. Such evidence would cast doubt on the role of skeletal muscle dysfunction in the reduced exercise capacity documented in this population. To determine the existence of a skeletal muscle metabolic reserve in patients with severe COPD, patients performed both maximal conventional cycle ergometry (large muscle mass: function constrained by central cardiorespiratory limits) and single-leg knee extensor exercise (small muscle mass: functionally free from cardiorespiratory limits) while breathing room air (RA), 100% O2 (increased O2 availability), and 79% helium + 21% O2 (HeO2) (reduced work of breathing: increased muscle blood flow). Specifically, we hypothesized that if a skeletal muscle metabolic reserve exists: (1) in comparison to cycle exercise the maximum muscle mass–specific knee extensor work will be greater (unrestrained by central limits, muscle will perform more work); (2) in comparison to air breathing, maximal cycle exercise work rate in the patients with COPD would be increased by breathing both 100% O2 (due to a maintenance/elevation of arterial O2 saturation) and HeO2 (increased ventilation with increased O2 saturation and reduced cost of ventilation, leading to a redistribution of blood from the respiratory muscles to working skeletal muscles); and (3) in comparison to air breathing, maximum knee extensor work rate would be enhanced by breathing 100% O2 (by maintenance/elevation of arterial saturation), but would be unaffected by the HeO2 (a maximally perfused small muscle mass cannot benefit from redistributing respiratory muscle perfusion).


Ten patients with well established and long-standing COPD (six females and four males) were recruited from previous participants in the University of California San Diego (UCSD) Pulmonary Rehabilitation Program. Subjects were selected based on a significantly reduced FEV1 (0.97 ± SE 0.01; 40 ± 3.8% predicted), but were not currently using supplemental oxygen. One subject was a current cigarette smoker. During initial contacts, a healthy history and informed consent were obtained according to the requirements of the University of California, San Diego Human Subjects Committee, which approved the study. The physical characteristics of the subjects were as follows (average ± SE): age, 64.7 ± 2.3 yr; height, 170.5 ± 2.6 cm; weight, 66.3 ± 4.1 kg (Table 1).


SexCorticosteroidsAge (yr)Height (cm)Weight (kg)FEV1(L/s)Predicted FEV1(L/s)% Predicted FEV1

Exercise Protocols

All subjects were already experienced with bicycle exercise and exercise testing through participation in and completion of the UCSD Pulmonary Rehabilitation Program. All subjects were physically active, but none exercised for more than 1 h/d. Each subject was familiarized with the dynamic knee extensor ergometer prior to testing. Subjects performed three graded maximal exercise tests on both the bicycle ergometer (Quinton Instruments Co., Holland) (electronically braked) and the dynamic knee extensor apparatus (modified Monark ergometer, Sweden) while breathing RA, 100% O2, or HeO2 (a total of six exercise tests per person). The protocol for each subject was customized to achieve a maximum effort in 8–12 min. This equated to approximately 5-watt (W) increments/min on the bicycle ergometer and 2-W increments on the knee extensor ergometer. The three tests on a single ergometer were performed in 1 d with at least 1 h between tests, utilizing a balanced order design to avoid ordering effects. There was a period of at least 72 h between the two testing days. Subjects were blinded to the gas breathed and were instructed not to talk during or for 2 min after the cessation of exercise because of the change in the tonal quality of the voice with helium. The two test days were separated by a minimum of 48 h.

Knee Extensor Ergometer

We utilized a single-leg knee extensor ergometer similar to those reported previously (6, 10, 11). Active contractions of the quadriceps femoris muscle group alone caused the lower part of the leg to extend from approximately 90 to 170 degrees flexion. Force tracings (6), electromyogram (EMG) and T2-weighted magnetic resonance imaging (MRI) (12) have previously indicated that active contraction is limited to the 2.0–2.5 kg of the quadricep muscles during this exercise.

Ventilation and Gas Exchange

Throughout maximal tests subjects breathed through a low-resistance two-way breathing valve (Hans-Rudolph 2700, Kansas City, MO) and the nose was sealed by a nose clip. Expired gas passed into a 7.2-L heated low resistance mixing chamber and was continuously sampled from a multiport manifold by a Beckman (Anaheim, CA) OM11 oxygen analyzer and Beckman LB-2 carbon dioxide analyzer in series (total inflow rate, 300 ml/min). Expired gas flow was measured by a Fleisch pneumotachograph no. 3 (Hans-Rudolph). External airway resistance, measured from the mouth to the distal side of the pneumotachograph, was 1–1.5 cm water/L/s at the highest flow rates (breathing room air) achieved in these experiments and was similar to previous studies (9, 13). This value fell to less than 1 cm water/L/s with helium as the major gas. Electrical signals from the gas analyzers and pneumotachograph were logged at 100 Hz by use of a 12-bit analog-to-digital converter for a determination of minute ventilation (V˙e, btps) and gas exchange (oxygen consumption [V˙o 2], and carbon dioxide production [Vco 2], stpd) by a commercially available software package (Consentius Technologies, Salt Lake, UT). In hyperoxia, the technical limitations of measuring ventilatory O2 exchange at very high Fi O2 precluded collection of gas exchange data (14).

Statistical Analyses

Repeated measures analysis of variance were utilized with a Tukey Post Hoc (Instat, San Diego, CA). Variables were considered significantly different when the p value was 0.05 or less. One subject completed the bicycle test but not the knee extensor studies; therefore, n = 10 for the former test and n = 9 for the latter. Throughout this manuscript we report data as mean ± standard error (SE).

All but one female subject completed all exercise trials on both the cycle ergometer and the knee extensor ergometer. This subject retired from the study after completing the three cycle trials due to an orthopedic condition.

Two-legged Cycle Exercise

During cycle exercise peak work rates were significantly elevated while breathing both 100% O2 and HeO2 in comparison to RA (p < 0.05) (Table 2). HeO2 breathing significantly elevated pulmonary V˙o 2max, but not %O2 saturation (Table 2). Breathing 100% O2 significantly raised arterial O2 saturation above the arterial O2 saturation recorded during exercise breathing air and HeO2 (p < 0.05) (Table 2). When subjects breathed HeO2, pulmonary ventilation was significantly elevated in comparison to 100% O2 and to air (p < 0.05) (Table 2). Perceived muscle fatigue at peak work rate indicated a high intensity of effort, 4 to 5 (“severe”) on a Borg scale (0 to 10), but there was no difference across the gases breathed (Table 2). Perceived breathlessness at maximal work rate received a score of 4 on the cycle and was unaltered by the gas breathed (Table 2). It is interesting to also note that despite significantly affected maximal work rates in HeO2 and O2, maximal heart rate was unaffected, suggesting perhaps that cardiac output was maximal in these patients during each cycle test.


Two-legged CycleOne-legged Knee Extensor
Inspired Gas Mixture21% O279% N2 100% O2 21% O279% He21% O279% N2 100% O2 21% O279% He
Peak work rate, watts58 ± 465 ± 4* 67 ± 5* 16 ± 2   20 ± 2* 16 ± 2
Pulmonary V˙ o 2 peak, L/min1.23 ± 0.081.45 ± 0.04* 0.81 ± 0.05 0.93 ± 0.07
Ventilation, L/min 35 ± 1.434 ± 1.445 ± 3* 28 ± 1 26.7 ± 2 33.4 ± 3*,
Arterial O2 saturation, %93 ± 199 ± 0.2* 94 ± 0.695 ± 0.4    99 ± 0.2* 95 ± 0.5
Peak heart rate, beats/min134 ± 5132 ± 4135 ± 5110 ± 6  107 ± 5 109 ± 6
Perceived breathlessness3.7 ± 0.33.9 ± 0.14.0 ± 0.42.4 ± 0.5   2.7 ± 0.5 2.7 ± 0.6
Perceived muscle fatigue4.0 ± 0.44.3 ± 0.44.1 ± 0.54.2 ± 0.6 4.3 ± 0.24.6 ± 0.4

*Significantly different (p < 0.05) from other data collected with different gases during the same exercise modality.

Significantly different (p < 0.05) from two-legged cycling.

Knee Extensor Exercise

Peak work rate was elevated only while breathing 100% O2 in comparison to breathing air; HeO2 had no effect on peak work rate (p < 0.05) (Table 2). HeO2 breathing did not alter pulmonary V˙o 2max during knee extensor exercise (Table 1). Breathing 100% O2 significantly raised arterial O2 saturation above the arterial O2 saturation recorded during exercise breathing air and HeO2 (p < 0.05) (Table 2). Perceived muscle fatigue at peak work rate indicated a high intensity of effort, i.e., 4 to 5 (“severe”) on a Borg scale (0 to 10), but there was no difference across the gases breathed (Table 2). Perceived breathlessness at maximal exercise received a score of 4 (Table 2).

Cycle Exercise versus Knee Extensor Exercise

Estimated mass-specific work rates at maximal knee extensor exercise (8 W/kg) was greater than during cycle exercise (3.6 W/kg). Peak work rate while breathing 100% O2 was elevated to a greater extent during knee extensor exercise than during bicycle exercise (p < 0.05) (Table 2). While HeO2 had no effect on peak work rate during knee extensor exercise, it significantly increased peak work rate during bicycle exercise (p < 0.05) (Table 2). As anticipated, subjects demonstrated a significantly lower heart rate, pulmonary ventilation, and perceived breathlessness during maximal knee extensor exercise when compared to maximal cycle ergometry (p < 0.05) (Table 2). In fact, the maximum ventilation in RA was 20% less during knee extensor exercise than that recorded during cycle exercise, which in this population is equivalent to their maximum voluntary ventilation (MVV), unlike healthy subjects who exhibit a ventilatory reserve (15). Perceived muscle fatigue at peak work rate indicated a high intensity of effort 4 to 5 (“severe”) on a Borg scale (0 to 10), but there was no difference across the exercise modalities (Table 2). Perceived breathlessness at maximal exercise received a score of 4 on the bicycle, but was significantly decreased in knee extensor exercise when compared with bicycle exercise (Table 2).

Iso-work Rate Comparisons

Since different maximal work rates were achieved under certain conditions, it is also important to compare the responses to heavy exercise at the same work rates (Table 3). The two work rates for cycle and knee extensor exercise were selected to represent the highest work rate achieved in all three conditions. Here, too, HeO2 breathing significantly increased pulmonary ventilation (p < 0.05) (Table 3). Oxygen breathing maintained and elevated arterial O2 saturation in both cycle and knee extensor exercise, but also significantly reduced heart rate (p < 0.05) (Table 3) and tended to decrease ventilation during cycle exercise (Table 3). Measurements of perceived breathlessness and muscle fatigue did not document a differential response to the three conditions. However, these and other variables were again significantly different between the two exercise conditions, illustrating the reduced central demand during knee extensor exercise (p < 0.05) (Table 3).


Two-legged CycleOne-legged Knee Extensor
Inspired Gas Mixture21% O279% N2 100% O2 21% O279% He21% O279% N2 100% O2 21% O279% He
Iso-Work Rate, watts* 53 ± 353 ± 353 ± 314 ± 214 ± 214 ± 2
Pulmonary V˙ o 2 peak, L/min1.15 ± 0.061.21 ± 0.080.72 ± 0.06 0.81 ± 0.05
Ventilation, L/min 30 ± 0.8    27 ± 1.9 35 ± 1.9 20.2 ± 1 18.7 ± 1 24.4 ± 1,
Arterial O2 saturation, % 95 ± 0.9 99 ± 0.2  94 ± 0.795 ± 0.699 ± 0.2 95 ± 0.7
Heart rate, beats/min128 ± 7121 ± 5 131 ± 5102 ± 4 98 ± 4 100 ± 4
Perceived breathlessness2.8 ± 0.32.9 ± 0.2 2.9 ± 0.41.5 ± 0.4 1.6 ± 0.4 1.8 ± 0.4
Perceived muscle fatigue3.4 ± 0.63.5 ± 0.33.5 ± 0.42.5 ± 0.33.0 ± 0.43.0 ± 0.3

*Highest work rate achieved in all three conditions.

Significantly different (p < 0.05) from other data collected with different gases during the same exercise modality.

Significantly different (p < 0.05) from two-legged cycling.

The major novel finding of this study is that at maximal exercise there is a significant skeletal muscle metabolic reserve in these patients with COPD, as evidenced by the greater mass-specific work performance during knee extensor exercise, the greater work rates achieved on a cycle ergometer (10%) with higher Fi O2 , and the even greater effect of Fi O2 during knee extensor exercise (25%), when the lungs are less challenged. Additionally, this conclusion is supported by both the positive effect on maximum bicycle work rate of substituting nitrogen with helium in a normoxic gas mixture and the lack of an effect on knee extensor exercise, where alterations in ventilation are less crucial due to the small muscle mass involved. The observation that maximal work rate was increased with 100% O2, which increased arterial O2 saturation from 93–99%, implies that O2 supply plays an important role in limiting maximal work capacity in these patients with COPD. The fact that this is similar to the response in healthy fit subjects supports the concept that the skeletal muscle of patients with COPD may be functioning adequately. Also, these data indicate that the issue is not simply one of inadequate or inappropriate ventilation, since maximum ventilation was unaffected by breathing 100% O2. However, it is important to recognize that breathing 100% O2 tended to reduce submaximal ventilation and heart rate in these subjects (Table 3), which culminated in a greater maximum work rate being achieved with ultimately the same maximal ventilation and maximal heart rate as in RA exercise (Table 2).

Hyperoxia and Exercise Capacity

As V˙o 2 = Q˙ (CaO2 − CvO2), where Q˙ is cardiac output and CaO2 and CvO2 are arterial and venous O2 content, respectively, it can be expected that breathing a hyperoxic gas may raise body V˙o 2max by 5 to 10% in normal fit healthy subjects through an increase in CaO2 (14). This has been experimentally confirmed at the muscular level in normal fit healthy subjects by Knight and coworkers (7), who reported an increase in leg V˙o 2max of 8% and a corresponding 9% increase in maximal work rate due to elevated CaO2 with an unchanged leg blood flow. These data directly support the concept that, in fit healthy subjects, muscle V˙o 2max is limited by O2 supply: When healthy muscle is provided with more O2, it performs more work and presumably utilizes more O2. Thus, there is evidence of a skeletal muscle metabolic reserve in fit healthy subjects at maximal exercise.

Studies of skeletal muscle in patients with COPD have revealed abnormally low levels of type I muscle fibers, citrate synthase, pH, ATP, and creatine phosphate as well increased lactic acid production (1, 2, 5, 16). This suggests that, in this population, there may not be a metabolic reserve at maximal exercise. However, in severe COPD, the most commonly ascribed limit to exercise is dyspnea, often assumed to be reached when minute ventilation during exercise approximates MVV (15). Although this may be the case, it should be recognized that when both perceived breathlessness and muscle fatigue are subjectively assessed, as in the present study (Table 1), both are often scored similarly by the patient. Hence, the usual conclusion that dyspnea alone results in the cessation of exercise may not be entirely correct. In the present study, we found that patients with COPD appeared to exhibit a skeletal muscle metabolic reserve in much the same way as healthy normal people. That is, when breathing 100% O2, which resulted in an elevated arterial saturation during bicycle exercise, these patients were able to achieve a 12% greater maximum work rate (Table 2). Although not measured in this study, it is reasonable to assume a similar increase in V˙o 2max (7).

As knee extensor exercise does not approach the upper limits of cardiac output, this exercise paradigm has previously unveiled a skeletal muscle metabolic reserve in healthy subjects and results in a very high mass-specific V˙o 2 and work rate (6, 8, 17). In fact, as noted above, this exercise modality has revealed maximal mitochondrial respiratory rates twice that observed when skeletal muscle is limited by the cardiorespiratory system (12, 23). A greater appreciation for the difference between bicycle exercise and knee extensor exercise can be achieved if one considers the estimated work rate normalized to the approximate muscle mass recruited in the present study. To illustrate this, if we make a reasonable assumption for this population based on age and sex of about 16 kg of leg muscle (two legs) recruited for bicycle exercise and only about 2.0 kg (quadriceps) recruited in single leg knee extensor exercise (12, 18), the work performed by these muscles normalized to muscle mass would be 3.6 W/kg muscle and 8 W/kg muscle, respectively. It has previously been demonstrated that the mechanical efficiency of knee extensor and cycle exercise are almost identical (10). Thus, this increased skeletal muscle work capacity with knee extensor exercise is, in itself, evidence of a skeletal muscle metabolic reserve that is unlocked during knee extensor exercise due to the small muscle mass, which is no longer competing for a portion of a finite cardiac or ventilatory support. This metabolic reserve has been recognized previously in young healthy subjects (19), but never before in a COPD patient population. As noted, while breathing 100% O2 during maximal knee extensor exercise, these patients were able to reach even greater maximal work rates than in normoxic knee extensor exercise, and the percentage improvement (25%) was significantly greater than that observed during hyperoxic cycle exercise (10%). These observations are again consistent with COPD patients having a skeletal muscle metabolic reserve that becomes apparent when the constraints of the respiratory system become less important during knee extensor exercise and is even more evident when Fi O2 is elevated.

Helium Breathing and Exercise Capacity

Experimentally it has been confirmed that the ventilatory responses to HeO2 breathing during exercise are, in general, the opposite of those seen with resistance or “loading” experiments (13). However, there has been little accord among investigators who have studied the effect of breathing HeO2 on exercise performance. In fact, in normal healthy people, data to support a positive (20), negative (20, 21), and no effect (22, 23) on exercise performance are readily available. Some of this variability may be explained by the issue that HeO2 breathing will not only decrease the internal resistance of the subject, but will have an effect on the internal resistance of the breathing apparatus utilized. In this study, since the indirect open circuit calorimetry system was the same in all cases we are able to report the effects of the HeO2, but not compartmentalize the effect to subject or apparatus.

Due to abnormal breathing mechanics and high ventilatory requirement for a given level of exercise (due to a large “wasted ventilation,” dead space volume/tidal volume), patients with COPD appear to be ideal candidates to benefit from low-density gas breathing during exercise, if they exist. To date, the literature on this subject is somewhat marred by experimental design flaws. Raimondi and coworkers (24) showed no effect of HeO2 on performance or V˙o 2, but utilized such large increments in work rate (17 W) that all but large effects would be masked. Bradley and associates (25) also found no effect on peak V˙o 2, but did not allow an increase in performance to become apparent by restricting subjects to the same work rate in air and HeO2. Martin and colleagues (26) found no effect of HeO2 on peak V˙o 2 or work rate but studied 11 subjects with cystic fibrosis who, as described by FEV1, ranged widely from near normal to severely limited. In contrast, the subjects in the present study were a homogeneous group of patients with severe COPD (FEV1 = 0.97 ± 0.01). Also, in the present study work rates were incremented in small amounts, and no ceiling work rate was set but was determined by volitional cessation of the exercise. With this experimental design, HeO2 breathing in patients with COPD during maximal cycle exercise has, for the first time, demonstrated significantly increased peak work rates and V˙o 2max with no change in arterial O2 saturation but with a large increase in maximum pulmonary ventilation. During knee extensor exercise, however, no effect was recorded other than an increase in maximum pulmonary ventilation.

What mechanism can account for these observations? It is apparent that in these patients HeO2 breathing did not influence arterial saturation. However, during cycle ergometry, blood flow (the other component of oxygen delivery) may have been redistributed from the respiratory muscles due to unweighting of these muscles by HeO2 breathing, allowing an increased O2 delivery to locomotor muscles. Such a redistribution of blood flow from the respiratory muscles to the legs is corroborated by a recent study by Harms and coworkers (9), who determined that, even in normal healthy subjects, respiratory muscle work compromises leg blood flow. In this elegant study, Harms and coworkers (9) found that at maximal exercise the work of breathing caused vasoconstriction within locomotor muscles and compromised locomotor perfusion and V˙o 2. The work of breathing in normal healthy subjects at maximal exercise accounts for approximately 10% of pulmonary V˙o 2 at V˙o 2max (27). In COPD this may be more than doubled (28). Thus, we suggest that in this population, reducing the work performed by the respiratory apparatus may have a profound effect on O2 availability to the locomotor muscles during cycle ergometry.

If the above explanation of the effect of HeO2 is correct, the lack of an effect of HeO2 breathing on knee extensor exercise would be expected. During this mode of small muscle mass exercise, maximum pulmonary ventilation is lower, as is the demand placed upon the respiratory muscles (Table 2), thus reducing the benefits of unweighting these muscles. Additionally, as this mode of exercise has previously been demonstrated to produce some of the highest muscle blood flows recorded in humans, blood flow in these muscles may now be restrained by vascular flow dynamics (i.e., having reached maximal perfusion (8). In this scenario the quadricep muscles would only benefit from increased O2 content, as seen when breathing 100% O2, and not from an increase in flow afforded by reduced respiratory muscle metabolic demand. This is the first evidence suggesting that patients with COPD may be able to recruit their maximal muscle conductance during small muscle mass exercise.

In conclusion, this study provides evidence of a skeletal muscle metabolic reserve in patients with COPD, similar to that seen in fit healthy subjects. This suggests that whole body exercise in these patients is not limited by skeletal muscle function.

The authors with to express their appreciation to the patients who participated in this study.

Supported by funds provided by the National Heart, Lung, and Blood Institute grants HL-17731 and HL-50306.

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Correspondence and requests for reprints should be addressed to Dr. R. S. Richardson, Department of Medicine, 0623, University of California San Diego, La Jolla, CA 92093-0623. E-mail:

Dr. Richardson is a Parker B. Francis Fellow in Pulmonary Research.


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