Impairment of ventilatory function represents the main limiting factor for exercise, for most patients with chronic obstructive pulmonary disease (COPD). However, it has now been well established that other extrapulmonary factors participate in the peripheral functional limitation among these patients (26). Peripheral muscle dysfunction syndrome seems to be shown structurally by the reduction of mass and functionally by the reduction of muscle strength, power, and endurance (4,9,28).
On the other hand, recent studies have advocated that physical inactivity is a determining factor for low muscle performance, through mechanisms of predominant atrophy of the locomotor muscles (31,32). This assertive makes it possible to suggest that there is a direct relationship between peripheral muscle structure and function, thereby contradicting the theory that COPD is a disease with systemic manifestation.
However, it is still uncertain whether muscle function (strength, endurance, and maximal aerobic capacity) is proportional to muscle mass (MM) in patients with COPD. The main hypothesis of our study was that lower-limb strength in patients with COPD would depend on MM, whereas the endurance and aerobic capacity properties would be related to intrinsic muscle abnormalities. This assumption is important because it suggests that by restoring MM, muscle strength should become normalized and also that strategies other than MM gain should be considered to achieve improvement of exercise tolerance among patients with COPD.
Within this context, this study aimed to investigate the relationships between peripheral muscle structure (mass) and function (strength, endurance, and maximal aerobic capacity), involving patients with moderate to severe COPD, with remnant MM and with muscle depletion, in comparison with healthy sedentary controls of the same age.
Experimental Approach to the Problem
This was a cross-sectional study involving patients with COPD and healthy control subjects. The protocol consisted of 3 visits (Figure 1). During the first visit, the subjects underwent pulmonary function evaluation and maximal cardiopulmonary exercise testing. On a separate day (48 hours later), each patient underwent anthropometric and body composition evaluations, and, subsequently, the subjects performed the peripheral muscle function evaluation by means of the isokinetic test. Forty-eight hours after the second visit, the same procedure of peripheral muscle function evaluation was performed again. The patients were asked to continue to take their usual medication while this study was being conducted. All visits took place at the same time of the day, for all subjects.
Thirty-nine sedentary patients (31 men) with clinically and functionally diagnosed COPD (21) and 17 healthy sedentary individuals (14 men) were evaluated, matched by age and gender. The patients were screened at an outpatient follow-up clinic. The inclusion criteria were as follows: clinical diagnosis of COPD (forced expiratory volume in the first second/forced vital capacity [FEV1/FVC] < 70%) (21) and dyspnea (dyspnea score of I-III on the Medical Research Council scale) (11), with stable disease (no modifications to the medication over the preceding 6 weeks). The exclusion criteria were as follows: presence of ischemic cardiac disease, recent surgery, chronic consumptive diseases, neuromuscular diseases, and locomotion problems that placed limits on exercise tests and participation in pulmonary rehabilitation programs. Patients who presented significant hypoxemia at rest or during exercise (PaO2 ≤ 55 mm Hg and SpO2 ≤ 88%) in a previous test were also excluded. The control group of healthy individuals was matched for age and gender and was formed by nonsmoking individuals who had not had any regular physical activity for at least 1 year. The institutional research ethics committee approved the study, and all participants were informed of the experimental risks and signed an informed consent before the investigation.
Pulmonary Function Tests
Spirometry was performed before and after administering a bronchodilator (400 μg of salbutamol), using the CPF-S® system (Medical Graphics Corporation [MGC], St. Paul, MO, USA). For this study, only the values obtained after using the bronchodilator were considered. At least 3 acceptable and reproducible forced expiratory maneuvers were obtained in accordance with the American Thoracic Society criteria (27). The FVC, FEV1, and the FEV1/FVC ratio were recorded and expressed as percentages of the expected values. Maximum voluntary ventilation (MVV) was estimated by multiplying FEV1 by 37.5. In this study, the predictions for the Brazilian population were used, as suggested by Pereira et al. (22). Full body plethysmography was performed using the 1085 ELITE D® system (MGC) to obtain static pulmonary volumes (residual volume [RV] and total lung capacity) (30) and the lung diffusion capacity (DLCO), in accordance with the standardized technique recommendations (1). These were evaluated by measuring the transference of carbon monoxide through the pulmonary alveolus-capillary membrane, by means of the same system, using the modified Krogh technique (a single breath of 0.3% CO, 10% He and 21% O2, with the balance composed of N2, sustained for 10 seconds). The reference values used for both measurements (static pulmonary volumes and DCO) were obtained from a healthy Brazilian population sample Neder et al. (17,18). An arterial blood sample was obtained from the radial artery under conditions of resting for at least 10 minutes and was subsequently evaluated using the ABL 330™ gas analysis apparatus (Radiometer, Copenhagen, Denmark).
Anthropometry and Body Composition
The anthropometric evaluation consisted of measuring weights and heights. Body weight was measured using a Filizola™ mechanical anthropometric scale, of capacity 150 kg and with divisions every 100 g. Weights were measured to the nearest 0.1 kg and were expressed in kilograms (13). Height was measured using a fixed stadiometer (Saany, São Bernardo do Campo, Brazil), after deep inspiration, while maintaining an upright position with feet parallel and body weight distributed between them. From these measurements, the body mass index (BMI, i.e., weight divided by height squared, in kg·m−2) was calculated. In addition, to classify the nutritional state as depleted or nondepleted, the gold standard of dual-energy x-ray absorptiometry (DEXA; Hologic QDR—4500A™) was also used. This is a clinically validated method for assessing whole-body composition and bone mineral loss in patients with COPD that enables separation between mineralized tissue (bone), fat body mass and lean body mass (LBM) (10). The LBM index (LBMI) uses the ratio between the LBM (in kilograms) and height squared (in meters) to categorize COPD subgroups with and without muscle depletion. Muscle depletion was defined as LBMI <16 (kg·m−2) for men and <15 (kg·m−2) for women, respectively (24).
Peripheral Muscle Function
The strength of the knee extensor muscles (femoral quadriceps) on the dominant side was evaluated by means of an isokinetic dynamometer (CON-TREX™, CH-8046, Zurich, Switzerland), coupled to a microprocessor that was calibrated to obtain the torque generated from previously determined angles. Before each measurement, the torque was corrected for limb weight against gravity, and the lever arm was positioned. After a warm-up exercise (gentle walking), the patient was positioned in a seated position with the trunk and limbs aligned at standard angles in the equipment. The maximal knee extension strength was obtained and recorded as the angular peak torque (PT; N·m). This was generated through 5 maximal contractions, repeated at an angular velocity of 60°·s−1. After 5 minutes of resting, the isometric torque (IT) was obtained against the lever arm of the dynamometer, fixed at a 60° angle, with maximum voluntary contraction sustained for 5 seconds. After a recovery period of 5 minutes, the muscle endurance of the knee extensors was obtained by measurement of total work (TW; Joules) achieved during a series of 30 consecutive repetitions, at an angular velocity of 300°·s−1. All strength (PT and IT) and endurance (TW) measurements were obtained bilaterally and were also repeated on another subsequent day. The highest values from all of the tests were taken for the analyses. The reference values for the Brazilian adult population were those established by Neder et al. (19).
Maximal Cardiopulmonary Exercise Test
The rapidly incrementing maximal cardiopulmonary exercise test was performed on cycle ergometers (CPE 2000®, MGC), and the data were directed to the CardiO2 System® (MGC). All the procedures for this test were performed in accordance with the American Thoracic Society and American College of Chest Physicians statement (2).
The incremental rates varied from 5 to 15 W·min−1 to reach a duration of between 8 and 12 minutes. The patients were asked to pedal at a frequency of 60 ± 5 rpm during the entire test, up to their maximum tolerance limit, with standard verbal encouragement given every minute. During the test, the following were obtained: metabolic variables: oxygen consumption (V̇O2, ml·min−1), carbon dioxide production (V̇CO2; ml·min−1) and respiratory exchange ratio; ventilatory variables: minute ventilation, respiratory frequency, ventilatory equivalents for O2 and CO2 (V̇E/V̇O2 and V̇E/V̇CO2) and V̇E/MVV ratio; cardiovascular variables: 12-derivation electrocardiogram, resting heart rate and arterial pressure; and gas exchange variables: peripheral oxygen saturation with pulse oximetry. Perception of dyspnea and fatigue in the lower limbs were evaluated at rest, at 1-minute intervals and at the exercise peak by means of Borg's modified scale (5). Ventilatory limitation was deemed to be present if the V̇E exercise peak values were ≥80% of the MVV estimate. The values obtained were compared with those proposed by Neder et al. based on healthy sedentary individuals among the Brazilian population (20) .
The sample size (n = 39) was calculated with a type 1 error of 0.05 and a power of 0.9 to detect a difference in the LBMI of 3.0 kg·m−2 between depleted and nondepleted patients with COPD (23,29). Considering the population with COPD, it is known that the prevalence of nutritional depletion is about 30% (24). In our study, the prevalence of depleted patients was 28%, that is, 11 of 39 patients.
The data collected were analyzed using a specific statistical analysis program (SPSS—Statistical Package for the Social Sciences™, version 13.0). The independent variables analyzed for muscle function were PT, IT, and TW; and for aerobic capacity V̇O2peak was evaluated. The MM of limbs, determined by DEXA, was selected as the dependent variable. The variables were expressed as means and SDs. One-way analysis of variance was used for comparisons between the 3 groups: control, COPD without muscle depletion and COPD with muscle depletion, with a post hoc difference identification test (Tukey). Student's t test was used to compare the mean values of different variables between patients and controls. Pearson's correlation was used to evaluate the degree of association between continuous variables. The probability for type I error was set at 5% for all tests (p ≤ 0.05).
There were no age differences between the groups. In relation to body composition, the body weight, BMI, and total and segmental LBMI were lower among the patients with COPD than in the control group (p ≤ 0.05; Table 1). Additionally, of the 39 patients evaluated, only 11 presented nutritional depletion, whereas no healthy individuals from the control group presented this characteristic.
As expected, all the patients presented airway obstruction of moderate to severe degree (states II and III) (21) and all the individuals in the control group presented spirometry values within normal limits and superior to those found among the patients (Table 2). Evidence of pulmonary hyperinflation and reduced pulmonary diffusion capacity was observed in the patient group and, more notably, among the patients with COPD and muscle depletion, compared with the controls. Although no patient presented hypoxemia at rest, the mean PaO2 values were significantly lower among the patients with COPD than among the controls (Table 2).
The absolute values for all the functional muscle attributes were lower among the patients with COPD than in the control group. As expected, the patients with COPD and peripheral muscle depletion presented greater functional impairment than did the patients without depletion, thereby indicating greater severity of the disease. The whole group of patients with COPD and, more notably, the subgroup of patients with depletion showed more limited maximal exercise capacity than did the healthy sedentary controls (Table 2).
Relationship between Peripheral Muscle Structure and Function
The association found between the isokinetic strength of the right leg (represented by PT) and the lean body mass of this segment (N·m·kg−1) in the subgroup of patients with COPD without depletion and in the control group was significant and of the same magnitude in these 2 groups (r2 = 0.36 with p = 0.01 and r2 = 0.32 with p = 0.01, respectively, Figure 2). The subgroup of patients with COPD with depletion had only a tendency toward this association (r2 = 0.29 with p = 0.07). Only the regression line slope of the subgroup of patients with depletion presented a difference in relation to the slope of the control group. Although both patient subgroups presented equal intercepts for this linear regression, the subgroup with depletion presented a slope that was slightly less than that for the subgroup without depletion (Figure 2). In mean values, the isokinetic strength correction for the MM of the right leg in the groups with and without depletion and the controls corresponded to 13.3 ± 3.4, 14.8 ± 2.8, and 15.8 ± 2.7 N·m·kg−1, respectively (p > 0.05).
Figure 3 shows that the isometric strength presented a high correlation with lean body mass in the right lower limb (N·kg−1) in the subgroups of patients with COPD with and without depletion (r2 = 0.50 with p = 0.01 and r2 = 0.53 with p = 0.01, respectively). In the control group, there was only a tendency toward this association (r2 = 0.18 with p = 0.09). The mean values ± SDs of the isometric strength correction for MM were identical for the groups with and without depletion and the controls (16.8 ± 3.3; 17.5 ± 3.2; and 17.5 ± 3.3 N·kg−1, respectively; p > 0.05), although the regression line slope was greater in the subgroups of patients with COPD than in the control group (Figure 3).
Figure 4 shows that there was a significant association between local endurance, represented by the TW of the femoral quadriceps, and the lean body mass of the right lower limb (kJ·kg−1), in the group of patients without depletion and the controls (r2 = 0.32 with p = 0.01 and r2 = 0.22 with p = 0.05, respectively). This association was not observed in the subgroup of patients with muscle depletion. Although the subgroup of patients without depletion presented lower intercept than shown by the controls, this difference was not maintained after correcting the endurance for the MM (207.1 ± 61.0 vs. 210.9 ± 45.8 kJ·kg−1, respectively; p > 0.05). The correction of this function for the MM was shown to be significantly less among the patients with muscle depletion, in comparison with the group without depletion and the controls (157.5 ± 44 vs. 207.1 ± 61.0 with p < 0.01; and 157.5 ± 44 vs. 210.9 ± 45.8 with p < 0.01, kJ·kg−1, respectively).
The relationship between maximal aerobic capacity, represented by the peak oxygen consumption, and the total lean body mass of the lower limbs (ml·min·kg−1) was found only in the control group (r2 = 0.54 with p = 0.01). However, no relationship was observed in either of the patient subgroups (Figure 5). When this function was corrected for the lean body mass of the lower limbs (ml·min·kg−1), both patient subgroups (with and without depletion) presented lower peak oxygen consumption for a given MM, compared with the control group (19.1 ± 3.7 and 21.8 ± 4.9 vs. 28.5 ± 4.2 ml·min·kg−1, respectively; p < 0.01 for the difference between the 2 patient subgroups and the control group).
This study evaluated the relationship between muscle structure and function among patients with COPD with and without muscle depletion and in healthy controls. The main finding from this study involving patients with COPD and muscle depletion is that the muscle strength was greatly associated with MM. These results point toward a direct interaction between muscle atrophy and weakness in this population. On the other hand, no association was observed in this patient subgroup between local endurance and segmental MM, or between peak oxygen consumption and total body MM. These results suggest that other determinants (independent of mass) contribute toward lower muscle endurance and lower maximal exercise capacity among patients with COPD and muscle depletion. In patients with COPD with preserved MM and healthy controls, strength, and endurance of quadriceps femoris were significantly related to segmental MM. However, only the control group presented an association between maximal aerobic capacity and total body mass.
In comparison with healthy individuals, all patients presented mass and muscle strength reductions (Table 2), along with a notable association between these attributes (Figures 2 and 3). However, patients with COPD and muscle depletion presented greater impairment of peripheral muscle strength. Although with the same intercept, patients with muscle depletion presented greater slope for the line of this relationship, in comparison with patients with preserved MM. These findings indicate that larger variations in mass are needed to trigger a given change in strength. Our findings are similar to those of Franssem et al. (12) in which patients with muscle depletion presented marked reductions in peripheral muscle strength. Bernard et al. (4) observed a direct relationship between atrophy and weakness, particularly in the muscles of the lower limbs of patients with COPD, suggesting that underuse because of chronic inactivity was the determining factor for this syndrome. However, the reduction in strength was not maintained after correction according to the cross-sectional area of the femoral quadriceps. In the same way, in our study, when we made strength corrections for segmental MM, we found identical mean values for all the groups: patients with depletion and without depletion and healthy controls. These findings give consistency to a previous study that found the “mass-dependent” aspect is more relevant for strength determination in patients with COPD and muscle depletion than with preserved MM (16).
Recently, despite different methods for MM estimation, Vilaro et al. (29) showed similar results regarding strength properties in a modest sample of patients with COPD.
This finding indicates that sedentarism is the main element triggering muscle weakness in COPD, through muscle atrophy. This hypothesis seems plausible, firstly because muscle weakness frequently precedes cachexia. In 2 studies evaluating quadriceps performance in COPD patients, weakness was present in two-thirds of the sample, with one-third being judged as muscle depletion according to bioimpedance (12,14). Secondly, muscle weakness in COPD shows a regional distribution once upper limbs and trunk muscle function remain preserved. Thirdly, in the study of Crul et al., it was observed that muscle weakness was unrelated to cytokine expression (7). These aspects go against the notion of a multifactorial systemic cause.
On the other hand, the “mass-dependent” aspect did not seem to be the main determinant of the muscle endurance attribute in patients with COPD and with muscle depletion. In our study, the patients showed a notable reduction in quadriceps muscle endurance in comparison with the controls. Therefore, in patients with muscle depletion, the endurance remained impaired despite the correction for the MM.
Nonetheless, there are many controversies regarding the main mechanisms (local or systemic) involved in the impairment of muscle endurance in these patients. Serres et al. were the first to show that the impairment of quadriceps endurance was associated with physical inactivity and with the degree of pulmonary obstruction (25). Coronell et al. (6) showed that quadriceps endurance was impaired, independent of the physical activity level, even among patients with mild-moderate pulmonary obstruction. Contrasting with these studies, Degens et al. observed that patients with COPD with preserved MM and normal physical activity level showed strength, fatigue and contractile properties of quadriceps similar to healthy controls (8). Only the study of Vilaro et al. (29) analyzed this relationship in subgroups of COPD patients with remaining or depleted MM. However, these authors showed that local muscle endurance remained impaired to the same degree in both patient subgroups, even when this muscle function was normalized with regard to MM. It is worthwhile mentioning that, in the study of Vilaro et al. (29), the sample was notably small in each patient subgroup, and the categorization method for muscle depletion was different from the gold standard used in our study. On the other hand, our results showed that among the patients with muscle depletion, the adjustment of the endurance to the local MM was not capable of normalizing this relation. Because muscle endurance is related to the susceptibility to fatigue, it is translated by failure during localized exercise. The higher quadriceps fatigue observed among the patients with COPD could be partially attributed to the reduction in MM, although it was more likely to be related to the systemic manifestation of the disease, such as low capillarity, bioenergetic abnormalities, and intrinsic disorders of muscle contractibility in the lower limbs.
This study also aimed to analyze whether the MM of the lower limbs determines the maximal aerobic capacity of patients with COPD, taking the nutritional state into consideration. For this analysis, the total MM of the lower limbs was considered because lower limb activity is more involved during maximal cycle ergometer test, which was used to assess aerobic capacity. In this regard, although only the control group has presented a significant relationship with these attributes, both subgroups of patients showed reductions in maximal aerobic capacity, particularly the subgroup of patients with muscle depletion, in comparison with the control group, independent of the correction for the mass of the lower limbs. In the same way, Kobayashi et al. (15) did not find this association among patients with COPD of greater severity. On the other hand, Baarend et al. (3) showed an association between maximal aerobic capacity and the MM index among patients with muscle depletion and abnormal pulmonary diffusion.
The lack of association between the MM of the lower limbs and the maximal aerobic capacity of the patients evaluated in our study suggests that leg mass does not constitute a significant predictor of peak V̇O2 in this population, thereby configuring a “mass-independent” aspect. This observation can be explained in terms of susceptibility of the relationship between MM and V̇O2 to distortion in patients with COPD, considering that the ventilatory limitation to maximal exercise (lower V̇O2max because of nonperipheral or cardiovascular factors) may have underestimated the muscle aerobic function in these patients, that is, lower V̇O2max for a given mass.
The main limitation of this study may be because peripheral muscle function measurements were made using volitional methods. This may have allowed the degree of quadriceps muscle activation to be submaximal during the maneuvers. However, this can be minimized through prior familiarization of the study subjects to the maneuvers, through standardized instructions before and during the tests and through the examiner's experience.
It has been well established that rehabilitation strategies such as ergogenic and nutritional interventions, neuromuscular electrical stimulation and resistance exercise therapy increase MM among patients with COPD, with an impact on muscle strength. However, our study highlights the finding that in patients with COPD, muscle endurance and aerobic capacity are affected to a greater extent than muscle strength is, even in patients with preserved MM. Therefore, within the process of muscle assessment and training, coaches and practitioners should consider approaches that improve cardiorespiratory and muscle fitness in this population.
In conclusion, our results indicate that among patients with moderate-severe COPD, the relationship between muscle structure and function seems to be direct only with regard to the attribute of peripheral muscle strength. Furthermore, this study shows that muscle structure was not related to peripheral muscle endurance functions or maximal aerobic capacity of these patients, especially among those affected by muscle depletion. It can also be suggested that impairment of peripheral muscle endurance is manifested at a greater extension than strength impairment is, and that this is related not only to atrophy because of disuse but also and particularly to other factors relating to COPD.
This research was supported by the National Council for Scientific and Technological Development (Conselho Nacional de Desenvolvimento Científico e Tecnológico, PBIC-CNPq) and Nove de Julho University. The authors declare that they do not have any financial or other potential conflict of interest.
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