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(Chest. 2001;119:93-98.)
© 2001 American College of Chest Physicians

Distribution of Muscle Mass and Maximal Exercise Performance in Patients With COPD*

Masanori Yoshikawa, MD; Takahiro Yoneda, MD; Hideaki Takenaka, MD; Atsuhiko Fukuoka, MD; Yukinori Okamoto, MD; Nobuhiro Narita, MD and Kunimoto Nezu, MD, FCCP

* From the Second Department of Internal Medicine (Drs. Yoshikawa, Yoneda, Takenaka, Fukuoka, Okamoto, and Narita) and Department of Surgery III (Dr. Nezu), Nara Medical University, Nara, Japan.

Correspondence to: Masanori Yoshikawa, MD, Second Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, Japan 634-8522


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: To investigate the distribution of reduction in lean body mass (LBM) and whether LBM in legs (LBMlegs) can be a determinant of maximal exercise performance in COPD patients.

Methods: Thirty-eight male outpatients with COPD (mean ± SD FEV1, 47.4 ± 24.0% of predicted) who underwent complete pulmonary function testing were classified into two groups according to FEV1 expressed as a percentage of predicted value. Group A comprised 21 patients with mild-to-moderate airflow limitation (FEV1 >= 35% predicted), and group B comprised 17 patients with severe airflow limitation (FEV1 < 35% predicted). LBM, which represents skeletal muscle mass, was measured by dual energy x-ray absorptiometry (DXA) and was assessed separately in arms, legs, and trunk. Maximal oxygen uptake (O2max) was measured during maximal exercise on a cycle ergometer.

Results: LBM in each region was expressed as a percentage of ideal body weight (IBW). LBM in arms (LBMarms)/IBW, LBMlegs/IBW, and LBM in trunk (LBMtrunk)/IBW were significantly depleted in group B compared with group A (p < 0.01). LBMlegs expressed as a percentage of total LBM (LBMlegs/total LBM) was significantly lower in group B (p < 0.05), although there was no significant difference in LBMarms/total LBM and LBMtrunk/total LBM between the two groups. O2max correlated significantly with LBMlegs/IBW in group A, but not in group B. By stepwise regression analysis, LBMlegs/IBW appeared to be a significant predictor of O2max in group A, while not in group B.

Conclusion: LBMlegs was a significant predictor of maximal exercise performance in patients with mild-to-moderate airflow limitation, but not in patients with severe airflow limitation who had disproportional reduction in LBMlegs.

Key Words: body composition analysis • COPD • distribution of peripheral muscle mass • dual energy x-ray absorptiometry • maximal exercise performance


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Presently, body composition analysis is performed by bioelectrical impedance analysis (BIA)1 2 and dual energy x-ray absorptiometry (DXA)3 4 in patients with COPD. Fat-free mass (FFM) by BIA and lean body mass (LBM) by DXA, which represent muscle mass, were reported to be associated with respiratory muscle strength2 3 and exercise performance.4 5 However, the distribution of muscle wasting has not been clearly elucidated. It would be useful to know the distribution for organization of the optimal training strategy for pulmonary rehabilitation because muscle strength is closely related to muscle mass in patients with COPD,6 as well as in normal subjects.7

Peripheral muscle strength8 9 and oxidative capacity10 11 were found to be related to exercise performance in COPD patients. In contrast, no significant effect of strength training on exercise performance12 13 in COPD patients has been demonstrated. These data suggest that it is still unclear whether peripheral muscle function may determine the exercise performance in all patients with COPD, regardless of the severity.

The purpose of this study is to investigate the distribution of the reduction of LBM by DXA and to analyze the potential relationship between leg muscle mass and maximal exercise performance in COPD patients with various degrees of airflow limitation.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
Thirty-eight ambulatory male patients with COPD were recruited to participate in this study. The criteria for diagnosis of COPD were based on the standards of the American Thoracic Society.14 The entry criteria included the following: (1) clinical diagnosis of COPD; (2) clinically stable condition (no recent infection or cardiac complaints); (3) absence of other pathologic conditions, including neuromuscular, metabolic, and malignant disease; and (4) not receiving oral corticosteroids. All patients had a history of cigarette smoking and evidence of COPD by spirometry.

The patients were classified into two groups on the basis of FEV1 as a percentage of predicted value, using the criteria of the American Thoracic Society statement.14 Group A consisted of 21 patients with mild-to-moderate airflow limitation in stage I or stage II (FEV1 >= 35% predicted). Group B consisted of 17 patients with severe airflow limitation in stage III (FEV1 < 35% predicted).

The experimental protocol was approved by the Committee for Protection of Human Subjects, Nara Medical University, according to the Declaration of Helsinki. All the subjects gave their informed consent prior to the initiation of the study.

Pulmonary Function Tests
All patients underwent pulmonary function testing. Vital capacity (VC), FVC, FEV1, residual volume (RV), total lung capacity (TLC), and maximal voluntary ventilation (MVV) were measured using a pulmonary function instrument with computer processing (FUDAC 70; Fukuda Denshi; Tokyo, Japan), and the FEV1/FVC ratio was calculated. The values obtained were compared to the normal values of Berglund and coworkers.15 Lung volumes were determined by the helium gas dilution method, and diffusing capacity of the lung for carbon monoxide (DLCO) was measured by the single-breath method.

Body Composition Analysis
Body composition was measured by DXA with a total body scanner (Lunar DPX; Lunar Radiation; Madison, WI) that uses a constant-potential x-ray generator and a K-edge filter (cerium) to separate the beam into high-energy and low-energy regions. The attenuated x-rays that passed through the subjects were measured with an energy-discriminating detector. The differential attenuation of the two energies was used to estimate the bone mineral content and soft-tissue mass. Bone mineral content and soft-tissue mass, partitioned into fat mass and LBM, were calculated separately based on the difference in mass attenuation coefficients. DXA makes it possible to analyze each body composition in accurate and reproducible fashion with very low radiation exposure.16 The entire scanning from head to toe was usually completed within 15 min. LBM in subregions, including trunk, arms, and legs, can be determined separately as well as the whole body. LBM in trunk (LBMtrunk), LBM in arms (LBMarms), and LBM in legs (LBMlegs) were normalized for ideal body weight (IBW).17 LBM in each region, expressed as a percentage of total LBM, LBMarms/total LBM, LBMlegs/total LBM, and LBMtrunk/total LBM, was also investigated.

Exercise Performance
All patients underwent maximal exercise tests on a cycle ergometer (STB-1350; Nihon Kohden; Tokyo, Japan). After 3 min of unloaded pedaling, the workload was increased by 10 W/min in a ramp protocol until exhaustion. Gas exchange was monitored during the exercise test with a computerized metabolic cart (Vmax 229; SensorMedics; Yorba Linda, CA). Minute ventilation (E), oxygen uptake, and carbon dioxide output were measured by the breath-by-breath method. Arterial oxygen saturation was also monitored using pulse oximetry (BSM-8500; Nihon Kohden; Tokyo, Japan).

Statistical Analysis
Values obtained were expressed as mean ± SD. The differences among measured parameters in the two groups were determined by unpaired t tests. Pearson’s correlation coefficients among static lung function, LBM, and maximal oxygen uptake (O2max) were calculated. Stepwise multiple regression analysis was performed to determine the best predictors of O2max. LBMlegs/IBW and pulmonary function, which showed significant correlation with O2max, were selected as independent variables in this analysis. The level of statistical significance for each test was set as p < 0.05.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Anthropometric and Pulmonary Function Data
Anthropometric characteristics and pulmonary function data of the two patient groups are described in Table 1 . There was no significant difference in age and height, although the percentage of IBW and body mass index were statistically different between the two groups. VC, FEV1, and MVV in group B were significantly lower than those in group A, while RV/TLC and PaCO2 were significantly higher in group B. DLCO and PaO2 showed no significant difference between the two groups.


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  		Table 1. Anthropometric and Pulmonary Function Data of Patients With COPD*

 
Distribution of LBM
The total LBM and distribution of LBM in the two groups are shown in Table 2 . Absolute values of LBM in total, trunk, arms, and legs in group B were significantly lower than those in group A. LBMtrunk/IBW, LBMarms/IBW, and LBMlegs/IBW were significantly depleted in group B. LBMtrunk/total LBM in group B was comparable to that in group A. There was no significant difference in LBMarms/total LBM between the two groups (p = 0.25). In contrast, LBMlegs/total LBM was significantly decreased in group B (p = 0.02).


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  		Table 2. Distribution of LBM in Patients With COPD*

 
Exercise Performance
Physiologic variables during maximal cycle ergometry in the two groups are summarized in Table 3 . Maximal E, maximal work rate, and O2max in group B were significantly lower than those in group A. Maximal E/MVV was significantly higher in group B, while no difference was observed in maximal heart rate as a percentage of predicted between the two groups. There was no difference in arterial oxygen desaturation during maximal exercise between the two groups.


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  		Table 3. Physiologic Variables During Maximal Exercise on Cycle Ergometry*

 
Determinants of O2max
Correlation coefficients between O2max and pulmonary function and LBM are shown in Table 4 . FEV1, RV/TLC, and MVV correlated significantly with O2max in both groups. Although total LBM/IBW and LBMlegs/IBW correlated significantly with O2max in group A, they did not have significant correlations with O2max in group B.


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  		Table 4. Relationship Between O2max and Pulmonary Function and LBM*

 
We also found a significant correlation between LBMlegs/IBW and O2max in total group (r = 0.66, p < 0.0001; Fig 1 ). In addition, there was no significant correlation between LBMtrunk/IBW and O2max in group A or group B (p = 0.26 and p = 0.09, respectively; data not shown).



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  		Figure 1. Relationship between O2max and LBMlegs (LBMlegs/IBW) in group A (open circles) and in group B (closed circles). The continuous line shows the regression line in the total group.

 
Stepwise multiple regression analysis was performed to determine the best combination of predictors for O2max (Table 5 ). MVV and LBMlegs/IBW appeared to be significant determinants of O2max in group A. Total variance explained in this model for O2max was 77% in group A. In contrast, LBMlegs/IBW was not selected as a significant predictor in group B. Only 44% of total variance was explained in this model for O2max.


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  		Table 5. Results of Stepwise Multiple Regression Analysis for O2max

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, we measured LBM by DXA and assessed it separately in arms, legs, and trunk. It was shown that a significant reduction of LBM, expressed as a percentage of IBW in each region, was present in patients with severe airflow limitation compared to patients with mild-to-moderate airflow limitation.

DXA has been validated against independent methods, including {gamma}-neutronactivation model, total body potassium, and hydrodensitometry, and is becoming one of the reference methods for body composition analysis.18 BIA is an another recent method of body composition analysis. Schols and coworkers5 have demonstrated that FFM measured by BIA, which was almost equivalent to LBM, was a better indicator of body-mass depletion than body weight in patients with clinically stable COPD. However, BIA was reported to overestimate FFM.18 Furthermore, whole-body DXA systems in contrast with BIA allow regional measurements, and this permits separation of the extremity from the trunk measurements. DXA makes it possible to quantify skeletal muscle mass of the extremities, because the fat-free soft tissue of the extremities is almost entirely skeletal muscle, except for a small amount of skin connective tissues.

To investigate the distribution of muscle-mass wasting, LBM of each subregion expressed as a percentage of total LBM was evaluated. LBMlegs/total LBM was significantly reduced in patients with severe airflow limitation, while no significant difference in LBMtrunk/total LBM and LBMarms/total LBM between the two groups was observed. This finding may suggest that patients with severe disease exhibited disproportional leg muscle wasting. In states associated with simple muscle atrophy, such as nutritional depletion, the loss of upper-limb muscle function is equal to or greater than that of the lower limbs.19 However, the distribution of muscle wasting found in patients with severe disease who were more severely malnourished than those with mild-to-moderate disease is not consistent with atrophy induced by malnutrition. The disproportional leg muscle wasting in patients with severe disease may attribute to the limitation in their daily activity due to limited respiratory reserve.

In this study, a matched healthy control group was not included. As the absence of a control group has limited quantitative estimation of total LBM and distribution of LBM in each group, it is not clearly defined whether muscle wasting is also a characteristic of patients with mild-to-moderate COPD.

The impact of peripheral muscle function on exercise performance has been investigated. Peripheral muscle weakness,8 9 reduction in oxidative enzyme activities,10 11 and a low proportion of type I myosin heavy chain20 have been reported to contribute to exercise intolerance in COPD. However, the relationship between peripheral muscle mass and exercise performance has not been clearly elucidated. In the present study, LBMlegs was found to be a significant predictor of O2max in patients with mild-to-moderate COPD. This finding may be reasonable because the mass of exercising muscles, as well as the dimensions of the cardiovascular and pulmonary systems, should determine the maximal quantity of oxygen that could be delivered and used.21

Excessive increase in blood lactic acid in COPD patients during exercise compared with normal subjects is associated with exercise limitation. Previously, a reduction in oxidative enzyme activity, including citrate synthase and 3-hydroxyacyl-coenzyme A dehydrogenase in biopsy specimens from the quadriceps femoris muscle10 11 and a strong correlation between the activity of these enzymes and O2max, have been demonstrated.11 It is unclear whether a decrease in enzyme activities may attribute to either a loss of muscle mass, to some alteration in muscle structure, or to a combination of these two mechanisms. Our data suggest that a loss of muscle mass may contribute to the decrease in oxidative enzyme activity. In addition, Kutsuzawa and coworkers22 found an early activation of anaerobic glycolysis during exercise in patients with COPD and demonstrated a significant correlation between indexes of this early activation and muscle mass. Our observations are consistent with their statement that muscle atrophy may contribute to the metabolic changes in muscles.

We previously reported that total LBM was a significant determinant of O2max in stepwise regression analysis in patients with COPD (mean FEV1, 49.8 ± 26.4% of predicted). However, LBM in each subregion was not evaluated and the relation of leg muscle mass, which was mainly recruited for cycle ergometer exercise, to O2max was not investigated. In the present study, an independent effect of leg muscle mass on O2max was demonstrated in COPD patients with mild-to-moderate airflow limitation, while not in patients with severe disease. Furthermore, no significant correlation between LBMtrunk/IBW and O2max was observed in both groups in this study. These data may suggest that LBM in each subregion has a different effect on O2max.

Several reports12 13 demonstrated that strength training of leg muscles provided no significant improvements of O2max and 6-min walk distance, although it contributes to an increase in muscle strength. We found that leg muscle mass was a significant predictor of O2max in patients with mild-to-moderate airflow limitation, but not in patients with severe airflow limitation. Richardson and coworkers23 documented that the patients with severe COPD had significant skeletal muscle metabolic reserve at maximal exercise and concluded that reduced whole-body exercise capacity was the result of central restraints, rather than peripheral skeletal muscle dysfunction in these patients. These findings suggest that it may depend on the severity of the disease as to whether strength training of leg muscles can improve O2max.

In addition, Berry and coworkers24 have shown that peak oxygen consumption increased significantly after exercise training in patients with mild COPD, while the increase was insignificant in patients with moderate and severe COPD. A therapeutic approach to a reduction of central restraints (ie, lung volume reduction surgery) may be required for a substantial improvement of O2max in patients with severe airflow limitation.25 26

In conclusion, we found disproportional reduction of LBMlegs in COPD patients with severe airflow limitation. However, LBMlegs was not a significant predictor of O2max in these patients.


   Footnotes
 
Abbreviations: BIA = bioelectrical impedance analysis; DLCO = diffusing capacity of the lung for carbon monoxide; DXA = dual energy x-ray absorptiometry; FFM = fat-free mass; IBW = ideal body weight; LBM = lean body mass; LBMarms = LBM in arms; LBMlegs = LBM in legs; LBMtrunk = LBM in trunk; MVV = maximal voluntary ventilation; RV = residual volume; TLC = total lung capacity; VC = vital capacity; E = minute ventilation; O2max = maximal oxygen uptake

Received for publication January 24, 2000. Accepted for publication August 10, 2000.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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