Our results show that decreased leg and respiratory muscle strength are independently associated with poorer exercise capacity and lower extremity functioning across a spectrum of COPD severity. Furthermore, the effect of concurrent leg and respiratory muscle weakness on exercise capacity suggests a negative combined effect leading to far worse impairment. Our results also demonstrate that decreased leg and respiratory muscle strength have similar independent and combined effects on exercise capacity and lower extremity function for both men and women.
By investigating the effects of muscle weakness on exercise capacity across the spectrum of airflow obstruction, our findings build on previous work limited to patients with more severe COPD who are known to have both respiratory and peripheral muscle weakness.3,10
Furthermore, in prior work focused on severe COPD, the severity of quadriceps weakness was associated with graded reductions in work capacity during exercise testing.10
Our work expands on these findings by showing that patients across the spectrum of airflow obstruction have both respiratory and peripheral muscle weakness and that quadriceps weakness is associated with graded reductions in work capacity, even in patients with mild airflow obstruction.
Three features of our study help to provide a more complete picture of these relationships. First, we evaluated subjects with the full range of airflow obstruction ranging from mild to severe. Second, our cohort was systematically recruited from a population shown to be similar to the regional population of northern California.11
Third, because our study population was relatively large, we were able to make robust assessments of the independent and combined effects of leg and respiratory muscle weakness on exercise capacity in both men and women. These features expand our current knowledge of the effects of muscle weakness on exercise capacity to patients with a broad range of COPD severity, supporting the generalizability of our findings to patients being treated for COPD in general medical practice.
The relationship between leg muscle weakness and exercise capacity has multiple potential explanations. One is that skeletal muscles in COPD have diminished aerobic capacity.7
COPD patients exhibit a shift from type I to type II skeletal muscle fibers,26, 27
reduced mitochondrial density per fiber bundle,28
and reduced capillary density.29, 30
Each of these can correlate with reduced capacity for aerobic metabolism and, ultimately, poorer muscle endurance. Furthermore, higher levels of C-reactive protein and pro-inflammatory cytokines (eg, interleukin-8, interleukin-6, and tumor necrosis factor [TNF]-α) are seen in COPD.31–35
TNF-α inhibits muscle contractility36
and mitochondrial biogenesis,37
and promotes muscle wasting via apoptosis.38
Another explanation is disuse atrophy from decreased activity. Other explanatory factors, such as malnutrition, age, hypoxia, reactive oxygen species, and deficiencies in levels of oxidative enzymes have all been identified in patients with COPD.39–43
We recognize that our study has some limitations. First, the generalizability of our findings may be limited by the clinically-derived sampling, even if population-based through a large closed-panel health maintenance organization. Further, although we limited our study to persons with at least GOLD Stage 1 COPD or greater, we did not include subjects with potential COPD-related respiratory symptoms (productive cough or dyspnea) without concomitant airflow obstruction. Additionally, examiners used a hand-held dynamometer to measure leg strength rather than a computerized isokinetic dynamometer because they are also more feasible to deploy in epidemiologic studies, due to cost and complexity.44,45
While hand held dynamometers may be more subject to error, they have been shown to provide reliable and valid results that correlate strongly with isokinetic dynamometer results, and thus their use should not have systematically impacted our observations. Second, we used a relatively small cohort of referent subjects without COPD to generate predicted values for respiratory and leg muscle strength. This limited sample size could have introduced additional uncertainty for estimates of “normal” values, although it should not be a source of systematic bias. In addition, the percent predicted estimates were only used for the LOWESS procedure, while absolute measures for respiratory and leg strength, standardized to one-half standard deviation, were used for our regression models, providing a second approach independent of control values. Third, we used MIP and MEP as measures of respiratory muscle strength, which are effort dependent tests. While our measurement of MIP and MEP adhered to the ATS/ERS guidelines, it is possible that our findings could have been impacted by subject effort.
Another potential limitation is the possible misclassification of COPD. To reduce this bias, we developed and validated an algorithm that required utilization of COPD, concomitant treatment with COPD medications, and a physician diagnosis of COPD; then further limited the analysis to persons with pulmonary function obstruction meeting criteria for GOLD 1 disease or greater.11,12
Moreover, a sensitivity analysis limited to GOLD 3–4 only did not yield substantively different results.
Because our study population was relatively young with a broad spectrum of COPD severity, our findings have implications particularly relevant for disability prevention. For patients with severe COPD, pulmonary rehabilitation programs lead to improved exercise tolerance and health related quality of life.46,47
Evaluations of the exercise component of pulmonary rehabilitation programs have shown strength training of the lower extremities leads to improved muscle function and improvements in measures of submaximal and maximal exercise capacity in patients with COPD.46,48
While strength training of the respiratory muscles has been shown to improve inspiratory muscle function,49
translating these findings into improved exercise capacity beyond the gains afforded by general exercise in pulmonary rehabilitation programs has yet to be convincingly demonstrated.50,51
Targeting improved exercise capacity through pulmonary rehabilitation in patients with less severe disease has not yet been rigorously evaluated. Our findings suggest that earlier attention to skeletal muscle strength could be an important component of disability prevention. Future studies might focus on strength and/or endurance training of skeletal muscles to prevent or retard the loss of exercise capacity and lower extremity functioning in patients with earlier stages of disease. Our findings also suggest that clinicians might consider measuring leg muscle strength and/or recommending leg strengthening exercises to patients with COPD with complaints of exercise limitations irrespective of gender or their formal GOLD staging. Because we found that both respiratory and lower extremity skeletal muscles have independent effects on exercise capacity, our findings suggest that attention to both muscle groups might be important in maximizing the potential benefit of disability prevention programs.