Skeletal muscle dysfunction has been postulated as one of the extrapulmonary effects in patients with chronic obstructive pulmonary disease (COPD), resulting in reduced peripheral muscle strength and muscle mass.1,2 Reductions in muscle force production contribute to exercise intolerance and have been associated with an increased mortality risk and a decrease in quality of life.3,4 Lower extremity muscle power has been also recently posited as a more discriminating variable for understanding the relationship between impairments, functional limitations, and resultant disability with aging.5,6 Physical inactivity and systemic inflammation have been cited as factors responsible for muscle dysfunction in COPD.7,8 Considering that reductions in peripheral muscle strength have important clinical and functional implications for COPD patients, the search for effective pulmonary indices to predict peripheral muscle function is of paramount importance.

Among the pulmonary parameters, forced expiratory volume in 1 second (FEV1) is the most important spirometric indicator of the severity of airflow obstruction. However, several studies have shown the weak relationship between FEV1 and mortality,9,10 indeed, it cannot be used to detect abnormal skeletal muscle function. Recently, the inspiratory capacity-to total lung capacity (IC/TLC) ratio has emerged as a better marker of mortality and functional reserve and is associated with altered exercise capacity in COPD patients.11,12 Recently, Ramon et al.13 observed that the patients with COPD with lower IC/TLC experience a higher longitudinal decline in exercise capacity.

To date, only one study has investigated the role of IC/TLC ratio on the muscle function in the upper extremities in this population of patients. Its authors found that maximal hand grip strength was lower among IC/TLC≤25% than among patients with IC/TLC>25%.14 However, no previous studies have established the correlation between the IC/TLC ratio and lower extremity muscle mass, maximal strength, and muscle peak power output in this patient population.

Accordingly, the primary aim of the present study was to determine whether the inspiratory capacity-to-total lung capacity ratio or inspiratory fraction would be useful in predicting skeletal muscle dysfunction in the lower and upper extremities. We hypothesized that patients with IC/TLC≤25% would have less maximal muscle strength of the lower and upper extremities and peak power output of the lower limbs than IC/TLC>25% patients.

The salient findings of this study were that thigh muscle mass, lower and upper maximal strength, and leg muscle peak power output was reduced significantly in COPD patients with IC/TLC≤25%. In addition, the IC/TLC a predictor of mortality, was related to thigh muscle mass and the maximal strength of lower and upper extremities. The present findings suggest that IC/TLC≤25% may be valued as an applicable index of skeletal muscle dysfunction in chronic obstructive pulmonary disease patients.

An inspiratory-to total lung capacity ratio of ≤25% is an important independent predictor of increased mortality.11 Recently, Ramon et al.13 observed that the patients with COPD with lower IC/TLC experience a higher longitudinal decline in exercise capacity and IC/TLC and dyspnea in clinically stable patients with COPD predict their exercise capacity.

On the basis of previous studies suggesting that lower fat-free mass and reduced grip strength is related to an IC/TLC of ≤25%,14 we sought to determine whether an IC/TLC of ≤25% would translate to unfavorable changes in muscle mass and muscle function (maximal strength and power output normalized to muscle cross-sectional area) in the lower extremities. Skeletal muscle weakness in the lower extremities has previously been shown to be more established with the increase of the dyspnea, BODE index score, and disease severity in COPD patients.17 Previous studies have observed that reduced thigh muscle cross-sectional area3 and reduced maximal quadriceps strength,1 which result in an impaired functional capacity,18 is related to increased mortality19 and health care utilization.4 Recently, it has been also reported that lower extremity muscle power remains as a more discriminating variable for understanding the relationships between impairments, functional limitations, and resultant disability with aging.5,6 However, no previous study has determined that the IC/TLC ratio is a marker of muscle atrophy and reduced maximal strength and muscle power output in the lower limbs in COPD patients.

A unique findings in this present study was that thigh muscle mass and maximal dynamic strength in the lower limbs were lower in the IC/TLC≤25% group. This hypothesis was strengthened by the relationship observed between the IC/TLC and muscle mass (r=0.67; p<0.001) and lower maximal strength (r=0.57; p<0.01). In this study, we extended our investigation by determining the relationship between the IC/TLC>25% group and the maximal strength of the upper limbs. Indeed, reduced maximal strength in the upper extremities was found in the IC/TLC≤25% group. This suggests that the inspiratory-to-total lung capacity ratio of ≤25% is a surrogate marker of thigh muscle atrophy and peripheral skeletal muscle weakness.

Recently, impairments in muscle peak power output in the lower extremity have emerged as a more important predictor of limitations in mobility in tasks such as rising from a chair, climbing stairs, habitual walking speed, and even the prevention of falls, than maximal muscle strength in older adults.20–24 To the best of our knowledge, this is the first study to report the association between the IC/TLC ratio and lower extremity muscle peak power in patients with COPD. Our results indicate that muscle peak power output at 50 and 70% of 1RM is reduced in COPD patients with an IC/TLC of ≤25%. Furthermore, a slowed-down capacity for muscle power output and delayed responsiveness to accidental falls in the lower and upper limbs is associated with disability.5,6 It has been documented that in older adults25 with lower extremity power at high velocities (40% 1RM) contractions were a better predictor of habitual gait velocity than power at low velocities (70% 1RM). One of the major findings in this study was that when maximal bilateral dynamic strength and muscle power output were expressed relative to total MMT, the differences between the groups disappeared. This suggests that the impairment in peripheral muscle function of the lower limbs in patients with IC/TLC≤25% is mainly due to loss of muscle mass and that neural activation patterns and/or twitch tension per muscle mass volume under maximal concentric actions (typical leg extension actions also in normal daily activities) could be rather similar between groups.

It is no clear which physiological mechanisms explained the reductions in muscle mass in COPD patients with an IC/TLC of ≤25%. In healthy older adults, reduced maximal strength has been attributed to a great extent to the reduction in muscle mass, which is perhaps related to alterations in hormone balance26 and the decline in the quantity and intensity of physical activity.27 In this context, we postulated that lower limb muscle mass and reductions in maximal strength and peak power output might be due to elevated inflammation and the physical inactivity associated with the systemic inflammation.28,29 Consistent with the first part of the hypothesis, we found that patients with an IC/TLC of ≤25% have elevated CRP and IL-6 levels and also, we observed a negative relationship between IL-6 and muscle mass, lower extremity maximal dynamic strength and leg muscle peak power output. Therefore, the present results might indicate that the effects of circulating IL-6 may be associated with reduced muscle mass and skeletal muscle weakness. The results contradict the findings of Pleguezuelos et al.30 who did not observe any significant relationship between quadriceps strength and IL-6. These differences might occur because of the maximum strength measurement (i.e., dynamic maximum test vs. isokinetic test). Previous studies have shown that higher levels of systemic inflammation are associated with reduced physical activity in patients with COPD,7 and the older adults who are physically inactive have higher levels of systemic inflammatory markers than those who are physically active.31 In support of the second part, the IC/TLC≤25% group demonstrated a 23% lower habitual physical activity. Moreover, physical activity was positively associated with lower extremity maximal strength, muscle power output, and thigh muscle mass in the pooled group. In the present study, IC/TLC ratio was positively associated with physical activity (r=0.55; p=0.001) for the entire group, suggesting that those patients with higher static hyperinflation (low IC/TLC) are less physically active. A limitation of our study is that there was no direct dynamic hyperinflation during the 6MWT measurements. Garcia-Rio et al.32 have reported that the reduced daily physical activity of patients with moderate-severe COPD might be partially explained by the development of dynamic hyperinflation, regardless of the severity of the disease. Garcia-Rio et al.32 have showed that the increase in EELV during exercise was associated with dyspnea as evaluated by the MRC scale. This breathlessness could promote the limitation when the patients performed their daily physical activity, increasing the physical inactivity. At the same time, this physical inactivity could contribute to the weakness and atrophy of the muscles, leading to a vicious circle that causes more physical inactivity, atrophy and skeletal muscle dysfunction.

There are several methodological limitations in our experimental approach. First, as the size of the sample in the study was small, we used the bootstrapping procedure as part of the statistical analysis, strengthening our results. Second, we did not take into account patients who received corticosteroids. Previous studies1 have shown that quadriceps strengthened but thigh muscle mass was lower in those patients who received systemic corticosteroids. However, the patients in our study received the same medical treatment and exacerbation was an exclusion criteria.

In conclusion, the results of this study indicate that the inspiratory-to total lung capacity ratio may be an effective pulmonary measurement to determine muscle atrophy in the lower extremities and skeletal muscle dysfunction. The relationship observed is clinically important because an IC/TLC of ≤25% can be used as an index to detect skeletal muscle weakness.

The authors have no conflicts of interest to declare.