Muscle fatigability (MF) is an exercise-induced reduction in maximal voluntary muscle force, that depends on several mechanisms involving the central nervous system and peripheral muscle components.1 In clinical and rehabilitation settings, it can be assessed by the reduction in maximal voluntary contraction (MVC) i.e. the maximum force-generating capacity of the quadriceps after a fatiguing task: this parameter provides general but immediate information on the reduction in muscle performance.2 In healthy subjects, the reduction in MVC after a generic fatiguing task (i.e. cycling) has been found to average 15%, which is considered to be a commonly used threshold in the literature.3

The measure of muscle fatigability may serve as a primary limitation to peripheral muscle performance; however, after adequate recovery, it emerges as an essential prerequisite for improved muscle performance following exercise training.4

In addition, by measuring muscle fatigability in patients with COPD, healthcare providers can formulate individualized treatment strategies that incorporate tailored exercise regimens into pulmonary rehabilitation programs. This approach aims to improve both muscle function and overall health.5,6 However, it is known that not all patients with chronic obstructive pulmonary disease (COPD) are able to develop MF during different exercise tasks.7 Burtin et al.8 reported that 40% of patients with COPD were unable to reach a certain level of MF during a cycling task due to an early effort interruption, limiting potential adaptation to training.

In light of muscular fatigability, Mador et al.9 investigated this phenomenon using a mono-muscle fatigue protocol with minimal cardiorespiratory engagement, and found that people with severe COPD had heightened MF compared to both healthy counterparts and those with moderate COPD.9 These authors also evaluated MF during cycling by comparing subjects with moderate COPD and healthy subjects, at moderate intensity and iso-oxygen consumption, with similar results.10

However, in people with severe COPD during high-intensity “endurance” exercise, such as walking and cycling, an abnormal increase in ‘central’ cardio-respiratory involvement (e.g., higher dynamic hyperinflation, mechanical lung constraint, and respiratory muscle fatigability) can lead to an early interruption of the effort due to dyspnea and progressive deconditioning.11,12 These patients may experience susceptibility to locomotor muscle fatigability partly due to insufficient transport of O22 as a consequence of exaggerated arterial hypoxemia11,12 and supplemental oxygen administration can improve exercise tolerance in patients with COPD by reducing ventilatory requirements for the same workload and producing lower levels of lactate.11,12

Few studies have investigated MF in patients with COPD and chronic respiratory failure (COPD-CRF) who have already developed chronic hypoxia. Paneroni et al.13 recently reported that COPD-CRF patients had lower workability but similar endurance and quadriceps MF to COPD patients without CRF during high-intensity exercise under long-term oxygen therapy (LTOT). The authors speculated that these results might be related to the oxygen supplementation given to CRF patients.

No studies have investigated the impact of lung function parameters as well as respiratory muscle strength and oxygenation status on MF following a high-intensity “endurance” exercise task in COPD-CRF. The aim of this study was to investigate the influence of these parameters on MF as a decrease in quadriceps maximal voluntary contraction (MVC), in COPD-CRF subjects following an endurance exercise task.

We hypothesized that COPD-CRF patients on oxygen therapy with blood concentration within the appropriate range (PaO2>60mmHg) would have varying degrees of quadriceps MF based on the severity of lung obstruction, hyperinflation, respiratory muscle strength, and/or oxygenation status (SpO2/FiO2).

This is a cross-sectional study, being a post hoc analysis performed on partial data obtained between 2019 and 2022 in Istituti Clinici Scientifici Maugeri Lumezzane (BS) relative to a prospective study in COPD-CRF (Maugeri Ethics Committee, CE 2288; 14/05/2019). Participants gave their specific informed written consent and all experimental procedures were performed in accordance with the Declaration of Helsinki.

We included 45 patients [20 with severe obstruction (SO) and 25 with very severe obstruction (VSO)] (Table 1). The whole group was predominantly males and had a high rate of comorbidities. As expected, patients with VSO had worse lung obstruction, degree of hyperinflation, dyspnea during ADL, effort tolerance at 6MWDT, and endurance time than patients with SO.

The study found statistically significant differences in the duration in CWRCT and total work between groups. Patients with greater lung obstruction had lower effort tolerance and stopped the test earlier. However, there were no differences in baseline MVC or reasons for stopping the test (45%, 15%, and 40% of patients stopped for dyspnea, perceived muscle fatigability, or both, respectively) between the two groups of patients.

There were 10 patients (50%) in the SO group and 4 patients (16.0%) in the VSO group with a decrease in MVC of more than 15% (p=0.014). Fig. 1 shows the percentage of MVC change after CWRCT: the absolute values are defined in panel A, while the values normalized by the work performed are shown in panel B. The figure describes that, at exhaustion, SO patients had a greater and statistically significant reduction in MVC when compared to VSO patients (−15.15±9.13% vs −9.29±8.90%, p=0.0357) although with a high variability of the measurements. When MVC was normalized to CWRCT work, quadriceps MF was similar between groups (SO −1.7±1.2 vs VSO −2.0±2.7, p=0.7471).

Fig. 1.

Percentage of MVC change on baseline after CWRCT: absolute values (panel A) and values normalized by work performed (panel B). Δ: delta; MVC: maximal voluntary contraction; KJ: kilojoules; SO: patients with severe obstruction group; VSO: patients with very severe obstruction group.

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Significant correlations were found between MF (% delta change of MVC after CWRCT) and MIP (r=−0.4412, p=0.0056) and MEP (r=−0.3561, p=0.0282), while there was a trend toward significance for FEV1% (r=−0.2931=0.0507), suggesting that patients with less pronounced pulmonary obstruction and higher respiratory muscle strength were more likely to develop quadriceps MF.

According to these results, Table 2 describes the best multivariate linear regression model to explain the quadriceps MF. Taking into account respiratory and oxygenation factors, the most important variables with a significant influence are FEV1, MIP and TLC. Patients with higher values of FEV1 and MIP and lower levels of TLC may develop higher quadriceps MF. These three factors contribute similarly to MF, but the ability to reduce MVC (i.e. the ability to achieve a higher MF) was only partially explained (coefficient of determination R2=47%).

Our study supports the hypothesis that among COPD-CRF patients, those with different degrees of lung obstruction have different responses to quadriceps muscle fatigability (MF).

Compared with COPD-CRF patients with severe lung obstruction (FEV1 ≥30% predicted), our findings demonstrate that individuals with more severe lung obstruction (FEV1 <30% predicted) have a shorter endurance time, a lower propensity to develop quadriceps MF and increased dyspnea both at rest and after a fatiguing cycling task. Better lung function expressed as FEV1% prd and TLC % prd and better respiratory muscle strength are associated with a higher likelihood of developing quadriceps muscle fatigability during exercise.

The literature on post-exercise MF in COPD remains inconclusive and somewhat controversial. Mador et al.9 conducted a study comparing severe COPD (FEV1%=26%), mild to moderate COPD (FEV1%=53%), and healthy controls using a quadriceps fatiguing protocol with little cardiopulmonary system involvement. The results showed that patients with severe COPD, without chronic respiratory failure (CRF), experienced more MF during exercise compared to those with milder disease and healthy controls.9

In patients with moderate to severe COPD (FEV1%=41%) without CRF, Burtin et al.8 demonstrated that only 63% of the general group reached a threshold for quadriceps MF after a cycling task. This assessment was based on a reduction in the potentiated resting quadriceps twitch (Qtw, pot), with no significant differences in clinical and functional characteristics observed between patients with and without contractile fatigability.

The development of MF in COPD patients has been suggested to depend on muscle characteristics such as fiber types, enzymes, capillarization, and lactate accumulation, as well as the nature of the exercise task. For example, walking may induce less peripheral MF than cycling,7 and short-term oxygen supplementation in COPD without CRF can reduce MF development about a third.12

In patients with severe COPD-CRF (FEV1%=25%) on oxygen therapy, perceived muscle fatigue and dyspnea were reported to be higher after high-intensity cycling exercise compared with less severe COPD without CRF (FEV1%=38%).13 However, the extent of quadriceps MF (defined as a decrease in MVC and Qtw, pot) was found to be similar in both groups.13 The authors speculated that the similar MF was due to comparable muscle conditions and characteristics between the groups, possibly due to the protective effect of oxygen consumption during exercise in CRF patients.13

Our study represents a pioneering investigation exclusively focused on chronic obstructive pulmonary disease with chronic respiratory failure (COPD-CRF) patients undergoing LTOT. This study has shown that the response of the MF varies between individuals with different degrees of lung obstruction. Our findings suggest that as lung obstruction progresses, there is a concomitant decrease in effort tolerance, which is accompanied by a decreased development of quadriceps MF observed at the peak of a high-intensity constant load test. In this regard, our dataset shows that only 15% of COPD-CRF patients with a FEV1 less than 30% of predicted reached a predefined threshold level of quadriceps MF (maximal voluntary contraction reduction <15%). These data support the notion that the decline in effort tolerance is associated with a reduced development of quadriceps MF, which is particularly pronounced in patients with severe lung obstruction.

Notably, the difference in quadriceps fatigability between patients with significant obstruction (SO) and very severe obstruction (VSO) is attenuated when the change in maximal voluntary contraction (MVC) is normalized to the total work performed. This normalization highlights that the observed differences in MF response may be influenced not only by the severity of lung obstruction but also by the overall workload endured during the test. Moreover, the fact that both groups of patients show the same normalized fatigability suggests that they have a common impairment of their peripheral muscles; the lower absolute fatigability in VSO could therefore be explained by the greater ventilatory limitation shown by this group.

Our data are consistent with the study by Butcher et al.22 which showed an inverse relationship between the magnitudes of ventilatory constraints due to dynamic hyperinflation and skeletal muscle contractile capacity after high-intensity exercise cycling in room air in patients with COPD. Their patients were more likely to increase exercise tolerance with heliox, resulting in greater leg MF. Unfortunately, we lack data describing dynamic volumes during effort, but these results are consistent with the notion that the worse the respiratory mechanics, the lower the potential for peripheral muscles to reach a given fatigue threshold. In this direction, our data showed that total lung capacity (TLC) is a component able to explain the quadriceps MF. Indeed, TLC increases during the course of the disease due to loss of lung recoil and is recognized as one of the markers of lung hyperinflation (LH). LH is partially independent of the degree of airflow limitation and is strongly associated with dyspnea, exercise limitation, reduced activities of daily living and mortality. A direct link between LH and peripheral muscle dysfunction has not been fully established. Peripheral muscle dysfunction is common in COPD, probably mainly driven by muscle deconditioning from disuse of the locomotor muscles.23

Disuse results from exertional dyspnea, dynamic hyperinflation and redistribution of blood flow during exercise from the musculoskeletal system to respiratory muscles.24 However, also LH may be indirectly related to peripheral muscle dysfunction.25

The reasons for the divergent MF development between SO and VSO patients at exhaustion may be primarily related to the early engagement of the respiratory system during exercise in patients with very severe obstruction (VSO). The early cessation of exertion may consequently lead to the development of less fatigability. In this context, the results of correlation and regression analyses show that patients with better lung function and inspiratory muscle strength were able to achieve higher levels of peripheral MF. Nevertheless, our results describe how the two patient groups show a “theoretical” similarity in intrinsic muscular fatigability when normalized for the actual work performed.

Structural alterations and dysfunction in limb muscles of patients with COPD have been studied with subsequent clinical implications such as exercise intolerance and premature mortality.26

Susceptibility to quadriceps contractile fatigability during exercise is more common in patients with higher glycolytic enzyme activity, lower muscle capillarization, and early lactate accumulation.9

In addition, several factors may influence the likelihood of developing peripheral fatigability. One such factor is the “metaboreflex phenomenon”27–29 induced by respiratory muscle fatigability, which increases sympathetic vasoconstrictor outflow, resulting in reduced blood flow to the locomotor muscles and subsequent fatigability of these muscles.30 It is plausible that more severe patients, in terms of lung obstruction and inspiratory muscle strength, may have had a relatively limited involvement of this mechanism, potentially hindering adequate quadriceps muscle stimulation. This limitation is suggested by their greater and earlier impairment of the central ventilatory component, as evidenced by greater dyspnea at rest and during exertion.

Further investigations are needed to elucidate the relationship between metaboreflex induced by respiratory muscle fatigability and quadriceps fatigability in the COPD-CRF population.

The utility of measuring muscle fatigability lies in the fact that it is an essential prerequisite for improved muscle performance following exercise training.4

Confirming this fact, Burtin et al.8 showed that COPD patients who were more likely to develop muscle fatigability had greater improvement in the 6-minute walk test (6MWT) after a training program.

Unfortunately, significant ventilatory limitations may prevent severe COPD patients with CRF from reaching a sufficient training intensity sufficient to induce a similar overload: this condition seems to be the most likely to occur in VSO patients.

To overcome this problem, several strategies have been proposed to reduce dyspnea and dynamic lung limitation during exercise allowing peripheral muscles to reach a sufficient training stress threshold, such as interval training31 small muscle mass training,32 the use of external respiratory devices (e.g., mechanical ventilation, high-flow oxygen therapy)33 and magnetic versus electrical muscle stimulation.34

The contributions of the author were as follows: conceptualization and methodology, MP, MVi, MVe; validation, MP; formal analysis, AC; investigation, AC, LB, BS; data curation, AC, BS; writing original draft preparation, AC, MP, MVi; writing-review and editing, AC, MP, MVi, MVe, BS, LB; supervision, MVi; project administration, AC, MP, MVi.

This work refers to a post hoc analysis of data coming from a study conducted in our Institute related to different training modalities in COPD and CRF patients entitled: “Confronto tra tre modalità di allenamento allo sforzo in pazienti BPCO con IRC: risposta clinica e histological”. The study was funded by a 5×1000 grant – year 2016 from the Italian Ministry of Health. The funder had no role in study design, data collection and analysis, and any interpretation of data; writing of the paper, or submission.

The author reports no conflicts of interest in this work.