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Original Research: COPD |

Is Quadriceps Endurance Reduced in COPD?Quadriceps Endurance Is Reduced in COPD: A Systematic Review FREE TO VIEW

Rachael A. Evans, MBChB, PhD; Eric Kaplovitch, MD; Marla K. Beauchamp, PhD; Thomas E. Dolmage, MSc; Roger S. Goldstein, MBChB, FCCP; Clare L. Gillies, PhD; Dina Brooks, PhD; Sunita Mathur, PhD
Author and Funding Information

From the Department of Respiratory Medicine (Drs Evans, Kaplovitch, Beauchamp, Goldstein, Brooks, and Mathur and Mr Dolmage), West Park Healthcare Centre, Toronto, ON, Canada; the Department of Medicine (Drs Evans, Kaplovitch, and Goldstein) and the Department of Physical Therapy (Drs Beauchamp, Goldstein, Brooks, and Mathur), University of Toronto, Toronto, ON, Canada; the Department of Physical Medicine and Rehabilitation (Dr Beauchamp), Harvard Medical School, Spaulding Rehabilitation Hospital, Cambridge, MA; and the Department of Infection, Immunity and Inflammation (Dr Evans) and the Department of Health Sciences (Dr Gillies), University of Leicester, Leicester, England.

CORRESPONDENCE TO: Rachael Evans, MBChB, PhD, Department of Respiratory Medicine, Glenfield Hospital, Leicester, LE3 9QP, England; e-mail: rachael.evans@uhl-tr.nhs.uk


FUNDING/SUPPORT: Dr Evans was supported with a National Institute for Health Research clinical lectureship.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(3):673-684. doi:10.1378/chest.14-1079
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BACKGROUND:  Although the aerobic profile of the quadriceps muscle is reduced in COPD, there is conflicting evidence regarding whether this leads to reduced quadriceps muscle endurance. We, therefore, performed a systematic review of studies comparing quadriceps endurance in individuals with COPD with that in healthy control subjects.

METHODS:  Relevant studies were identified by searching six electronic databases (1946-2011). Full-text articles were obtained after two researchers independently reviewed the abstracts. The results were combined in a random effects meta-analysis, and metaregression models were fitted to assess the influence of the type of measurement.

RESULTS:  Data were extracted from 21 studies involving 728 individuals with COPD and 440 healthy control subjects. Quadriceps endurance was reduced in those with COPD compared with healthy control subjects (standardized mean difference, 1.16 [95% CI, 1.02-1.30]; P < .001) with a 44.5 s (4.5-84.5 s; P = .029) reduction in COPD (large effect size) when measured using a nonvolitional technique. The relationship between quadriceps endurance in those with COPD and control subjects did not differ when comparing nonvolitional and volitional techniques (P = .22) or when high- or low-intensity tasks (P = .44) were undertaken.

CONCLUSIONS:  Quadriceps endurance is reduced in individuals with COPD compared with healthy control subjects, independent of the type of task performed.

Figures in this Article

Skeletal muscle alteration is a recognized extrapulmonary consequence of COPD, with particular involvement of the larger muscles of locomotion.1,2 Although the precise causes and mechanisms are still being elucidated, deconditioning from inactivity, systemic inflammation, oxidative stress, hypoxemia, and steroid use have all been implicated (all of which worsen with increasing disease severity).1,3 Reduced quadriceps muscle mass and strength in COPD4 have been associated with a higher mortality5,6 and morbidity, as well as increased hospital admissions.7

There is also considerable evidence that the oxidative capacity of the skeletal muscle is reduced in COPD, with preferential reduction in the type 1 fiber cross-sectional area of the quadriceps muscle and a reduction in oxidative enzyme concentration, mitochondrial density, and capillary density.8,9 Collectively, these changes likely contribute to exercise and activity intolerance.1012 These adaptations are associated with a loss of the aerobic profile of the muscle. This is exemplified during cycling exercise, during which the muscle energy requirements are unable to be met, with a resultant decline in phosphocreatine and adenosine trinucleotide phosphate at very low absolute power.12 Whole-body exercise tests, such as incremental cycling or treadmill walking, do not isolate the contribution of the peripheral muscles to the impaired aerobic capacity because the latter can also be attributed to ventilatory constraints13 and redistribution of cardiac output to the respiratory muscles.14 Therefore, tasks that specifically target localized muscle endurance are needed to determine the functional consequences of cellular changes observed in the limb muscles of individuals with COPD.

Muscle endurance and fatigue of the quadriceps (the knee extensor muscle group) have been measured in individuals with COPD by using a variety of techniques. Muscle endurance has been defined as the ability of muscle to perform repeated work and to resist fatigue, whereas muscle fatigue has been defined as a decline in the force-generating capacity of a muscle.15 Muscle fatigue occurs as a result of impairment at one or more points along the pathway for muscle contraction (Fig 1). Because different tasks target different aspects of this pathway, the measurement protocol chosen (type, intensity, frequency, and duty cycle) can have an important effect on study results.16 Different approaches have been used to measure the two interrelated concepts of muscle endurance and fatigue in individuals with COPD, with various results.1719 Consequently, it is not known definitively whether quadriceps muscle endurance is reduced in COPD or how different measurement protocols may influence the interpretation of results.

Figure Jump LinkFigure 1 –  Pathways involved in a muscle contraction. ATP = adenosine trinucleotide phosphate; O2 = oxygen.Grahic Jump Location

The primary aim of this study was to resolve the existing uncertainty about whether quadriceps muscle endurance is reduced in individuals with COPD compared with healthy control subjects and to quantify the difference. The secondary aims were to describe the methodologies reported to measure quadriceps endurance in COPD, investigate whether the type of measurement performed influenced the results, and determine whether disease severity affected the relationship between quadriceps endurance in those with COPD compared with healthy control subjects.

Study Design

We performed a systematic review of studies comparing quadriceps endurance in individuals with COPD with healthy control subjects; our study was consistent with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.20 This study is a systematic review so no ethical approval was sought.

Eligibility Criteria

We included studies involving individuals with COPD and any measurement of quadriceps/knee extensor endurance. Eligibility required a comparison with a healthy control group. All languages were accepted and, if necessary, translated into English. Gray literature searches were performed by screening the references from all relevant review articles and international guidelines.2

Search Strategy

Relevant electronic databases were searched from inception to August 2013: PubMed, EMBASE, CINAHL, PEDro, OVID MEDLINE, and The Cochrane Library. An example of the search strategy used is as follows: (COPD OR chronic obstructive pulmonary disease OR chronic obstructive lung disease OR pulmonary emphysema OR chronic airflow limitation OR chronic airflow obstruction OR chronic obstructive airway disease OR COAD) AND (quadriceps OR knee extensor OR lower limb OR leg OR knee OR thigh) AND (endurance OR contractile fatigue OR muscle fatigue OR muscle contraction. The full search strategy is available from the authors.

Study Selection

After duplicates were removed, the abstracts of all identified citations were reviewed independently by two assessors (R. A. E. and E. K.). The full-text citation was reviewed if one of the assessors concluded it was eligible. The full text was then reviewed by R. A. E., with the final decision for inclusion made by S. M.

Data Extraction

Two reviewers (E. K. and M. K. B.) performed data extraction, which was checked and, when needed, transformed by a third reviewer (R. A. E.) (see Statistical Analysis section). Baseline demographics, spirometry, details of the study design, measurement properties, and results of the measurement were extracted using a standardized form. Study authors were contacted if additional data were needed.

Outcome Measurements:

The primary outcome measure was quadriceps endurance. The units of measurement varied depending on the type of measurement used. A priori we included any measure of muscle endurance, both sustained and intermittent contractions, isometric or isokinetic movement, and intensity (% maximal voluntary contraction [MVC]), measured with either volitional or nonvolitional tasks. In studies in which both volitional and nonvolitional measurements were made, both outcomes were recorded. Studies involving exercise in which a predominant ventilatory limitation was observed were excluded. For example, studies in which the intent of exercise was to reduce the total active muscle, such as single-leg cycling or high-intensity knee-extensor training, but the limitation to exercise remained predominantly a ventilatory limitation rather than a peripheral one, were excluded. Practically, the studies excluded were those in which the mean peak ventilation (L/min) was > 80% of the maximal voluntary ventilation at the end of the test in question.

A high-intensity task was defined as a task involving contractions at > 50% MVC.21 The force-time index was used to quantify the endurance time over a range of power when different versions of a similar protocol had been used. It provides a way to relate fatigue of the muscle system to the relative energy requirements, power or rate of work, of the exercise. The total energy requirements can be related to the rate of relative force accumulation, the product of the force generated, and the duration of force production. The force-time index was plotted against the endurance time, where the force-time index = (contraction force × maximium voluntary contraction) × duty cycle, and the duty cycle = time of the contraction/total time of the cycle.

Quality Assessment

Assessment of the methodologic quality of the studies was performed by two independent researchers (E. K. and R. A. E.), based on the relevant components of the checklist by Downs and Black.22 Any disagreements were resolved by consensus with a third reviewer (S. M.).

Statistical Analysis

Standardized mean differences (SMDs) and their SEs were calculated for each study. The SMD is used as a summary statistic for meta-analyses for studies that all assess the same outcome but measure it in a variety of ways. It expresses the size of the intervention effect in each study relative to the variability observed in that study, and is calculated by taking the difference in the mean outcome measures between the two groups and dividing it by the SD.

When studies reported results by subgroups (eg, separated by sex), numbers were combined to give a single result for each study. SDs were calculated if originally presented as SE using SD = SE × √n, where n represents the sample size. A random-effects meta-analysis was carried out to combine the results across all 21 studies. Separate meta-analyses were also carried out for nonvolitional studies to explore the effects of heterogeneity among studies in terms of measurement technique, and Cohen’s d value was calculated for effect size.23 Metaregression models were fitted to assess the influence of the type of measurement (high vs low intensity) and the disease severity of the population studied on the relationship between quadriceps endurance in individuals with COPD and healthy control subjects.

Identification of Studies

Figure 2 summarizes the process of identifying eligible studies. Of 349 studies, knee extensor/quadriceps muscle endurance was compared between individuals with COPD and healthy control subjects in 25. Two studies (French and Chinese) required translation (the latter was included in the final meta-analysis). Four studies (n = 88 individuals with COPD [15%] and n = 79 healthy control subjects [22%]) were excluded because of missing data, which was unavailable from the authors.2427 Data were, therefore, extracted from 21 studies17,18,2846: 728 individuals with COPD (71.2% male; mean age, 65.1 years; FEV1, 41.5% predicted; FEV1/FVC, 41.7%) and 440 healthy control subjects (67.8% male; mean age, 63.5 years; FEV1, 103.2% predicted; FEV1/FVC, 80.0%). The FEV1/FVC ratio was not reported in nine studies, and one study did not describe the FEV1 % predicted. In 18 of 21 studies, individuals with comorbidities that could influence quadriceps endurance were excluded: cardiovascular (n = 18), renal (n = 8), endocrine (n = 14), liver (n = 7), orthopedic (n = 7), and neurologic (n = 3). Quadriceps strength was measured in all 21 studies and was significantly reduced in 16 of the studies.

Figure Jump LinkFigure 2 –  Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of the literature search.Grahic Jump Location
Description of the Techniques Used

The different techniques used to assess muscle endurance are described in Table 1. Five studies included nonvolitional measurements, and 10 of the 16 studies using volitional measurements involved high-intensity tasks.

Table Graphic Jump Location
TABLE 1 ]  Description of Measurement Used for Each Study and Quality Assessment

The fatigue index is the loss of force expressed either over a period of time or per contraction. EMG = electromyography; MRS = magnetic resonance spectroscopy; MVC = maximum voluntary contraction; N/A = not applicable; T limit = endurance time to exhaustion; reps/min = repetitions per minute.

a 

High intensity defined as a task involving contractions at > 50% MVC.

b 

Repeated dynamic contractions performed on gym equipment.

c 

Solely used a nonvolitional technique.

Quality Assessment

A quality assessment for each study is presented in Table 2. The quality scores tended to be low because of insufficient reporting on recruitment and retention rates and because of blinding. Of note, the study participants were not all clearly described; in five studies, full spirometric data were not reported in the healthy control group. The primary purpose of eight studies was to compare muscle endurance in individuals with COPD and healthy control subjects.

Table Graphic Jump Location
TABLE 2 ]  Quality Analysis of Studies Highlighted From Systematic Review
Quadriceps Endurance in Individuals With COPD Compared With Healthy Control Subjects

Based on the results from 21 studies, quadriceps endurance was reduced in those with COPD compared with healthy control subjects (SMD, 1.16 [95% CI, 1.02-1.30] in favor of the healthy control subjects, P < .001), as shown in Figure 3, In this meta-analysis, a positive SMD showed that the healthy individuals performed better than did the patients with COPD, whereas a negative value indicated that the patients with COPD performed better. Because the SMD combines outcomes that have been measured on different scales, the magnitude of the SMD cannot be interpreted further than this. There was significant heterogeneity among studies (I2 = 93.8%, P < .001).

Figure Jump LinkFigure 3 –  A comparison of quadriceps muscle endurance between individuals with COPD and healthy control subjects. The size of the square relates to the weight of study. ◆ = pooled effect estimate; ES = effect size (standardized mean difference); ID = identification.Grahic Jump Location
Results of Quadriceps Endurance Depending on the Type of Measurement Made

Five studies (from the same research group) used a nonvolitional approach by applying magnetic stimulation to the femoral nerve (Table 1).34,3739,42 For context, the mean duration for individuals with COPD (n = 199) was 87 s, and 107 s for healthy control subjects (n = 110), for a combined mean duration of 93 s. A meta-analysis of these five studies showed a mean difference of 44.5 s (4.5-84.5 s) (48% of the combined duration; P = .029; Cohen’s d = −0.68 [large effect size]) between healthy control subjects and individuals with COPD (Fig 4), with considerably less heterogeneity than for the overall meta-analysis: I2 = 0%, P = .913. Using metaregression analysis, the between-group difference (COPD vs control subjects) was not affected by whether the task was nonvolitional or volitional (P = .223).

Figure Jump LinkFigure 4 –  A comparison of quadriceps endurance between individuals with COPD and healthy control subjects using a nonvolitional measurement. The size of the square relates to the weight of the study. ◆ = pooled effect estimate. See Figure 3 legend for expansion of abbreviations.Grahic Jump Location

The intensity of the tasks was highly variable among the remaining 16 studies, resulting in durations from < 1 min to 20 min.28,30 Metaregression demonstrated that the effect sizes were independent of the task intensity (P = .44). No single study investigated the relationship between power (the energy demand) and endurance (response) across a range of power to test the “normality” of the response among the critical power, strength, and endurance. We, therefore, plotted endurance time vs force-time index for the four studies in which the force-time index could be calculated (Fig 5). It was not possible to calculate either the force-time index or the power from the information provided in the other studies.

Figure Jump LinkFigure 5 –  A comparison of endurance time plotted against the force-time index between individuals with COPD and healthy control subjects. Relative force-time index of repeated contractions = (contraction force × maximium voluntary contraction) × duty cycle, where duty cycle = time of contraction × total time of cycle. tlimit = endurance time.Grahic Jump Location
Results According to the Severity of COPD

There was no significant effect of severity of COPD (based on FEV1 % predicted) on the effect size between individuals with COPD and healthy control subjects in terms of muscle endurance (P = .93). However, most of the studies included only patients with moderate to severe COPD.

This systematic review and meta-analysis confirms a reduction in quadriceps muscle endurance in individuals with COPD compared with healthy control subjects (large effect size), irrespective of the type of measurement protocol used. To our knowledge, this is the first synthesis of measurements of quadriceps endurance in COPD, and it highlights the many different approaches that have been reported to examine localized muscle function in this population.

Impairment of any of the steps involved in muscle contraction, from CNS activation to the excitation-contraction coupling and energy metabolism to produce adenosine trinucleotide phosphate (Fig 1), can reduce the endurance of the muscle. The majority of tasks reported in the literature on COPD required repeated voluntary contractions of the quadriceps to obtain a measure of muscle endurance. Most of these studies reported a reduced endurance time or a faster decline in contractile force in individuals with COPD compared with healthy control subjects. However, because volitional tasks are effort dependent, they can be criticized on the basis of variable subject motivation. Two studies also included an additional nonvolitional measure of muscle fatigue (magnetic twitch force).32,46 Both these studies confirmed a significant reduction in twitch force after exercise in those with COPD, indicating that muscle fatigue had occurred even after a shorter endurance time than in the healthy control participants. A meta-analysis of the five studies34,3739,42 that included only nonvolitional measurements of quadriceps endurance using magnetic stimulation of the femoral nerve confirmed a reduced quadriceps endurance by 44.5 s (large effect size) in those with COPD compared with healthy control subjects. These data indicate that the reduction in muscle endurance reported in COPD is, in part, caused by peripheral mechanisms.

There was a large range in the intensity (% MVC), and thus task duration, across studies, which likely leads to different substrates and cellular pathways being used for energy production and muscular work. Coronell et al30 used very-low-intensity tasks (repeated contractions of 10% MVC) and showed the largest SMD between groups. This type of low-intensity task is more “aerobic” in nature because it allows for adequate blood flow to and from the muscle,47 but it can also be limited by changes in central activation or peripheral factors distal to the neuromuscular junction.48 As such, the expected curvilinear relationship between the force-time index and the endurance time (Fig 5) was observed in healthy control subjects but not in those with COPD3032,35,40; this was mainly influenced by two studies using very-low-intensity protocols. Therefore, it is speculated that both impaired aerobic capacity of the quadriceps muscle and central factors contribute to reduced muscle endurance in COPD.

Some of the studies involved a very-high-intensity task (< 1 min in duration)17,29,33,36,41,45 or sustained isometric contractions18,28,46 in which blood flow would likely be restricted, relying on anaerobic energy sources such as glycolysis.47,49 Type IIX fibers (fast-twitch, fatigable fibers) are known to be atrophied in COPD,50 which, in part, could account for this observation.51 Overall, the reduction in muscle endurance compared with control subjects was noted for both low- and high-intensity tasks.

Clinical Implications

Exercise training is a major therapeutic strategy for individuals with COPD and currently, a combination of aerobic (either cycling or walking) and strength training is recommended.52 The results of this synthesis show that muscle endurance in COPD is reduced, highlighting the need for the inclusion of muscle-specific training. Partitioned training, such as one-legged cycling, has been shown to be more effective than two-legged cycling in improving peak oxygen uptake in COPD,53,54 and one paper reported restored oxidative enzyme activity of the quadriceps using high-intensity knee extensor training (one leg at a time) in COPD.55 There has been interest in the pharmacologic manipulation of the oxidative capacity of skeletal muscle in animal models, and our review highlights the potential relevance of this for individuals with COPD.56,57

Limitations

Four studies (< 20%) had to be excluded because we were unable to obtain the necessary data from the original authors, but there were no differences in the demographics of the study sample between the excluded studies and those included in the meta-analysis. We included all types of muscle endurance and fatigue measures in the meta-analysis, which led to large heterogeneity (I2 = 93.8%). However, the main relationship was unchanged in the meta-analysis restricted to the nonvolitional studies, in which the heterogeneity was substantially reduced. Although the reduction in muscle endurance was independent of measured airflow obstruction, our results may be subject to population bias, given the lack of individuals with milder reductions in airflow obstruction. This review pertains to the large quadriceps muscle group of the leg only, and the results should not be extrapolated to other muscle groups that may have different usage and fatigue properties.

The low-quality assessment results of the included studies are also a limitation of the review, but likely did not affect our findings given the large number of studies that were included. Nonetheless, the results highlight the need for improved adherence to reporting standards for future work.

We have shown, in a large number of individuals with COPD, that quadriceps endurance is reduced compared with healthy control subjects, independent of type of task and measurement technique. In addition to the cellular changes that have been observed in muscle oxidative capacity, neuromotor changes that may contribute to the early onset of muscle fatigue should be further examined in this population. Our findings have implications for the development of pharmacologic and nonpharmacologic therapies targeted at improving skeletal muscle endurance.

Author contributions: R. A. E. is the guarantor of the paper, taking responsibility for the integrity of the work as a whole, from inception to the published article. R. A. E., R. S. G., D. B., and S. M. contributed to the study design; R. A. E. contributed to the identification of the eligible full-text studies and review of the quality assessment; E. K. contributed to the literature search; R. A. E. and E. K. contributed to the review of the abstracts for eligibility; E. K. and M. K. B. contributed to the data extraction and quality assessment; R. A. E., T. E. D., and C. L. G. contributed to the data analysis; C. L. G. contributed to the statistical support; S. M. contributed to the final consensus decisions; R. A. E. and S. M. contributed to the drafting of the manuscript; and E. K., M. K. B., T. E. D., R. S. G., C. L. G., D. B., and S. M. contributed to the critical revision of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: This article/paper/report presents independent research supported by the National Institute for Health Research (NIHR). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.

Other contributions: We are grateful to Erin Hamanishi, PhD, for designing Figure 1. We thank Amanda Natanek, PhD; Abigail Jackson, PhD; and Tania Janaudis-Ferreira, PhD, for the extra data they supplied.

MVC

maximal voluntary contraction

SMD

standardized mean difference

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Malaguti C, Nery LE, Dal Corso S, et al. Scaling skeletal muscle function to mass in patients with moderate-to-severe COPD. Eur J Appl Physiol. 2006;98(5):482-488. [CrossRef] [PubMed]
 
Man WD, Natanek SA, Riddoch-Contreras J, et al. Quadriceps myostatin expression in COPD. Eur Respir J. 2010;36(3):686-688. [CrossRef] [PubMed]
 
Natanek SA, Gosker HR, Slot IG, et al. Heterogeneity of quadriceps muscle phenotype in chronic obstructive pulmonary disease (COPD); implications for stratified medicine? Muscle Nerve. 2013;48(4):488-497. [CrossRef] [PubMed]
 
Natanek SA, Gosker HR, Slot IG, et al. Pathways associated with reduced quadriceps oxidative fibres and endurance in COPD. Eur Respir J. 2013;41(6):1275-1283. [CrossRef] [PubMed]
 
Orozco-Levi M, Coronell C, Ramírez-Sarmiento A, et al. Injury of peripheral muscles in smokers with chronic obstructive pulmonary disease. Ultrastruct Pathol. 2012;36(4):228-238. [CrossRef] [PubMed]
 
Rabinovich RA, Bastos R, Ardite E, et al. Mitochondrial dysfunction in COPD patients with low body mass index. Eur Respir J. 2007;29(4):643-650. [CrossRef] [PubMed]
 
Swallow EB, Gosker HR, Ward KA, et al. A novel technique for nonvolitional assessment of quadriceps muscle endurance in humans. J Appl Physiol (1985). 2007;103(3):739-746. [CrossRef] [PubMed]
 
van den Borst B, Slot IG, Hellwig VA, et al. Loss of quadriceps muscle oxidative phenotype and decreased endurance in patients with mild-to-moderate COPD. J Appl Physiol (1985). 2013;114(9):1319-1328. [CrossRef] [PubMed]
 
Van’t Hul A, Harlaar J, Gosselink R, Hollander P, Postmus P, Kwakkel G. Quadriceps muscle endurance in patients with chronic obstructive pulmonary disease. Muscle Nerve. 2004;29(2):267-274. [CrossRef] [PubMed]
 
Vilaro J, Rabinovich R, Gonzalez-deSuso JM, et al. Clinical assessment of peripheral muscle function in patients with chronic obstructive pulmonary disease. Am J Phys Med Rehabil. 2009;88(1):39-46. [CrossRef] [PubMed]
 
Ju CR, Chen RC. Investigation of the quadriceps strength in patients with chronic obstructive pulmonary disease [in Chinese]. Zhonghua Jie He He Hu Xi Za Zhi. 2008;31(8):566-570. [PubMed]
 
Sjøgaard G, Savard G, Juel C. Muscle blood flow during isometric activity and its relation to muscle fatigue. Eur J Appl Physiol Occup Physiol. 1988;57(3):327-335. [CrossRef] [PubMed]
 
Gandevia SC. Spinal and supraspinal factors in human muscle fatigue. Physiol Rev. 2001;81(4):1725-1789. [PubMed]
 
Sjøgaard G, Kiens B, Jørgensen K, Saltin B. Intramuscular pressure, EMG and blood flow during low-level prolonged static contraction in man. Acta Physiol Scand. 1986;128(3):475-484. [CrossRef] [PubMed]
 
Gosker HR, Kubat B, Schaart G, van der Vusse GJ, Wouters EF, Schols AM. Myopathological features in skeletal muscle of patients with chronic obstructive pulmonary disease. Eur Respir J. 2003;22(2):280-285. [CrossRef] [PubMed]
 
Thorstensson A, Karlsson J. Fatiguability and fibre composition of human skeletal muscle. Acta Physiol Scand. 1976;98(3):318-322. [CrossRef] [PubMed]
 
Nici L, Donner C, Wouters E, et al; ATS/ERS Pulmonary Rehabilitation Writing Committee. American Thoracic Society/European Respiratory Society statement on pulmonary rehabilitation. Am J Respir Crit Care Med. 2006;173(12):1390-1413. [CrossRef] [PubMed]
 
Bjørgen S, Hoff J, Husby VS, et al. Aerobic high intensity one and two legs interval cycling in chronic obstructive pulmonary disease: the sum of the parts is greater than the whole. Eur J Appl Physiol. 2009;106(4):501-507. [CrossRef] [PubMed]
 
Dolmage TE, Goldstein RS. Effects of one-legged exercise training of patients with COPD. Chest. 2008;133(2):370-376. [CrossRef] [PubMed]
 
Brønstad E, Rognmo O, Tjonna AE, et al. High-intensity knee extensor training restores skeletal muscle function in COPD patients. Eur Respir J. 2012;40(5):1130-1136. [CrossRef] [PubMed]
 
Narkar VA, Downes M, Yu RT, et al. AMPK and PPARdelta agonists are exercise mimetics. Cell. 2008;134(3):405-415. [CrossRef] [PubMed]
 
Goodyear LJ. The exercise pill—too good to be true? N Engl J Med. 2008;359(17):1842-1844. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Pathways involved in a muscle contraction. ATP = adenosine trinucleotide phosphate; O2 = oxygen.Grahic Jump Location
Figure Jump LinkFigure 2 –  Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of the literature search.Grahic Jump Location
Figure Jump LinkFigure 3 –  A comparison of quadriceps muscle endurance between individuals with COPD and healthy control subjects. The size of the square relates to the weight of study. ◆ = pooled effect estimate; ES = effect size (standardized mean difference); ID = identification.Grahic Jump Location
Figure Jump LinkFigure 4 –  A comparison of quadriceps endurance between individuals with COPD and healthy control subjects using a nonvolitional measurement. The size of the square relates to the weight of the study. ◆ = pooled effect estimate. See Figure 3 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 5 –  A comparison of endurance time plotted against the force-time index between individuals with COPD and healthy control subjects. Relative force-time index of repeated contractions = (contraction force × maximium voluntary contraction) × duty cycle, where duty cycle = time of contraction × total time of cycle. tlimit = endurance time.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Description of Measurement Used for Each Study and Quality Assessment

The fatigue index is the loss of force expressed either over a period of time or per contraction. EMG = electromyography; MRS = magnetic resonance spectroscopy; MVC = maximum voluntary contraction; N/A = not applicable; T limit = endurance time to exhaustion; reps/min = repetitions per minute.

a 

High intensity defined as a task involving contractions at > 50% MVC.

b 

Repeated dynamic contractions performed on gym equipment.

c 

Solely used a nonvolitional technique.

Table Graphic Jump Location
TABLE 2 ]  Quality Analysis of Studies Highlighted From Systematic Review

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Man WD, Natanek SA, Riddoch-Contreras J, et al. Quadriceps myostatin expression in COPD. Eur Respir J. 2010;36(3):686-688. [CrossRef] [PubMed]
 
Natanek SA, Gosker HR, Slot IG, et al. Heterogeneity of quadriceps muscle phenotype in chronic obstructive pulmonary disease (COPD); implications for stratified medicine? Muscle Nerve. 2013;48(4):488-497. [CrossRef] [PubMed]
 
Natanek SA, Gosker HR, Slot IG, et al. Pathways associated with reduced quadriceps oxidative fibres and endurance in COPD. Eur Respir J. 2013;41(6):1275-1283. [CrossRef] [PubMed]
 
Orozco-Levi M, Coronell C, Ramírez-Sarmiento A, et al. Injury of peripheral muscles in smokers with chronic obstructive pulmonary disease. Ultrastruct Pathol. 2012;36(4):228-238. [CrossRef] [PubMed]
 
Rabinovich RA, Bastos R, Ardite E, et al. Mitochondrial dysfunction in COPD patients with low body mass index. Eur Respir J. 2007;29(4):643-650. [CrossRef] [PubMed]
 
Swallow EB, Gosker HR, Ward KA, et al. A novel technique for nonvolitional assessment of quadriceps muscle endurance in humans. J Appl Physiol (1985). 2007;103(3):739-746. [CrossRef] [PubMed]
 
van den Borst B, Slot IG, Hellwig VA, et al. Loss of quadriceps muscle oxidative phenotype and decreased endurance in patients with mild-to-moderate COPD. J Appl Physiol (1985). 2013;114(9):1319-1328. [CrossRef] [PubMed]
 
Van’t Hul A, Harlaar J, Gosselink R, Hollander P, Postmus P, Kwakkel G. Quadriceps muscle endurance in patients with chronic obstructive pulmonary disease. Muscle Nerve. 2004;29(2):267-274. [CrossRef] [PubMed]
 
Vilaro J, Rabinovich R, Gonzalez-deSuso JM, et al. Clinical assessment of peripheral muscle function in patients with chronic obstructive pulmonary disease. Am J Phys Med Rehabil. 2009;88(1):39-46. [CrossRef] [PubMed]
 
Ju CR, Chen RC. Investigation of the quadriceps strength in patients with chronic obstructive pulmonary disease [in Chinese]. Zhonghua Jie He He Hu Xi Za Zhi. 2008;31(8):566-570. [PubMed]
 
Sjøgaard G, Savard G, Juel C. Muscle blood flow during isometric activity and its relation to muscle fatigue. Eur J Appl Physiol Occup Physiol. 1988;57(3):327-335. [CrossRef] [PubMed]
 
Gandevia SC. Spinal and supraspinal factors in human muscle fatigue. Physiol Rev. 2001;81(4):1725-1789. [PubMed]
 
Sjøgaard G, Kiens B, Jørgensen K, Saltin B. Intramuscular pressure, EMG and blood flow during low-level prolonged static contraction in man. Acta Physiol Scand. 1986;128(3):475-484. [CrossRef] [PubMed]
 
Gosker HR, Kubat B, Schaart G, van der Vusse GJ, Wouters EF, Schols AM. Myopathological features in skeletal muscle of patients with chronic obstructive pulmonary disease. Eur Respir J. 2003;22(2):280-285. [CrossRef] [PubMed]
 
Thorstensson A, Karlsson J. Fatiguability and fibre composition of human skeletal muscle. Acta Physiol Scand. 1976;98(3):318-322. [CrossRef] [PubMed]
 
Nici L, Donner C, Wouters E, et al; ATS/ERS Pulmonary Rehabilitation Writing Committee. American Thoracic Society/European Respiratory Society statement on pulmonary rehabilitation. Am J Respir Crit Care Med. 2006;173(12):1390-1413. [CrossRef] [PubMed]
 
Bjørgen S, Hoff J, Husby VS, et al. Aerobic high intensity one and two legs interval cycling in chronic obstructive pulmonary disease: the sum of the parts is greater than the whole. Eur J Appl Physiol. 2009;106(4):501-507. [CrossRef] [PubMed]
 
Dolmage TE, Goldstein RS. Effects of one-legged exercise training of patients with COPD. Chest. 2008;133(2):370-376. [CrossRef] [PubMed]
 
Brønstad E, Rognmo O, Tjonna AE, et al. High-intensity knee extensor training restores skeletal muscle function in COPD patients. Eur Respir J. 2012;40(5):1130-1136. [CrossRef] [PubMed]
 
Narkar VA, Downes M, Yu RT, et al. AMPK and PPARdelta agonists are exercise mimetics. Cell. 2008;134(3):405-415. [CrossRef] [PubMed]
 
Goodyear LJ. The exercise pill—too good to be true? N Engl J Med. 2008;359(17):1842-1844. [CrossRef] [PubMed]
 
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