235

ORIGINAL RESEARCH

Distal Leg Muscle Function in Patients with COPD Philippe Gagnon,1 François Maltais,1 Laurent Bouyer,2 Fernanda Ribeiro,1 Valérie Coats,1 Cynthia Brouillard,1 Martin Noël,2 Mathieu Rousseau-Gagnon,1 and Didier Saey1

1 Centre de recherche, Institut Universitaire de cardiologie et de pneumologie de Québec, Université Laval, Québec, Canada

2 Centre interdisciplinaire de recherche en réadaptation et intégration sociale, Université Laval, Québec, Canada

P. Gagnon is a recipient of a research training award of the Fonds de la Recherche en Santé du Québec (FRSQ). F. Maltais holds a GSK/CIHR Research Chair on COPD at Université Laval. L. Bouyer was supported by the Natural Sciences and Engenering Research Council of Canada (NSERG). For this study, D. Saey has been supported by the Réseau en Santé Respiratoire du FRSQ and Association Pulmonaire du Québec (APQ).

Additional Methods and Results data are available on the online supplementary material.

Keywords: Chronic obstructive pulmonary disease, Mmuscle fatigue, Eexercise, Mmuscle function, Mmuscle strength.

Correspondence to: Didier Saey, Institut Universitaire de cardiologie et de, pneumologie de Québec, 2725 Chemin Ste-Foy, Québec, Québec, G1V 4G5, Canada, phone: 418-656-8711, # 2614, fax: 418-656-4509, email: didier.saey@rea.ulaval.ca

Abstract

Quadriceps muscle weakness and increased fatigability are well described in patients with chronic obstructive pulmonary disease (COPD). Whether these functional alterations also exist in distal leg muscles in patients with COPD is uncertain. Fifteen patients with COPD and 15 aged-matched healthy controls performed a 12-minute standardized treadmill exercise during which a ! xed total expense of 40 Kcal was reached. The strength of i) dorsi" exors, ii) plantar " exors and iii) quadriceps was assessed at rest and after exercise using maximal voluntary contraction (MVC) and potentiated twitch force (Twpot). Resting MVC and Twpot were signi! cantly lower in patients with COPD when compared with controls respectively for i) dorsi" exors (24.9 ± 8.4 vs. 31.2 ± 8.5 Nm, p < 0.05 and 4.3 ± 1.3 vs. 5.7 ± 1.8 Nm, p < 0.05), ii) plantar " exors (49.5 ± 11.8 vs. 62.1 ± 19.6 Nm, p < 0.05 and 10.8 ± 3.5 vs. 13.4 ± 2.7 Nm, p < 0.05), and iii) quadriceps muscles. There was a greater force loss in the distal leg muscles 15 minutes post-exercise in patients with COPD, while the strength of the quadriceps muscle remained stable in both groups. Patients with COPD had weaker dorsi" exor and plantar " exor muscles when compared to age-matched healthy controls. In addition, when exposed to the same absolute walking task, the fatigability of the distal leg muscles was higher in patients with COPD.

COPD, 10:235–242, 2013ISSN: 1541-2555 print / 1541-2563 onlineCopyright © Informa Healthcare USA, Inc.DOI: 10.3109/15412555.2012.719047

IntroductionExercise intolerance is a hallmark feature in chronic obstructive pulmonary disease (COPD) and plays an important role in compromising quality of life in this disease (1). Although ventilatory and gas exchange abnormalities are crucial to explain exercise limitation in patients with COPD, some studies also point to the contributing role of peripheral muscle function (2, 3). For instance, quadriceps muscle strength, endurance and metabolic e! ciency are often compromised in patients with COPD when compared with healthy controls (4, 5).

" e quadriceps has been the main focus in the characterization of the peripheral muscle alterations occurring in COPD (6, 7). However, leg muscles such as the tibialis anterior and the gastrocnemius may also be involved in the process of limb muscle dysfunction associated with COPD (8). " erefore, despite their importance in walking activities, a more complete characteriza-tion of the function of these additional leg muscles in patients with COPD is still awaiting. " is information could be relevant in providing a better understanding of limb muscle dysfunction in COPD and also contribute to optimizing pulmonary rehabilitation programs.

COPD

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f Lav

al o

n 04

/02/

13Fo

r per

sona

l use

onl

y.

Copyright © 2013 Informa Healthcare USA, Inc

236 P. Gagnon et al.

Most of the work investigating the issue of quadriceps fatigue in COPD was done using cycle ergometry (3, 9, 10) because quadriceps is intensely solicited during this form of exercise. As opposed to walking, cycling does not elicit an important demand for the distal leg muscles such as the dorsi and plantar fl exors, and is therefore not the exercise modality of choice to investigate their function. In fact, cycling and walking have di# erent con-sequences in the development of muscle fatigue (11). Although cycling can easily induce quadriceps fatigue in the context of COPD (7, 12), walking is likely to be more appropriate to study leg muscle fatigue suscepti-bility (8). Moreover, a walking-based exercise protocol is more likely to refl ect daily life activities of patients with COPD than cycling.

Consequently, we aimed to characterize the strength and fatigability of distal leg muscles following a stan-dardised walking e# ort in patients with COPD. We hypothesized that dorsi and plantar fl exors would show weakness and greater fatigability following walking exercise in patients with COPD compared to healthy controls. To test this hypothesis, volitional and non-volitional strength of i) the dorsifl exors, ii) the plantar fl exors, and iii) the quadriceps where measured and compared before and after a treadmill walking exercise inducing similar energy expenditure in patients with COPD and healthy controls.

MethodsSee the supplementary material for additional information.

SubjectsFifteen GOLD stage II-III patients with COPD (post-bronchodilator FEV1 > 30% and < 80% predicted and FEV1/FVC < 0.70) (13) and 15 sedentary healthy sub-jects paired for gender and age were included in the study. Patients were excluded if they had a recent exac-erbation ($ 4 weeks), diabetes mellitus, neoplasia or any medical condition, other than COPD, likely to infl uence muscle and exercise testing (i.e., cardiovascular, neuro-logical, musculoskeletal, locomotor or other respiratory diseases as well as ß-blockers therapy). Subjects were asked to avoid alcohol, ca# eine and heavy meals 3 hours before the visit and high intensity physical activity for at least 24 hours before testing. " e research protocol was approved by the institutional ethics committee and a signed informed consent was obtained from every subject prior to enrollment.

Study design" e study consisted in three distinct visits. " e initial visit included anthropometric measurements, complete pulmonary function test and familiarization with the incremental maximal walking test to be performed dur-ing the second visit. During the second visit, a progres-sive maximal walking test was performed on a treadmill.

During the same visit, parameters (slope, speed) of the standardized 40 Kcal-expense walking exercise were determined and patients were familiarized with endur-ance walking exercise. " e second and third visits were seven days apart, a period during which the level of daily physical activity was directly quantifi ed using a portable activity monitor.

" e third visit included resting strength measure-ments of i) the dorsifl exors, ii) the plantar fl exors, and iii) the quadriceps. Finally, following a standardized 40 Kcal-expense walking exercise, fatigue of the aforemen-tioned muscle groups was again assessed by measur-ing muscle strength at 15 minutes post-exercise and by calculating the di# erence between the resting and the respective post-exercise value. In a small subset of patients (8 patients with COPD and 6 healthy subjects), fatigue was also quantifi ed at 40 minutes post-exercise.

Pulmonary function testingStandard pulmonary function tests, including spirom-etry, lung volumes, and di# usion capacity were obtained according to previously described guidelines (14) and related to predicted normal values (15). " e predicted value for inspiratory capacity was obtained by subtract-ing the functional residual capacity predicted value from total lung capacity predicted value. Maximum voluntary ventilation was estimated by multiplying FEV1 by 35 (16).

Physical activity levelPhysical activity in daily life was monitored during 7 consecutive days for at least 12 hours a day via a portable device (SenseWear® ArmBand, Bodymedia inc., Pitts-burgh, USA) worn on the right upper arm. " e device measures the number of daily steps and estimates the total caloric expense for moderately intense activities, i.e., beyond a fi xed metabolic equivalent (>3 METs). We reported the mean daily values for these variables over the whole measurement period.

Exercise testingIncremental walking test (IWT)" e test was performed on a treadmill to determine peak exercise capacity. Accordingly, we used an algo-rithm designed to yield a linear increase in workload on a treadmill until exhaustion (17). " e test was built on a 10-minute ramp-fashion (20 steps of 30 seconds) with a prior 3-minute warm-up period. During the test, sub-jects were connected to a portable gas exchange analyzer (Oxycon Mobile, Viasys Healthcare, Jaeger, Germany) to monitor ventilation (V

.E), oxygen consumption (V

. O2), CO2 output (V

. CO2 ) and respiratory exchange ratio (RER). Oxygen pulse saturation (SpO2) was measured at baseline and during exercise using a pulse oxymeter (Nellcor N-395, Covidien, Boulder, CO, USA). Blood pressure was measured manually at baseline and at end-exercise. Dyspnea and leg fatigue Borg scores (18) were obtained at baseline, every 2 minutes and at the end of

COPD

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f Lav

al o

n 04

/02/

13Fo

r per

sona

l use

onl

y.

Distal Leg Muscles in COPD 237

www.copdjournal.com

exercise. A 12-lead electrocardiogram (JECG 12ch, Via-sys Healthcare, Jaeger, Germany) was used to monitor cardiac electrical activity throughout exercise.

Standardized endurance walking test (EWT)" e EWT was realized in the same setting as the IWT. Parameters of the endurance test were set to obtain a 40 Kcal expense in every subject during a fi xed walking duration of 12 minutes, according to prediction equa-tions (19). " e required treadmill slope to obtain the pre-determined 40 Kcal energy expenditure was determined according to the weight of the patient, after choosing his own comfortable walking pace. " e fi xed energy expenditure of 40 Kcal was chosen mainly to reproduce a realistic daily living task performed by patients with COPD. " e 40 Kcal energy expenditure was calculated to represent a 12-minute walking exercise at 4 km/h, a pace that can be maintain by most patients with mod-erate-to-severe patients with COPD (20) and refl ecting daily physical tasks such as a walk to the grocery. Car-diorespiratory response was monitored using the same setup as for IWT. Dyspnea and leg fatigue Borg scores (18) were obtained every 2 minutes during exercise and blood pressure was measured manually at the beginning and at the end of EWT.

Muscle strength measurementsStrength of the dominant lower extremity was mea-sured at rest and 15 minutes after EWT. Subjects were seated in a recumbent chair (N-K 330 Exercise Table; N-K Products, Elsinore, CA) with 90° knee fl exion and the ankle attached to a strain gauge (Hewlett-Packard, Houston, TX). Maximal voluntary contraction (MVC) and potentiated twitch force (Twpot) of the quadriceps were measured as previously reported (3). To mea-sure the strength of the dominant dorsi and plantar fl exors, the ankle was fi xed into a custom-made ankle foot orthosis (AFO) specifi cally designed to measure torque production at the ankle (Figure 1). Muscle force was transmitted to a load cell (Transducer Techniques, model MLP-150) inserted in a rod of the orthosis: plan-tar fl exors contraction produces load cell compression, although dorsifl exors contraction produces tension.

" e foot was always parallel to the ground during torque measurements. Volitional strength of the dorsi and plantar fl exors were measured during a set of 3 iso-metric MVCs sustained for 3 seconds, and subjects were asked to produce their maximum e# ort. During this manoeuver, verbal encouragements were provided and each MVC was separated by 1 minute of rest. " e great-est value sustained over 2 seconds was defi ned as MVC. Twpot force of the dorsi and plantar fl exors was obtained with the foot in the same device, using magnetic stimu-lation (Magstim 200; Magstim Co Ltd; Whitland, Dyfed, Wales, UK) connected to a 42 mm fi gure-of-eight coil to stimulate the peroneal and tibial nerves, respectively. A Tw/power output relationship was obtained for each patient and for each muscle to evaluate whether the

magnetic stimulation was supramaximal and to ensure an optimal localization of the coil. Reported values for twitch measures are the mean of the two strongest contractions, and torque is reported in Newton meters (Nm).

In 8 patients with COPD and 6 controls, strength measurements were repeated 40 minutes post-exercise. Additional details on the AFO, validity, reproducibility of this method and supramaximality in distal leg mus-cles in COPD are available on the online supplementary material.

Statistical analysisResults are expressed as mean ± S.D. Baseline charac-teristics of the subjects were compared using unpaired t-test. End-exercise values for ventilation (V

.E), oxygen

consumption (V. O2), carbon dioxide output (V

.CO2), V

.E/V

.CO2, tidal volume (VT), breathing frequency (Bƒ),

respiratory exchange ratio (RER), heart rate (HR), O2pulse, pulse oxygen saturation (SpO2) and Borg scores were compared between the two groups using one-way ANOVA analysis. Time courses of muscle strength data before and after exercise were analyzed by a mixed model using two fi xed experimental factors, one asso-ciated with the between-group comparisons and the other with the within-group comparisons. Pearson cor-relations coe! cients corrected for multiple testing were performed to examine the association between quadri-ceps and ankle muscles strength and markers of physical activity in daily life. A statistical level of signifi cance of 0.05 was used for all analysis. " e data were analyzed using JMP statistical package (Version 8.0.1, SAS Insti-tute Inc., Cary, NC).

Because no data are available on dorsi and plantar fl exors strength in patients with COPD, the study sample size calculation was based on the expected di# erence in baseline MVC of the quadriceps as previously reported

Aluminum shaft(upper part)

Aluminum shaft(lower part)

Load cell

Footplate

Calf band

Figure 1. Custom-made ankle foot orthosis designed to measure dorsi and plantar ! exors muscle force.

COPD

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f Lav

al o

n 04

/02/

13Fo

r per

sona

l use

onl

y.

Copyright © 2013 Informa Healthcare USA, Inc

238 P. Gagnon et al.

by our laboratory (3). Eleven subjects in both groups were necessary to detect an 11 ± 10 Nm di# erence in quadriceps strength between controls and patients with COPD, with % = 0.05 and 1–& = 0.90.

ResultsSubjectsCharacteristics of the subjects are presented in Table 1. Groups were well matched for age, gender distribution and body mass index. Patients with COPD had, on average, moderate to severe airfl ow obstruction with evidence of gas trapping and reduced di# usion capac-ity. " ey also exhibited decreased exercise capacity and lower levels of daily physical activity when compared with healthy controls.

Resting muscle strength assessmentVolitional and non-volitional resting strengths of the dorsifl exors, plantar fl exors and quadriceps were sig-nifi cantly lower in patients with COPD than in controls (Figure 2, panels A, and B). Signifi cant correlations were found between resting MVC and Twpot for the dorsifl ex-ors (r = 0.67, p < 0.001), plantar fl exors (r = 0.39, p < 0.05) and quadriceps (r = 0.76, p < 0.001). " e number of daily steps per day (r = 0.44, p < 0.05) and the energy expenditure > 3 METs (r = 0.54, p < 0.01) were related to resting plantar fl exors MVC. Finally, the peak work-load reached during the IWT was related to the plantar fl exors (R = 0.45, p = 0.01) and dorsifl exors (R = 0.51, p = 0.003) MVCs.

Exercise response to standardized endurance walking test To reach the targeted 40 Kcal expense during the fi xed walking time of 12 minutes, patients with COPD and healthy controls respectively completed the exercise with a similar mean treadmill speed (2.9 ± 0.3 vs. 3.1 ± 0.4 km h–1, p = 0.12) and slope (1.8 ± 1.8 vs. 1.4 ± 1.5 %, p = 0.54). Patients with COPD reached the predetermined energy expenditure at the expense of a higher ventilatory requirement (the consequence of lower ventilatory e! -ciency) and a lower ventilatory reserve (higher V

.E/MVV

ratio) in comparison to controls (Table 2). Patients with COPD were also more short of breath and perceived more leg fatigue at the end of exercise, as indicated by a higher Borg score. Heart rate was higher at the end of exercise in COPD.

Table 1. Subject characteristics.

Controls (n =15)

COPD (n =15)

Age, yr 64 ± 4 65 ± 3

Gender (M/F) (10/5) (9/6)

Height, cm 167 ± 9 166 ± 8

Weight, kg 69 ± 8 70 ± 12

Body mass index, kg/m2 25 ± 2 26 ± 4

Pack-years 16 ± 20 48 ± 37*

FEV1, L 3.19 ± 0.78 1.38 ± 0.49**

% predicted 118 ± 17 54 ± 19**

FVC, L 4.19 ± 0.90 3.11 ± 1.02*

% predicted 125 ± 15 96 ± 21**

FEV1/FVC, % 76 ± 5 45 ± 12**

IC, L 2.93 ± 0.76 2.31 ± 0.66*

% predicted 107 ± 16 90 ± 16*

TLC, L 6.23 ± 1.14 6.42 ± 1.52

% predicted 105 ± 13 109 ± 12

FRC, L 3.31 ± 0.76 4.04 ± 1.16

% predicted 104 ± 23 126 ± 26*

RV, L 1.98 ± 0.54 3.13 ± 0.88*

% predicted 89 ± 25 141 ± 33**

DLCO, % predicted 84 ± 12 51 ± 15**

V.

O2peak, mL•kg1•min–1 28.1 ± 4.9 18.7 ± 2.8**

Daily physical activity

Steps per day 8949 ± 3217 5081 ± 2758*

Energy expenditure > 3 METs, Kcal 582 ± 342 229 ± 211*

De! nitions of abbreviations: FEV1= forced expiratory volume in 1 second; FVC = forced vital capacity; IC = inspiratory capacity; TLC = total lung capacity; FRC = functional residual capacity; RV= residual volume; DLCO = diffusion capacity; V

.O2

peak= peak oxygen uptake during incremental walking; METs= metabolic equivalent. Values are mean ± SD. *p < 0.05 vs. healthy controls; ** p < 0.0001 vs. healthy controls.

Mus

cle

torq

ue (N

m)

0

20

40

60

80

100

120

140

QuadricepsDorsiflexors Plantarflexors 0

20

40

60

80

QuadricepsDorsiflexors Plantarflexors

ControlsCOPDA B

*

**

*

*

*

Figure 2. Baseline strength of i) dorsi! exors, ii) plantar ! exors and iii) quadriceps for maximal voluntary contraction (MVC – panel A) and potentiated twitch force (Twpot – panel B) in patients with COPD (! lled bars) and healthy control subjects (open bars). Values are mean ± SD. * p < 0.05 vs. controls.

COPD

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f Lav

al o

n 04

/02/

13Fo

r per

sona

l use

onl

y.

Distal Leg Muscles in COPD 239

www.copdjournal.com

Muscle fatigue assessmentBoth, volitional and nonvolitional strength of the dorsi and plantar fl exors were signifi cantly reduced follow-ing walking in patients with COPD (Figure 3, panels A and B). " e fall in dorsi and plantar fl exors MVC and Twpot after walking was more pronounced in patients with COPD than in controls (Figure 3, panels A and B). " ere was no signifi cant decline in quadriceps strength following walking in both groups. Finally, fatigue at 15 minutes post-exercise as assessed by the fall in Twpot

expressed in % resting value was inversely related to the peak workload determined during IWT for plantar fl ex-ors (R = –0.47, p = 0.009) and dorsifl exors (R = –0.57, p = 0.001).

Dorsifl exors Twpot was still reduced at 40 minutes post-exercise in patients with COPD, yet values in healthy controls had returned to resting values (Figure 4, panel B). At the same time post-exercise, plantar fl ex-ors’ strength had recovered in both groups (Figure 4, panel D).

Discussion" e novel contribution of the present study is to provide a specifi c characterization of the strength and fatigue susceptibility of the leg dorsi and plantar fl exors in patients with COPD. To this extent, our results empha-size that patients with COPD presenting weaker quadri-ceps muscles strength also have weaker dorsi and plantar fl exors muscles when compared to age-matched healthy controls. Similarly, these patients exhibit an increased susceptibility to fatigue in the distal leg muscles follow-ing a walking exercise of similar energy expenditure. " ese fi ndings are particularly relevant considering that walking is a central activity in daily living for patients with COPD.

Weakness of the leg muscles in COPDQuadriceps muscle dysfunction has been well described in patients with COPD, as much for its functional (4, 21), structural (22) and metabolic properties (23). Interest-ingly, very few studies focused on the distal leg muscles in COPD, probably because the quadriceps is readily acces-sible for study and that it is considered to be representa-tive of all the lower limb muscles. Our results highlight that distal leg muscles fatigue may also occur in conjunc-tion with quadriceps weakness in patients with COPD. " is is likely to be clinically relevant given the important contribution of distal leg muscles during walking (24) and the cardinal importance of walking for daily living (25).

-20

-15

-10

-5

0QuadricepsDorsiflexors Plantarflexors

*-60

-50

-40

-30

-20

-10

0QuadricepsDorsiflexors Plantarflexors

**

*ControlsCOPD BAFo

rce

loss

from

bas

elin

e (%

)

Figure 3. Post-exercise loss in strength for the i) dorsi! exors, ii) plantar ! exors and iii) quadriceps for maximal voluntary contraction (MVC – panel A) and potentiated twitch force (Twpot – panel B) in patients with COPD (! lled bars) and healthy control subjects (open bars). Values are mean ± SD and expressed as the % fall from resting values. * p < 0.05 vs. controls.

Table 2. End-exercise cardiorespiratory response to standardized endurance walking test.

Controls (n =15)

COPD (n =15) p-value

V.

O2, L/min 0.811 ± 0.188 0.858 ± 0.163 0.48

V.

O2, % V.

O2peak during IWT 42 ± 12 70 ± 25* 0.001

V.

CO2, L/min 0.749 ± 0.183 0.787 ± 0.133 0.53

V.

E, L/min 23.2 ± 6.1 27.6 ± 5.1* 0.04

V.

E/MVV, % 22 ± 8 64 ± 30* < 0.001

V.

E/V.

CO231.0 ± 3.7 35.3 ± 3.5* 0.004

VT, L 1.04 ± 0.24 1.16 ± 0.22 0.19

Bƒ, breath/min 24 ± 6 24 ± 6 0.81

RER 0.92 ± 0.04 0.92 ± 0.04 0.89

HR, beat/min 86 ± 9 95 ± 9* 0.02

O2 pulse, mL O2/beat 9.4 ± 2.0 9.1 ± 1.8 0.66

SpO2, % 97 ± 1 95 ± 4 0.07

Dyspnea, Borg score 1 ± 1 4 ± 2* < 0.001

Leg fatigue, Borg score 1 ± 1 4 ± 2* 0.001

De! nitions of abbreviations: V.O2 = oxygen uptake; IWT: incremental walking test; V

.CO2 =

CO2 output; V.

E = minute ventilation; MVV = maximal voluntary ventilation obtained by multiplying FEV1 by 35; VT = tidal volume; Bƒ = breathing frequency; RER = respiratory exchange ratio; HR = heart rate; SpO2 = pulse oxygen saturation. Values are mean ± SD. * p < 0.05 vs. healthy controls.

COPD

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f Lav

al o

n 04

/02/

13Fo

r per

sona

l use

onl

y.

Copyright © 2013 Informa Healthcare USA, Inc

240 P. Gagnon et al.

Our results are at variance with those of Seymour and colleagues, who did not fi nd weakness of the dorsifl exors in COPD patients with similar fat-free mass to healthy controls (26). Body composition was not assessed in the present study, and as such we cannot comment on whether leg muscle weakness in our subjects could be the result of an atrophying process. Along those lines, we pre-viously reported atrophy of the calf muscle in COPD (8).

Susceptibility to fatigue of the distal leg muscles in COPD" e development of fatigue after walking only in the distal leg muscle groups and not in quadriceps underlines the important solicitation of the former muscles during walk-ing. " ese fi ndings are important because they illustrate that fatigue of the distal limb may be an issue in patients during activity of daily living. Although the vastus latera-lis and the rectus femoris may express electrical evidence of fatiguing contraction during self-paced walking using electromyographic analysis in COPD patients (8), we only found trivial loss in muscle force of the quadriceps

after the treadmill exercise. " e absence of fatigue in the quadriceps is in line with other experiments involving walking exercises in patients with COPD (7, 12).

" e recovery time of fatigue may be indicative of the origin of fatigue that is developing during walking and also a refl ection of the metabolic profi le of the muscle involved in the fatiguing process. " e prolonged mus-cle fatigue seen in patients with COPD for dorsifl exor muscles suggests low-frequency fatigue likely to engage excitation-contraction coupling (27).

Exercise response to standardized walking exercise " e standardized walking e# ort elicited a signifi cantly larger fraction of the total capacity in patients with COPD as refl ected by higher ventilatory requirements, O2 con-sumption and heart rate response when compared to healthy controls. " is was further supported by greater dyspnea and leg fatigue Borg scores in patients with COPD. " ese fi ndings highlight that walking, as performed in the current protocol, imposes a considerable physiological demand in patients with COPD (8). Competition for the

MVC TwpotD

ors

ifle

xors

mu

scle

tor

qu

e (%

of

bas

elin

e va

lues

)P

lan

tarf

lexo

rs m

usc

le t

orq

ue

(% o

f b

asel

ine

valu

es)

Basel

ine

15-m

in

post-e

xerc

ise

40-m

in

post-e

xerc

ise

*

B

D

Basel

ine

15-m

in

post-e

xerc

ise

40-m

in

post-e

xerc

ise

A

C

40

60

80

100

120

Walking exercise

*

40

60

80

100

120

*

Walking exercise

40

60

80

100

120

*

40

60

80

100

120

140

Walking exercise

Walking exercise

*

Figure 4. Post-exercise loss in strength for the i) dorsi! exors and ii) plantar ! exors for maximal voluntary contraction (MVC – panel A and C) and potentiated twitch force (Twpot – panel B and D) in patients with COPD (! lled circles) and healthy control subjects (open circles) at 15 minutes and 40 minutes post-exercise. Values are mean ± SD. The values at 40 minutes post-exercise are only available for 8 patients with COPD (n = 8) and 6 healthy controls (n = 6). * p < 0.05 vs. baseline force values within groups.

COPD

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f Lav

al o

n 04

/02/

13Fo

r per

sona

l use

onl

y.

Distal Leg Muscles in COPD 241

www.copdjournal.com

available blood fl ow between the high working respira-tory muscles and the limb muscles to the benefi t of the former muscles was recently demonstrated during high intensity cycling exercise in patients with COPD (28). However, such a phenomenon would be unlikely to occur under our experimental protocol during which the inten-sity of ventilatory stimulation was submaximal.

Methodological considerationsWe report distal leg muscle fatigue assessment using magnetic stimulation, a validated and fatigue-sensitive technique (10). Additionally, our validation data (see online supplementary material) confi rmed highly reproducible measurements in MVC and Twpot. We refer to plantar and dorsifl exors as it was not possible to isolate the action of each muscle composing each of these muscle groups. We decided to impose a standard-ized walking e# ort of 40 Kcal for both groups in order to characterize muscle fatigue for a comparable task. " is predetermined energy expenditure was used to refl ect routine activities in daily life (i.e., walking to the grocery store). Although the slope imposed during endurance treadmill exercise di# ered slightly between groups, no statistically signifi cant correlations were found between the extent of distal leg muscle fatigue and the corre-sponding treadmill slope, supporting the thesis that increased fatigability observed in patients with COPD was not due to di# erences in this parameter. Finally, it was beyond the scope of the study to explore the electri-cal, biochemical, metabolic and structural muscle modi-fi cation that could underlie the susceptibility to distal leg muscle fatigue observed in COPD.

Clinical relevance of ! ndingsBeyond the potential consequences for walking exercise intolerance, our results may have other important func-tional implications. For example, muscle weakness and fatigue are known to increase the risk of falls in elderly people (29). " e present study thus emphasizes the poten-tial need for including specifi c leg muscles dorsi and plan-tar fl exors exercises in pulmonary rehabilitation programs where only larger muscle groups are typically targeted.

ConclusionWe conclude that patients with COPD presenting weaker quadriceps also have distal leg muscles weakness when compared with healthy controls. Also, following a standardized walking exercise, dorsi and plantar fl exors were much more prone to the development of fatigue in patients with COPD. Our results point to the relative contribution of fatigue of the distal limbs in daily physi-cal activities in COPD.

Acknowledgments" e authors acknowledge the help of Marthe Bélanger, Marie-Josée Breton, Brigitte Jean, Josée Picard in

accomplishing this study and are grateful to Éric Nadreau for his technical support during the exercise testing. " e authors are also thankful to Andréanne Guérin and Annie Lemelin for their contribution in the technical development of this project and to Serge Simard for his statistical assistance.

Declaration of Interest" e authors report no confl icts of interest. All authors were all substantially involved contributed in design, acquisition, analysis and interpretation of the study and contributed to the intellectual content of the manu-script. Accordingly, we did not omit any other author that would fulfi ll these authorship requirements.

References 1. Oga T, Nishimura K, Tsukino M, Sato S, Hajiro T. Analysis

of the factors related to mortality in chronic obstructive pulmonary disease: role of exercise capacity and health status. Am J Respir Crit Care Med 2003; 167(4):544–549.

2. Gosselink R, Troosters T, Decramer M. Peripheral muscle weakness contributes to exercise limitation in COPD. Am J Respir Crit Care Med 1996; 153(3):976–980.

3. Gagnon P, Saey D, Vivodtzev I, Laviolette L, Mainguy V, Milot J, et al. Impact of pre-induced quadriceps fatigue on exercise response in chronic obstructive pulmonary disease and healthy subjects. J Appl Physiol 2009; 107(3):832–840.

4. Allaire J, Maltais F, Doyon JF, Noel M, Leblanc P, Carrier G, et al. Peripheral muscle endurance and the oxidative profi le of the quadriceps in patients with COPD. ! orax 2004; 59(8):673–678.

5. Maltais F, Simard AA, Simard C, Jobin J, Desgagnés P, LeBlanc P. Oxidative capacity of the skeletal muscle and lactic acid kinetics during exercise in normal subjects and in patients with COPD. Am J Respir Crit Care Med 1996; 153(1):288–293.

6. Mador MJ, Deniz O, Aggarwal A, Kufel TJ. Quadriceps fatigability after single muscle exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003; 168(1):102–108.

7. Man WD, Soliman MG, Gearing J, Radford SG, Ra" erty GF, Gray BJ, et al. Symptoms and quadriceps fatigability after walking and cycling in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003;168(5):562–567.

8. Marquis N, Debigaré R, Bouyer L, Saey D, Laviolette L, Brouillard C, et al. Physiology of walking in patients with moderate to severe chronic obstructive pulmonary disease. Med Sci Sports Exerc 2009; 41(8):1540–1548.

9. Mador MJ, Kufel TJ, Pineda L. Quadriceps fatigue after cycle exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000; 161(2 Pt 1):447–453.

10. Saey D, Debigaré R, LeBlanc P, Mador MJ, Côté CH, Jobin J, et al. Contractile leg fatigue after cycle exercise: a factor limiting exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003; 168(4):425–430.

11. Gottschall JS, Kram R. Energy cost and muscular activity required for leg swing during walking. J Appl Physiol 2005; 99(1):23–30.

12. Pepin V, Saey D, Whittom F, LeBlanc P, Maltais F. Walking versus cycling: sensitivity to bronchodilation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005; 172(12):1517–1522.

13. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, et al. Global strategy for the diagnosis, management,

COPD

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f Lav

al o

n 04

/02/

13Fo

r per

sona

l use

onl

y.

Copyright © 2013 Informa Healthcare USA, Inc

242 P. Gagnon et al.

and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007; 176(6):532–555.

14. American ! oracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (ATS). Am J Respir Crit Care Med 1995; 152(5 Pt 2):S77–121.

15. Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory fl ows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Eur Respir J Suppl 1993; 16:5–40.

16. Gandevia B, Hugh-Jones P. Terminology for measurements of ventilatory capacity; a report to the thoracic society. ! orax 1957; 12(4):290–293.

17. Porszasz J, Casaburi R, Somfay A, Woodhouse LJ, Whipp BJ. A treadmill ramp protocol using simultaneous changes in speed and grade. Med Sci Sports Exer 2003; 35(9):1596–1603.

18. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exer 1982; 14(5):377–381.

19. Tipton CM, editor. ACSM’s Advanced Exercise Physiology. Lippincott Williams & Wilkins, Baltimore, MD, 2006.

20. Perrault H, Baril J, Henophy S, Rycroft A, Bourbeau J, Maltais F. Paced-walk and step tests to assess exertional dyspnea in COPD. COPD 2009; 6(5):330–339.

21. Man WD, Kemp P, Moxham J, Polkey MI. Skeletal muscle dysfunction in COPD: clinical and laboratory observations. Clin Sci (Lond) 2009; 117(7):251–264.

22. Gosker HR, Zeegers MP, Wouters EF, Schols AM. Muscle fi bre type shifting in the vastus lateralis of patients with COPD is associated with disease severity: a systematic review and meta-analysis. ! orax 2007; 62(11):944–949.

23. Saey D, Lemire BB, Gagnon P, Bombardier E, Tupling AR, Debigaré R, et al. Quadriceps metabolism during constant workrate cycling exercise in chronic obstructive pulmonary disease. J Appl Physiol 2011; 110(1):116–124.

24. Ericson MO, Nisell R, Ekholm J. Quantifi ed electromyography of lower-limb muscles during level walking. Scand J Rehabil Med 1986; 18(4):159–163.

25. Casaburi R, ZuWallack R. Pulmonary rehabilitation for management of chronic obstructive pulmonary disease. N Engl J Med 2009; 360(13):1329–1335.

26. Seymour J, Ward K, Steier C, Jolley C, Reilly C, Polkey MI, et al. Distribution of leg muscle weakness in chronic obstructive pulmonary disease (COPD). Eur Respir J 2008; (A1330):223s.

27. Edwards RH, Hill DK, Jones DA, Merton PA. Fatigue of long duration in human skeletal muscle after exercise. J Physiol 1977; 272(3):769–778.

28. Amann M, Regan MS, Kobitary M, Eldridge MW, Boutellier U, Pegelow DF, et al. Impact of pulmonary system limitations on locomotor muscle fatigue in patients with COPD. Am J Physiol Regul Integr Comp Physiol 2010; 299(1):R314–324.

29. Moreland JD, Richardson JA, Goldsmith CH, Clase CM. Muscle weakness and falls in older adults: A systematic review and meta-analysis. J Am Geriatr Soc 2004; 52(7):1121–1129.

Table S1. Subject characteristics.

COPD (n = 10)

Age, yr 63 ± 5

Gender (M/F) (6/4)

BMI, kg/m2 26 ± 4

Pack-years 47 ± 24

FEV1, L 1.41 ± 0.34

% predicted 54 ± 14

FVC, L 2.88 ± 0.68

% predicted 83 ± 18

FEV1/FVC, % 51 ± 15

De" nitions of abbreviations: BMI = body mass index; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity. Values are mean ± SD.

Supplementary materials are available in the online version of this article.

COPD

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f Lav

al o

n 04

/02/

13Fo

r per

sona

l use

onl

y.