Resistance Training Prevents Deterioration

in Quadriceps Muscle Function During Acute

Exacerbations of Chronic Obstructive
Pulmonary Disease
Thierry Troosters1,2*, Vanessa Suziane Probst3*, Tim Crul1, Fabio Pitta4, Ghislaine Gayan-Ramirez1,
Marc Decramer1,2, and Rik Gosselink1,2
1
Respiratory Rehabilitation and Respiratory Division, University Hospital Leuven, Leuven, Belgium; 2Kinesiology and Rehabilitation Sciences,
Department of Rehabilitation Sciences, Katholieke Universiteit Leuven, Leuven, Belgium; 3Centro de Pesquisa em Ciências da Saúde, Universidade
Norte do Paraná, Londrina, Brazil; and 4Laboratório de Pesquisa em Fisioterapia Pulmonar, Departamento de Fisioterapia, Universidade Estadual de
Londrina, Londrina, Brazil

Rationale: Exacerbations of chronic obstructive pulmonary disease

(COPD) acutely reduce skeletal muscle strength and result in long-
term loss of functional capacity.
Objectives: To investigate whether resistance training is feasible and
safe and can prevent deteriorating muscle function during exacer-
bations of COPD.
Methods: Forty patients (FEV1 49 6 17% predicted) hospitalized with
a severe COPD exacerbation were randomized to receive usual care
or an additional resistance training program during the hospital
admission. Patients were followed up for 1 month after discharge.
Primary outcomes were quadriceps force and systemic inflamma-
tion. A muscle biopsy was taken in a subgroup of patients to assess
anabolic and catabolic pathways.
Measurements and Main Results: Resistance training did not yield
higher systemic inflammation as indicated by C-reactive protein
levels and could be completed uneventfully. Enhanced quadriceps
force was seen at discharge (19.7 6 16% in the training group; 21 6
13% in control subjects; P 5 0.05) and at 1 month follow-up in the
patients who trained. The 6-minute walking distance improved after
discharge only in the group who received resistance training
(median 34; interquartile range, 14–61 m; P 5 0.002). In a subgroup
of patients a muscle biopsy showed a more anabolic status of skeletal
muscle in patients who followed training. Myostatin was lower (P 5
0.03) and the myogenin/MyoD ratio tended to be higher (P 5 0.08)
in the training group compared with control subjects.
Conclusions: Resistance training is safe, successfully counteracts
skeletal muscle dysfunction during acute exacerbations of COPD,
and may up-regulate the anabolic milieu in the skeletal muscle.
Clinical trial registered with www.clinicaltrials.gov (NCT00877084).
Keywords: skeletal muscle; resistance training; exacerbations; chronic
obstructive pulmonary disease
Acute exacerbations of chronic obstructive pulmonary disease
(COPD) contribute to the disease progression and have a sig-
nificant systemic impact. Severe exacerbations are characterized
(Received in original form August 6, 2009; accepted in final form February 3, 2010)
* These authors contributed equally to this article.
Supported by Research Foundation Flanders grants KAN 1.5.139.06N and
G.0386.05N.
Correspondence and requests for reprints should be addressed to Thierry
Troosters, P.T., Ph.D., Respiratory Rehabilitation and Respiratory Division, UZ
Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. E-mail: thierry.troosters@
med.kuleuven.be
This article has an online supplement, which is accessible from this issue’s table of
contents at www.atsjournals.org
Am J Respir Crit Care Med Vol 181. pp 1072–1077, 2010
Originally Published in Press as DOI: 10.1164/rccm.200908-1203OC on February 4, 2010
Internet address: www.atsjournals.org
AT A GLANCE COMMENTARY
Scientific Knowledge on the Subject
Severe exacerbations of chronic obstructive pulmonary
disease have a significant impact on skeletal muscle func-
tion. Rehabilitation is recommended after exacerbations,
but its safety and effects have not been studied during
exacerbations.
What This Study Adds to the Field
This randomized controlled study shows that resistance
training is a form of exercise training that can be conducted
safely and was successful in preventing the deleterious
impact of exacerbations on muscle function.
by a hospital admission and changes in the medical treatment.
Typically, lung function is acutely reduced during acute exac-
erbations. Significant skeletal muscle weakness has been
observed (1, 2) along with a negative protein balance (3).
Several mechanisms may contribute to this acute muscle
weakness. These include the presence of systemic inflammation
(1), a negative nutritional balance (4), and administration of
oral corticosteroids (5). Recently we have identified physical
inactivity as an important factor contributing to the skeletal
muscle weakness during acute exacerbations. Clearly physical
inactivity can be both cause and consequence of skeletal muscle
dysfunction. Compared with patients with stable COPD, those
with exacerbations spend only a limited time in weight-bearing
activities (2). Consistent with inactivity as an important driver
of the acute skeletal muscle abnormalities, we recently showed
reduced MyoD and insulinlike growth factor-I in skeletal
muscle biopsy specimens obtained during acute exacerbations
(6). In the latter study we were unable to detect inflammation in
the skeletal muscle of patients suffering from acute exacerba-
tions. Physical inactivity is well known as a potent stimulus for
loss in skeletal muscle function. In healthy elderly patients 10
days of bed rest led to a reduction in isokinetic quadriceps
strength of 15% and a decrease in lower limb lean muscle mass
of 6.3% (7). Under conditions of stress the effect of inactivity
may be larger. Indeed, it has been shown that corticosteroids
may enhance the deleterious effects of bed rest alone (8).
Exercise training, particularly resistance training, has been
shown effective in counteracting the deleterious effects of inactivity-
induced skeletal muscle atrophy (9). Resistance training has
a relatively low ventilatory burden (10) and may therefore be
the preferred form of skeletal muscle loading during acute
Troosters, Probst, Crul, et al.: Rehabilitation During COPD Exacerbations
exacerbations of COPD. It is unclear, however, whether training-
induced acute inflammation could result in deleterious effects in
patients already suffering from systemic inflammation. Hence,
feasibility and safety need to be further investigated in the context
of acute exacerbations.
We speculated that resistance training is able to counteract
the deleterious effects of acute exacerbations on skeletal muscle
force. A randomized controlled trial set out to investigate the
feasibility and safety of such a training program during a hospital
admission for an acute exacerbation of COPD. The primary
outcome of the study was skeletal muscle force after resistance
training or usual care. Skeletal muscle biopsies were obtained
after the training or control period to confirm the impact of the
resistance training on anabolic and catabolic markers in skeletal
muscle.
METHODS
A detailed description of the methods used in the present study is
available in the online supplement. The trial has been submitted to
www.clinicaltrials.gov with identification number NCT00877084. Pre-
liminary data were presented in abstract form (11, 12).
Study Design and Subjects
Consecutive patients with COPD (FEV1/FVC , 70%) admitted to the
University Hospital Gasthuisberg with acute exacerbation were
included in this randomized controlled parallel-group study. Inclusion
ran from January 2004 to March 2005. The decision to admit patients to
the hospital was made by the attending chest physician who was not
familiar with the present study protocol. Patients were screened at the
emergency department and contacted on the first day of hospitalization
on the ward of a Respiratory Division. The following criteria were used
for patient selection: (1) diagnosis of acute exacerbation of COPD, (2)
age , 85 years, (3) no hospitalization within the previous 14 days, (4)
no current participation in rehabilitation program, (5) no locomotor or
neurological condition or disability limiting the ability to perform
exercise, (6) no lung transplantation or lung volume reduction surgery
foreseen within 1 month after discharge. For logistical reasons only
patients admitted to the ward from Mondays through Thursdays were
included to allow for the testing.
Patients and Randomization Procedure
Details on the sample size calculation and randomization procedure as
well as a consort flow chart (13) are provided in the online data
supplement. Forty patients who had a diagnosis of COPD for 8.5 6 8.6
years met the inclusion criteria and gave informed consent to take part
in the study. The study was approved by the Medical Ethical Board of
the University Hospitals Leuven. Patients were randomized using
opaque envelopes prepared by an independent secretary. Thirty-six
patients were reevaluated at discharge, and 30 were reassessed after
1 month. Patients were not blind to the interventional group, and tests
were performed by researchers who were not blind to the allocation of
the patients.
Methods
Maximal voluntary quadriceps force (QF) was assessed on Day 2, Day 8,
and at follow-up (1 mo after discharge). Functional exercise tolerance
and lung function were assessed at discharge and after 1 mo. Details on
these assessments can be found in the online supplement. Symptoms of
dyspnea were assessed using the Medical Research Council dyspnea
scale on Day 1 and at 1 month after discharge (14).
A morning venous blood sample was taken on Days 1, 3, 8, and
1 month after discharge. Circulating levels of C-reactive protein,
testosterone, and insulinlike growth factor-I (IGF-1) were assessed in
serum and plasma, respectively.
In 20 patients willing to undergo the procedures, a percutaneous
Bergström needle muscle biopsy (103 6 51 mg) of the m. vastus lateralis
was obtained on the day of discharge. Baseline characteristics of these
representative patients are given in the online data supplement. Quan-
titative real-time polymerase chain reaction assay with Sybr Green was
1073
performed by investigators blind to the group allocation on an ABI Prism
7700 Sequence Detection System to investigate expression of genes
related to anabolism and catabolism. Genes up-regulated with anabolism
are IGF-I, mechano growth factor (MGF), and the myogenic regulatory
factors MyoD and myogenin. Genes for which up-regulation is poten-
tially associated with catabolism were growth and differentiation factor 8
or myostatin and the ubiquitin protein ligases: muscle ring finger-1
(MURF-1), MAFbx, and NEDD4 (specific for deconditioning).
Interventions
During the hospital admission, patients in the control group received
usual care according to a strict clinical pathway (2). Patients received
standard doses of oral corticosteroids to treat the exacerbation.
In principle, patients received 32 mg
day21 oral methylprednisolone
for 1 week, followed by 16 mg
day21 for 4 days and a subsequent
decrease of 4 mg
week21. However, steroids were given and tapered as
judged possible by the treating chest physician. Physiotherapy was
limited to mucous secretion clearance techniques and breathing
exercises. Patients were not restricted in their physical activities but
no formal exercise therapy was offered. The training group received
usual care and in addition performed daily quadriceps resistance
training for 7 days on a knee-extension chair (Gymna, Bilsen,
Belgium). The initial load was set at 70% of the 1RM (one repetition
maximum: the maximum load that can be moved only once over the
full range of motion without compensatory movements). Patients
performed three sets of eight repetitions and adjustments in the load
were made based on symptoms (Borg scores of dyspnea and fatigue;
see online supplement for further details and picture). The individual
training sessions were supervised by two physiotherapist-researchers
(V.S.P. and T.T.).
Statistical Analysis
Statistical analysis was performed using the Statistical Analysis System
v9.2 (SAS Institute, Cary, NC). Results were described as mean 6 SD
unless specified otherwise. All patients who had their outcome
measures assessed were included in the analysis, regardless of the
number of sessions they successfully completed. No imputations were
made for missing data. To minimize baseline differences, QF was
expressed as a percentage of the value obtained at Day 2. A two-way
analysis of variance was performed to analyze the effect of the
intervention. In addition, the effect of the intervention during the
hospital admission was analyzed using an unpaired t test. Differences
in mRNA expression were analyzed using nonparametric testing.
We speculated that myostatin, MAFbx, MURF-1, and NEDD4 would
be up-regulated in the control group as these molecules are
up-regulated with unloading. By contrast, we speculated that MGF
and IGF-I would be up-regulated with resistance training. These
hypotheses were tested with one-tailed nonparametric testing. The
relative anabolic–catabolic balance was obtained by calculating
the relative mRNA expression as a value from 0 to 100 with 0 being
the lowest expression and 100 the highest expression observed in the
available biopsies from patients in both groups. The mean expression
of the anabolic (MGF, IGF-I, MyoD, and myogenin) and the catabolic
(myostatin, MAFbx, MURF-1, and NEDD4) were subtracted. A value
greater than zero would indicate a balance in favor of anabolism, and a
value less than zero would indicate a balance in favor of catabolism.
For all analyses the level of significance for all comparisons was set
at P < 0.05.
RESULTS
Thirty-six patients were assessed at the end of the hospital
discharge. Their characteristics are displayed in Table 1. There
was a trend for a better FEV1 in the control group. No other
differences were seen between the groups. A similar number of
patients in the control and training groups (53% vs. 76%) had
received steroids before admission to the hospital by their general
practitioner. The cumulative dose of methylprednisolone over
the exacerbation tended to be lower in control subjects (157 6
54 mg) compared with those in the training group (185 6 27 mg;
P 5 0.06).
1074 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 181 2010

TABLE 1. BASELINE CHARACTERISTICS OF THE

STUDIED PATIENTS
Control Group Training Group
(n 5 19) (n 5 17)

Gender, f/m 5/14 4/13

Age, yr 69 6 7 67 6 8
Hospital stay, d 8 (8–14) 8 (8–9)
Methylpred before, % (mg) 53% (80 6 107) 76%* (103 6 108)
BMI, kg
m22 24 6 6 25 6 6
FEV1, % predicted 50 6 18 40 6 12†
FRC, % predicted 142 6 34 151 6 36
TL,co, % predicted 54 6 23 50 6 21
PaO2, mm Hg 63 6 12 70 6 10
PaCO2, mm Hg 44 6 4 44 6 3
MRC, points 2.3 6 1.1 2.2 6 1.1
Smoking, pack-years 48 6 22 43 6 12
6-Min walking distance, m 380 6 117 330 6 137
Current smokers, no. 8 5

Definition of abbreviations: MRC 5 Medical Research Council dyspnea scale;

TL,co 5 single-breath diffusion capacity.
Baseline characteristics of patients in the training and the control group who
could be discharged per protocol. The proportion of patients who received
methylprednisolone by their general practitioner (Methylpred before) and the
cumulative dose over the last 14 d before the admission in these patients is given.
Lung function, including TL,co is given as a percentage of the predicted normal
value obtained at discharge from the hospital. Arterial blood gases (PaO2 and
PaCO2) are given in mm Hg. Data are mean and SD or median and interquartile
range for hospital stay.
* P 5 0.13.
†
P 5 0.08 versus control subjects.
Exercise Training Program
Patients allocated to the training group followed 6 6 1 sessions
(range 4–7). Forty-one percent of patients trained both legs
separately (single-leg training for left and right leg). On average
the intensity of the training was superior to 70% of the 1RM
(Figure 1). The weight lifted during the training was 6.8 6 2.7 kg
on Day 2 and was increased to 7.7 6 3.0 kg on Day 8.
Effect of the Training Program
The training program had no impact on the hospital stay, which
was 8 days in both groups, as outlined in the clinical pathway in
our institute (Table 1).
A significant time by group effect was seen for QF in favor of
the training group for the whole study period (P 5 0.04;
Figure 2). During the exacerbation, the QF increased signifi-
cantly more in the training group (9.7 6 16%) compared with
the control group (21 6 13%; P 5 0.05 between groups). In the
patients followed up after 1 month, QF remained unchanged
compared with the values at discharge.
The 6-minute walking distance improved in the training group
after discharge (median, 34; interquartile range, 61–14 m; P 5
0.002), whereas it remained unchanged in the control subjects
(median, 17.5; interquartile range, 62 to 241 m; P 5 0.59). There
was, however, no significant difference between groups (P 5 0.23).
C-reactive protein and white blood cell neutrophil counts
were elevated at hospital admission in both groups and de-
creased similarly in both groups over the course of the hospital
admission (Table 2). Total testosterone and IGF-I were reduced
in the emergency room and after 3 days, compared with
discharge (Day 8) in both groups (15). No between-group
differences were observed.
Effect of the Intervention on Anabolic and Catabolic
Pathways in Skeletal Muscle Biopsies
In the training group, the mRNA expression level of myostatin
was significantly lower (P 5 0.03), whereas the myogenin/MyoD
Figure 1. Upper panel: symptoms of fatigue (solid circles) and dyspnea
(open circles) at the end of the first and third set of eight repetitions
(second set was always intermediate). The lower panel represents the
training resistance (weight expressed as a percent of the 1 repetition
maximum [1RM]) on Day 2 (D2) to day 8 (D8) of the hospital
admission.
ratio tended to be higher (P 5 0.08) compared with CT
(Figures 3A and 3B). No differences between groups were
detected in mRNA expression levels of IGF-I, MGF, MURF-1,
MAFbx, and NEDD4 (see online supplement).
The anabolic/catabolic balance was more in favor of anabo-
lism in the training group compared with control subjects (Figure
3C). Although the correlation between the anabolic index and the
change in QF during the exacerbation was not significant (R 5
0.32; P 5 0.18; Figure 3D), it can be appreciated that patients with
the most enhanced QF did have an anabolic response to training
(upper right quadrant), whereas most control subjects with
a significant reduction in QF did indeed present relatively more
catabolism (lower left quadrant).
Effect on Readmission Rate
The resistance training program had no impact on the read-
mission rate of patients. After 6 months, nine patients from the
training group and eight control subjects were readmitted to the
hospital.
DISCUSSION
This randomized controlled trial shows that resistance training
can be applied during a hospital admission for a severe exac-
erbation of COPD. Resistance training has favorable effects on
quadriceps muscle force likely through a favorable impact on
the anabolic–catabolic balance. In particular it counteracts the
up-regulation of myostatin. We did not observe increased
systemic inflammation induced by the resistance training.
Quadriceps muscle weakness is an important systemic con-
sequence of severe acute exacerbations. Our group previously
showed an acute reduction in quadriceps strength (1, 2).
Hospital admissions for COPD exacerbations may lead to
skeletal muscle dysfunction. Several factors, including bed rest
combined with the administration of high doses of oral gluco-
Troosters, Probst, Crul, et al.: Rehabilitation During COPD Exacerbations 1075

TABLE 2. SERUM LEVELS OF INFLAMMATION AND

ANABOLIC FACTORS
ER Day 3 Day 8

CRP, mg
ml21 CT 53 6 77* 16 6 21 8 6 12

TR 56 6 65* 24 6 38 10 6 19
WBCneutro, 103 cells/ml CT 10.7 6 3.82* 8.14 6 2.85 7.76 6 2.47
TR 9.90 6 5.69* 6.70 6 2.92 6.75 6 2.68
Testtot, ng
dl21 CT 98 6 97 109 6 103 157 6 122
TR 100 6 114 107 6 127 141 6 132
IGF-I, ng
ml21 CT 108 6 37 125 6 44 148 6 45†
TR 135 6 51 127 6 42 149 6 62†

Definition of abbreviations: CRP 5 serum C-reactive protein; CT 5 control

Figure 2. Effect of the resistance training program (mean 6 SEM) in
the training group (solid circles) and the control subjects (open circles)
on quadriceps force (QF). QF is expressed as percent of the values
obtained on Day 2. * indicates a significant (P , 0.05) difference
between the training and control groups.
corticoids, systemic inflammation (1), poor nutritional intake
(16), and increased resting metabolism have been suggested to
be associated with the acute loss in muscle function and the
negative protein balance (3).
Feasibility of the Resistance Training Program
The program was well tolerated by most patients. No adverse
effects were noted during the training program (see online
supplement for details). From Figure 1 it can be appreciated
that dyspnea was important in the first days of training, but it
reduced by the end of the program. Fatigue remained at a score
of around 4 to 5 (heavy) throughout the program. Importantly,
the load was adjusted after every set of eight repetitions to
accommodate the patients’ symptoms. By increasing the train-
ing load we ensured a continued strenuous stimulus on the
skeletal muscle, which was sufficient to counterbalance the
group; ER 5 day of admission; IGF-I 5 insulinlike growth factor-I; Testtot 5 serum
total testosterone level; TR 5 training group; WBCneutro 5 white blood cell
neutrophil count.
Values are given for CT and TR as obtained on ER, on Day 3 of the hospital
admission, and at discharge (Day 8). Values for total testosterone in healthy
subjects previously studied in our laboratory in the studied age range are (median
and interquartile range) 355 (254–467) ng
dl21 (15). IGF-I values in healthy
subjects are 148 (101–201) (1).
* P , 0.05 versus Day 8.
†
P , 0.05 versus Day 3.
processes of atrophy, initiated by acute deconditioning. It is
important to note that systemic inflammation was not enhanced
in the training group. A study suggested enhanced systemic
inflammation after whole-body exercise (17). Local exercise,
however, did not exacerbate systemic inflammation in the
present study.
Anabolic Stimulus
It can be speculated that the increase in skeletal muscle function
may be due to enhanced neuromuscular coupling and reduced
antagonist inhibition after training, rather than because of an
adequate anabolic stimulus delivered to the skeletal muscle.
The large increase in muscle strength is undoubtedly partly due
to these principles (18). The present study aimed to prevent the

Figure 3. Expression level of (A) myo-

statin, (B) the myogenin/MyoD ratio,
and (C) the anabolic–catabolic (AC)
index of training group (TR, open bars)
and control group (CT, closed bars) at
discharge. In A and B, horizontal line
represents mean value of the group.
Data in C are expressed as mean and
SEM. (D) Relation of the AC index and
the change in quadriceps force (D QF)
during the hospital admission in the
training group (solid circles), and the
control group (open circles). The D QF
(Nm) is the difference in muscle torque
between Day 2 and Day 8 of hospital
admission, expressed in newton meters.
1076 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
deleterious effects of acute exacerbations on the muscle by
providing an adequate training stimulus. To confirm the poten-
tial to minimize the catabolic effect of the exacerbation on the
skeletal muscle, we did perform a skeletal muscle biopsy in
a subset of patients willing to undergo the procedure before
discharge. Unfortunately, due to the relatively small biopsy size
we were able to investigate the anabolic and catabolic markers
only at the mRNA level. In the present study, the biopsies were
taken to determine the extent to which resistance training in
this setting has the potential to counterbalance the deleterious
effects of an exacerbation on skeletal muscle. The present study
shows that the training program applied may yield some
interesting protective effects. First, the data suggest that
myostatin, a negative regulator of muscle growth (19, 20), was
lower in patients submitted to the resistance training program.
One bout of resistance training was shown to abruptly reduce
myostatin expression in healthy humans (21–23). Consequently,
activation of myogenic satellite cells after resistance training
during hospitalization might occur. Ultimately, this could
represent a very early trigger to induce muscle regeneration
in these patients.
Second, the observation that the balance of the relative
expression of mRNA leading to anabolism is larger than the
relative expression leading to catabolism in the training group
supports the adequacy of the training stimulus. In the control
subjects the balance favored catabolism. The anabolic–catabolic
index is based on the observed mRNA expression in the whole
group of patients. A positive value indicates that the patient
has—compared with his or her peers—a larger expression of the
anabolic factors compared with the catabolic factors. A value
less than zero means that the catabolic markers are more
importantly expressed. This analysis reflects the relative expres-
sion of mRNA rather than the absolute expression, wherein no
differences were observed. Our data suggest that patients in the
training group, compared with those in the control group, had
overall a predominance of expression of anabolic markers
compared with catabolic markers. Debigare and coworkers
reported similarly a disturbed anabolic–catabolic balance in
patients with COPD, particularly those with muscle weakness
(24). Although the anabolic–catabolic index does not have
a biological value per se, our data (Figure 3D) would suggest
that patients who gained substantial muscle force indeed did
present a predominantly anabolic response. By contrast, those
who lost substantial amounts of muscle force did have a cata-
bolic predominance. Participating in the training program
succeeded in shifting the relative expression of anabolic and
catabolic mRNA in favor of the former. Further and larger
studies with serial muscle biopsies could now focus on the key
mediators of hypertrophy in this setting.
A last argument for a significant and effective stimulus on
the muscle with resistance training is the trend for a higher
myogenin/MyoD ratio in the training group compared with
control subjects. This is consistent with a recent study by Costa
and colleagues demonstrating an increased myogenin/MyoD
ratio at Day 3 of a 6-day eccentric exercise training program in
healthy humans (25).
Effects 1 Month after Discharge
Interestingly, functional status and muscle force remained better
in the group that followed training during the exacerbation.
This is an interesting and somewhat unexpected finding, which
merits further research. We can only speculate why these
improvements remained. A plausible explanation would be that
patients who followed the resistance training program and were
discharged with enhanced skeletal muscle function became more
active at home. Although our research group previously assessed
VOL 181 2010
physical activity levels (2), this was unfortunately not done in the
present study. Six-minute walking and skeletal muscle force are
related to physical activity in patients with COPD (26).
In addition, muscle strength and 6-minute walking distance have
been shown to be related to self-efficacy for functional tasks in
patients with arthritis (27). It is tempting to speculate that patients
who are discharged from hospital with less impaired muscle
strength have more confidence to take up activities of daily living.
This clearly needs further investigation, however. It should be
mentioned that even the patients who followed resistance train-
ing during the hospital admission would likely have benefited
from further pulmonary rehabilitation after discharge (28, 29).
The present study may provide an effective bridge to such a
rehabilitation program. Several studies showed the effectiveness
of rehabilitation in patients who were recently discharged from
hospital after an exacerbation (29). The proposed intervention
alone, however, does not prevent readmission to hospital.
The present study has some limitations. First, the study was
powered to investigate the feasibility of resistance training and
its effectiveness in enhancing skeletal muscle function during
acute exacerbations. Other analysis should be regarded as
secondary. Larger studies are needed to investigate the impact
of this intervention on longer-term outcomes. Second, we
assessed maximal voluntary quadriceps strength. Although our
research group has extensive experience with this technique,
less effort-dependent measurements would be preferred. This is
why we obtained muscle biopsy samples in a subset of patients.
From these biopsies we conclude that indeed anabolism was
initiated in these patients. Third, patients in the control group
did not follow sham training. This was a considered choice
because no studies were performed to identify the minimal dose
of muscle activity in these patients to block the catabolism seen
during exacerbations.
The mechanisms by which resistance training enhances
muscle function in the context of an acute exacerbation remain
to be explored. Serial biopsies are needed to investigate the
series of events initiated by repeated bouts of exercise training.
In addition, expression of genes does not necessarily mean that
changes at the protein level are initiated or that the activity of
proteins is altered. Unfortunately, the small biopsy size did not
allow carrying out analyses at the protein level. Hence, the
present study cannot go much further than to suggest that the
catabolic mechanisms initiated by the inactivity seen during
exacerbations are at least to some extent counterbalanced by
the resistance training.
We conclude that resistance training during acute exacerba-
tions of COPD is a safe and effective strategy to counterbalance
loss of skeletal muscle function. Resistance training does
generate a protective stimulus to the skeletal muscle and may
facilitate functional recovery after an acute exacerbation.
Conflict of Interest Statement: T.T. has received advisory board fees from Bl-Pfizer
and AZ ($1,001–$5,000) and has received lecture fees from Bl-Pfizer and Chiesi
($1,001–$5,000). V.S.P. does not have a financial relationship with a commercial
entity that has an interest in the subject of this manuscript. T.C. does not have
a financial relationship with a commercial entity that has an interest in the subject
of this manuscript. F.P. does not have a financial relationship with a commercial
entity that has an interest in the subject of this manuscript. G.G.R. does not have
a financial relationship with a commercial entity that has an interest in the subject
of this manuscript. M.D. has received consultancy fees from Dompe ($5,001–
$10,000); fees for serving on an advisory board from Boehringer, GlaxoSmithKline,
and Nycomed ($5,001–$10,000); lecture fees from Pfizer ($5,001–$10,001); and
an industry-sponsored grant from AstraZeneca ($5,001–$10,000). R.G. does not
have a financial relationship with a commercial entity that has an interest in the
subject of this manuscript.
Acknowledgment: The authors thank Drs. M. Van Vliet and G. Maury for taking
the muscle biopsies in the present study and F. Vanderhoydonck for his help with
the RT-PCR. They also thank the clinical teams of the respiratory division
(particularly Unit 650 and 651 and the pulmonary rehabilitation department)
for assisting with the logistics of the study.
Troosters, Probst, Crul, et al.: Rehabilitation During COPD Exacerbations
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