(Revision Sistematica) Cambios Metabolicos y Estructurales en El Musculo de Pacientes Epoc Despues de Entrenamiento

Expert Review of Respiratory Medicine
ISSN: 1747-6348 (Print) 1747-6356 (Online) Journal homepage: http://www.tandfonline.com/loi/ierx20
Changes in structural and metabolic muscle

characteristics following exercise-based
interventions in patients with COPD: a systematic
review
Jana De Brandt MSc, Martijn A. Spruit PhD, PT, Wim Derave PhD, Dominique
Hansen PhD, PT, Lowie E.G.W. Vanfleteren PhD, MD & Chris Burtin PhD, PT
To cite this article: Jana De Brandt MSc, Martijn A. Spruit PhD, PT, Wim Derave PhD, Dominique
Hansen PhD, PT, Lowie E.G.W. Vanfleteren PhD, MD & Chris Burtin PhD, PT (2016): Changes
in structural and metabolic muscle characteristics following exercise-based interventions
in patients with COPD: a systematic review, Expert Review of Respiratory Medicine, DOI:
10.1586/17476348.2016.1157472
To link to this article: http://dx.doi.org/10.1586/17476348.2016.1157472
Accepted author version posted online: 22

Feb 2016.
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Download by: [University of Saskatchewan Library] Date: 24 February 2016, At: 15:34
Publisher: Taylor & Francis
Journal: Expert Review of Respiratory Medicine
DOI: 10.1586/17476348.2016.1157472
Changes in structural and metabolic muscle characteristics following exercise-
based interventions in patients with COPD: a systematic review
Jana De Brandt, MSc 1 Corressponding author: jana.debrandt@uhasselt.be
Martijn A. Spruit, PhD, PT 12

Downloaded by [University of Saskatchewan Library] at 15:34 24 February 2016
Wim Derave, PhD 3
Dominique Hansen, PhD, PT 1
Lowie E.G.W. Vanfleteren, PhD, MD 2
Chris Burtin, PhD, PT 1
Affiliations
1 REVAL - Rehabilitation Research Center, BIOMED - Biomedical Research Institute,
Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium
2 Department of Research and Education, CIRO, Center of Expertise for Chronic Organ
Failure, Horn, The Netherlands.
3 Dept. of Movement and Sports Sciences, Ghent University, Ghent, Belgium
1
Abstract
Patients with COPD suffer from lower-limb muscle dysfunction characterized by lower
muscle oxidative capacity and muscle mass. Exercise-based training is expected to
attenuate lower-limb intramuscular characteristics, but a detailed systematic approach
to review the available evidence has not been performed yet. PUBMED and PEDro
databases were searched. Twenty-five studies that implemented an exercise-based
training program (aerobic and/or resistance training, high intensity interval training,
electrical or magnetic stimulation) and reported muscle biopsy data of patients with
COPD were critically appraised. The coverage of results includes changes in muscle
structure, muscle protein turnover regulation, mitochondrial enzyme activity, oxidative
and nitrosative stress, and inflammation after exercise-based training interventions.
Study design and training modalities varied among studies, which partly explains the
observed heterogeneous response in muscle characteristics. Gaps in the current
knowledge are identified and recommendations for future research are made to
enhance our knowledge on exercise training effects in patients with COPD.
Key Words
COPD, exercise training, pulmonary rehabilitation, muscle biopsy, vastus lateralis,
quadriceps muscle, skeletal muscle, muscle morphology
2
Introduction
Chronic Obstructive Pulmonary Disease (COPD) is a chronic lung disease characterized
by persistent airflow limitation [1]. In addition, patients with COPD may also suffer from
extra-pulmonary features, such as an impaired lower-limb muscle function [2].
Structural and metabolic muscle alterations result in a decreased lower-limb muscle
strength and endurance. Patients with COPD typically have a decreased muscle fiber size
[3]; higher proportion of type II fibers [4, 5]; decreased capillary density and capillary to
fiber ratio [6]; decreased mitochondrial enzyme activity [7, 8]; and increased muscle
oxidative stress [9]. These muscular changes partly explain the decrease in muscle
oxidative capacity in patients with COPD when compared to healthy age-matched
subjects [9], and cause an earlier and greater dependence on the glycolytic metabolism,
associated to premature lactic acidosis and muscle contractile fatigue during exercise
[10]. Lower-limb muscle dysfunction clearly contributes to the observed exercise
intolerance and exercise-induced symptoms of dyspnea and fatigue in patients with
COPD [11]. Moreover, lower-limb muscle dysfunction has been associated with a worse
health status, more hospitalizations, and worse survival [9].
Patients with COPD generally are less physically active compared to healthy peers [12,
13], which is directly related to lower-limb muscle dysfunction [14]. In line with that,
the observed decrease in lower-limb strength is proportional to the decrease in muscle
mass in the majority of patients, suggesting the onset of disuse muscle atrophy over
myopathy muscle atrophy [15]. In turn, exercise-based interventions have the potential
to reverse or at least stabilize the muscular changes in patients with COPD.
3
Exercise-based pulmonary rehabilitation programs are a cornerstone of the
comprehensive care of patients with COPD [2]. Indeed, international
statements/guidelines state that exercise training is the best available non-
pharmacological therapy to improve lower-limb muscle function in patients with COPD
[2, 16]. In comparison to the comprehensive ATS/ERS statement which reviews muscle
dysfunction in patients with COPD [9], this current review is the first systematic and
detailed critical appraisal of the peer-reviewed literature aiming to determine the

impact of a wide range of exercise-based therapies on structural and metabolic muscle
characteristics in patients with COPD.
4
Methods
In- and exclusion criteria
Studies that investigated the effect of any form of exercise training on structural and
metabolic muscular characteristics in the lower-limb muscles in patients with COPD
were included. Only studies reporting muscle biopsy data were included. Studies
including patients with unstable COPD (during exacerbation) or studies that only
reported changes in muscle strength and/or endurance capacity after a training

program were excluded. Studies investigating the muscle response to a single exercise
test or exercise session were also excluded. The selected studies needed to include
original data, but no restrictions were included in terms of study design or muscle
outcome used. Only studies published in English were included.
Search methods
Electronic databases PUBMED and PEDro were searched for articles published from
inception until September 3, 2015. In PUBMED the following search strategy was used:
COPD AND (exercise OR exercise training OR rehabilitation OR pulmonary rehabilitation
OR physical activity OR aerobic training OR endurance training OR resistance training
OR strength training OR cycling OR walking). The search strategy was adapted to
COPD alone when searching in PEDro to identify all relevant articles. Corresponding
authors were contacted to provide full-texts when not accessible via electronic
databases.
Selection of studies
Two reviewers (JDB and CB) performed the study screening based on the listed
inclusion and exclusion criteria. In a first phase, both reviewers conducted a part of the
5
title screening in a conservative manner, excluding only titles that undoubtedly did not
fulfil the criteria. Next, both reviewers screened all remaining abstracts independently.
Results were compared, discrepancies between reviewers were discussed and a
consensus-based decision was taken. Finally, full text screening was performed in a
similar way.
Data extraction
Information on sample size, study design, baseline FEV 1 , age, exercise training
parameters (frequency, intensity, modality, session and program duration), setting and
relevant outcome measures were extracted from the articles. Mean relative change
(percentages of baseline) between pre and post measurements of outcome measures
were extracted as data. If mean relative change percentages of baseline were not
available, pre and post values were used to manually calculate mean relative change
percentage of baseline: ((post - pre) / pre) x 100). All extracted data is presented in
tables 1 to 5, according to outcome measure.
6
Results
Search results
The study selection process is outlined in Figure 1. We identified 9503 articles with our
search strategy. After title screening, 8462 articles were excluded, resulting in 1041
remaining articles for abstract screening. Finally, 140 full text articles were screened,
whereof 115 articles were excluded. Twenty-five exercise-based intervention studies
were included in our systematic review: six investigated aerobic training [3, 17-21], four
resistance training [22-25], three combined aerobic and resistance training [26-28],
nine high-intensity interval training (HIIT) [29-37], two neuromuscular electrical
stimulation (NMES) [38, 39] and one magnetic stimulation training (MST) [40]. All
studies used muscle biopsies of the vastus lateralis muscle of the quadriceps.
Structural changes
Fourteen studies measured structural changes in the vastus lateralis muscle after
different training interventions in patients with COPD (table 1). Fiber type proportion,
fiber type size and capillary to fiber ratio were most frequently measured.
Fiber type proportion
Four HIIT studies reported significant changes in fiber type proportion [29-32], while
two aerobic training, one resistance training, three combined aerobic and resistance
training, two high-frequency (>50 Hz) NMES (HF-NMES) and one MST studies did not
report a change [3, 21, 24, 26-28, 38-40] (table 1). A mean decrease of 6% in type IIb/x
fiber proportion was reported after HIIT in patients with COPD [29-31]. One HIIT
training study reported differences in fiber type proportion changes according to
cachectic status. Cachectic COPD patients showed an increased proportion of type IIa
7
fibers whereas non-cachectic patients showed an increased proportion of type I fibers.
Type IIb/x fibers decreased in both cachectic and non-cachectic patients [29]. Another
HIIT training study reported differences in fiber type proportion changes according to
COPD GOLD stage [32]. Type I fiber proportion was significantly increased in COPD
GOLD stage II and IV, but not in GOLD stage III patients. Type IIa fiber proportion was
significantly increased in GOLD stage III, but not in GOLD stage II and IV patients. Type
IIb/x fiber proportion was significantly decreased in patients of GOLD stages II to IV

[32]. There were no differences between patients in different GOLD stages for fiber type
I, IIa, IIb/x proportion after training. The proportion of hybrid fiber type I-IIa and IIa-
b/x did not change after aerobic and/or resistance training [3, 26, 27].
Fiber size
The mean change in fiber size differed greatly between studies (table 1). Four studies
reported a significant increase in mean fiber size of 12 to 21% after combined aerobic
and resistance training in normoxemic patients or HIIT [26, 29, 30, 32]; three studies,
whereof one combined aerobic and resistance training study in hypoxemic patients and
two HF-NMES studies reported no significant change [26, 38, 39]; and one study
reported an 11% decrease in mean fiber size after combined aerobic and resistance
training, while healthy controls did not show a change [27]. The change in size per fiber
type also differed between training studies, mainly depending on the studied training
modality (table 1). Aerobic training showed conflicting results for fiber size, with one
study showing no significant changes in type I and II fiber size [21], while Whittom et al.
reported an increase in type I and IIa fiber size, but not in type IIa-b and IIb/x fiber size
[3]. Resistance training also did not change type I fiber size, but did increase type II fiber
size with 15.4% [22]. In contrast, another resistance training study did not report
8
significant changes in type I, IIa and IIb/x fiber size [24]. Combined aerobic and
resistance training showed a decrease in type I and IIa fiber size [27]. HIIT training
increased type I, IIa and IIb/x fiber size, but cachectic patients showed a significant
increase in type IIa and type IIb/x fiber size only [29-32]. HF-NMES showed conflicting
results with one study showing a 9.8% decrease in type I and a 12.5% increase in type II
fiber size [38], while another study did not report significant changes [39]. MST
increased type I fiber size but did not change type II fiber size [40].
Capillary to fiber ratio and markers of angiogenesis
Combined aerobic and resistance training and HIIT studies reported a 10 to 16%
increase in capillary to fiber ratio in COPD patients [26, 27, 29, 31] and an increase of
37% in healthy controls after combined aerobic and resistance training [27] (table 1).
Hypoxemic patients showed no significant change in capillary to fiber ratio after
combined aerobic and resistance training, which was significantly different from
normoxemic COPD patients [26]. Aerobic training and HF-NMES did not report a
significant change [3, 38, 39]. Angiogenesis measured by VEGF-A protein and TSP-1
protein showed no change in VEGF-A in patients and healthy controls, a 44% decrease in
TSP-1 in patients with no change in healthy controls, and a 65% and 35% increase of
VEGF-A/TSP-1 ratio in patients and healthy controls, respectively, after combined
aerobic and resistance training [27].
Regulation of muscle protein synthesis and breakdown
Eight studies measured changes in expression levels of mRNA and proteins involved in
the regulation of muscle protein synthesis and breakdown in the vastus lateralis muscle
after different training interventions in patients with COPD (table 2).

9
Regulation of muscle protein synthesis
Reported genes and proteins involved in the up-regulation of muscle protein synthesis
include genes and proteins of the insulin growth factor (IGF) system, the muscle protein
synthesis (hypertrophy) signalling pathway and of myogenesis and muscle
regeneration.
IGF system. The IGF system plays an important role in the regulation of muscle
cell growth, muscle cell proliferation and muscle cell survival [41, 42]. It consists of two
ligands, IGF-I and IGF-II, several receptors, binding proteins and proteases [41]. After
HIIT, mRNA expression of IGF-I and MGF (mechano growth factor), an isoform of IGF-I,
increased with 67 to 88% and 48 to 90%, respectively. Cachectic COPD patients showed
an enhanced increase in MGF mRNA expression in comparison to non-cachectic patients
[29, 30]. However, no significant change in mRNA expression of IGF-I was reported after
combined aerobic and resistance training [26]. mRNA expression of isoforms of IGF-I, i.e.
IGF-IEa and IGF-IEc, IGF-II and IGF-BP4 (IGF-binding protein 4) tended to be more
increased after resistance training combined with testosterone supplementation
compared to resistance training alone and non-training groups [24]. Protein expression
of IGF-I and MGF increased significantly, except for cachectic COPD patients, after HIIT
[29, 30], and IGF-I even increased with 90% after resistance training combined with
testosterone supplementation, while resistance training alone increased IGF-I solely
with 20% [24] (table 2).
Muscle protein synthesis signalling pathway. IGF-I activates the PI3K/Akt
(phosphoinositide 3-kinase/protein kinase B) pathway [43]. This pathway showed no
significant changes at mRNA, protein and phosphorylation level of Akt (PAkt) and in
PAkt/Akt ratio after different training interventions in COPD patients [23, 26, 29, 39]
10
(table 2). However, a decrease in PAkt was reported in hypoxemic COPD patients after
combined aerobic and resistance training [26]. Similar to the observations in Akt, no
significant changes were found in mRNA expression and phosphorylation/protein
expression ratio of downstream hypertrophy mediators of PI3K and Akt, i.e. GSK-3 and
(glycogen synthase kinase 3), p706SK (p706S kinase), 4EBP-1 (eukaryotic translation
initiation factor 4E binding protein 1) and Redd1 (DNA damage-inducible transcript 4
protein), after resistance and combined aerobic and resistance training in COPD patients
[23, 26]. Phosphorylation/protein expression ratio of GSK-3 and p706SK, however, did
increase significantly in healthy controls after resistance training [23]. Phosphorylation
of GSK-3, p706SK, 4EBP1 showed no significant change after HF-NMES and combined
aerobic and resistance training [26, 39], except in hypoxemic COPD patients were
phosphorylation of GSK-3 and p706SK decreased [26].
Myogenesis and muscle regeneration. IGF-I and the subsequent activation of
the muscle protein synthesis signalling pathway stimulates myogenesis and muscle
regeneration [42]. Myogenesis and muscle regeneration consists of the following steps:
activation, proliferation, migration, differentiation, fusion and maturation [42]. Satellite
cells, myogenic regulatory factors and myostatin play an important role in myogenesis
and muscle regeneration and were measured in several studies [22-24, 26, 29, 30]
(table 2). Satellite cells, identified by marker PAX7, 24 hours after exercise, did not
change after an 8 week resistance training program in both patients and healthy
controls [22]. mRNA expression of myogenic regulatory factor MyoD (myogenic
differentiation 1), involved in the proliferation process, did not change after resistance
training with or without nutritional (19g protein and 49g glucose polymer carbohydrate
in 500 ml of water after each training session) or testosterone supplementation in COPD
patients [23, 24]. MyoD mRNA and protein expression increased after HIIT, but no
11
changes were observed in cachectic COPD patients after HIIT [29, 30]. MyoD protein
expression increased after resistance training with or without nutritional
supplementation in patients and healthy controls [23]. mRNA expression of myogenic
regulatory factor myogenin, involved in the differentiation process, was not different
between a resistance training group and a non-training group, while addition of
testosterone supplementation to resistance training increased myogenin mRNA
expression compared to the non-training group [24]. On the other hand, Constantin et al.
reported an increased myogenin mRNA expression after resistance training, but these
differences were not confirmed in terms of protein expression [23]. mRNA and protein
expression of myostatin, which is a myogenic inhibiting factor, showed no significant
change after resistance training in both patients and healthy controls, and after
combined aerobic and resistance training [23, 26]. After HIIT, however, non-cachectic
COPD patients showed a significant decrease in mRNA and protein expression of
myostatin, while cachectic COPD patients only showed a decrease in protein expression
of myostatin [29]. mRNA expression of a negative regulator of cell proliferation, i.e.
Kruppel-like factor 10 (KLF10), was increased after aerobic training in patients, but not
in healthy controls [20].
Regulation of muscle protein breakdown
Reported genes and proteins involved in up-regulation of muscle protein breakdown
include Forkhead transcript factors, the nuclear factor B (NF-B), and the mitogen
activated protein kinase (MAPK) pathway, which all play a role in activating the muscle
protein breakdown signalling pathway.
Forkhead transcript factors. The translocation and activation of Forkhead
transcript factors is required to upregulate MuRF1 (muscle ring finger protein 1) and
12
Atrogin1, which are E3 ligases involved in the breakdown of muscle protein [43]. No
change in mRNA and protein expression of FOXO1 (forkhead box O) and FOXO3 and
phosphorylation level/protein expression ratio of FOXO1 and FOXO3 was reported after
resistance training in both patients and healthy controls [23]. mRNA expression of
RUNX1 (runt-related transcription factor) increased after resistance training in both
patients and healthy controls [23].
NF-B. Activation of NF-B upregulates MuRF1 [43]. After HIIT phosphorylation

level/protein expression ratio of IB- (nuclear factor of kappa light polypeptide gene
enhancer in B-cells inhibitor) decreased in non-cachectic and cachectic COPD patients
[29]. IB- is a regulatory protein that inhibits NF-B.
MAPK-pathway. Stress stimuli can activate the MAPK pathway, which in turn
activates Forkhead transcript factors [44]. Aerobic training increased mRNA expression
of mitogen activated protein kinases such as MAPK-9 and MAPK activated protein kinase
3 (MAPKAPK-3) in COPD patients [20].
Muscle protein breakdown signalling pathways. Before muscle protein
degradation can be initiated, myofibrillar disruption needs to occur regulated by the
autophagy/lysosomal pathway. mRNA expression of autophagy related genes, i.e. Beclin,
LC3 (microtubule-associated protein light chain 3), Bnip and Gabarapl, and Cathepsin
B+L enzyme activity, showed no significant change after combined aerobic and
resistance training [26]. Subsequently muscle protein degradation by the ubiquitin
proteasome pathway is activated. Markers of this pathway showed no significant
changes in mRNA expression of MuRF-1, Atrogin-1, NEDD4 (neural precursor cell
expressed developmentally down-regulated protein 4), ZNF216 (zinc finger protein)
and Calpain-3, and in protein expression of MuRF-1, Atrogin-1, NEDD4, and Calpain-3
after resistance and combined aerobic and resistance training in COPD patients [23, 26].
13
mRNA expression of 20S proteasome, ubiquitin specific protease 15 (USP15), ubiquitin
conjugating enzyme E2G 1 (UBE2GI) and RAD23 homolog B increased after resistance
training and aerobic training in COPD patients but not in healthy controls [20, 23].
Protein expression of 20S proteasome only increased significantly in healthy controls
and not in COPD patients after resistance training [23]. After HIIT, non-cachectic COPD
patients significantly decreased protein expression of MuRF-1 and Atrogin-1, while
cachectic COPD patients significantly increased protein expression of MuRF-1 and

Atrogin-1 [29]. HF-NMES also decreased Atrogin-1 protein expression, while sham
NMES did not [39].
Metabolic enzymes
Seven studies measured changes in metabolic enzymes in the vastus lateralis muscle
after different training interventions in patients with COPD (table 3).
Mitochondrial (oxidative) enzymes
The most frequently measured mitochondrial (oxidative) enzymes were citrate synthase
(CS) and hydroxyacyl-Coenzyme A dehydrogenase (HADH) (table 3). CS and HADH are
involved in the Krebs cycle and the -oxidation, respectively, and are used as an activity
measure of those pathways. CS activity was reported to be increased by 16 47% after
training in one HIIT, two aerobic training and two combined aerobic and resistance
training studies [17, 18, 26, 28, 34], while one HF-NMES study reported no change [39].
HADH activity after aerobic training showed conflicting results, with one study
reporting no significant change [17] while another study showed an increase of 40%
[18]. Further, no change in HADH activity was reported after combined aerobic and
resistance training and HF-NMES [28, 39]. mRNA expression of cytochrome C oxidase
14
assembly protein 11 (COX 11) and 15 (COX 15), which are part of the production of the
cytochrome C oxidase enzyme involved in the electron transport chain, were increased
after aerobic training [20]. The respiratory capacity of the mitochondria in the muscle
fibers was reported to be improved after HIIT, shown by a 40% increase of
mitochondrial respiration. Basal respiration and maximal activity of complex II and IV of
the respiratory chain did not change after HIIT [34] (table 3).
Glycolytic enzymes and other metabolic enzymes
Reported glycolytic enzymes were lactate dehydrogenase (LDH), phosphofructokinase
(PFK), hexokinase (HK) and glycogen phosphorylase (GlyP) (table 3). Two aerobic
studies and one HF-NMES reported no change in LDH activity after training [17, 18, 39],
while Costes et al. reported an increase in LDH activity only in normoxemic, but not in
hypoxemic COPD patients [26]. PFK, HK, and GlyP activity did not show a significant
change after any kind of training intervention [17, 18, 28]. One other metabolic enzyme
measured was creatine kinase (CK) activity, which decreased with 11% after aerobic
training [17].
Markers of oxidative and nitrosative stress, and antioxidants
Eight studies measured changes in markers of oxidative and nitrosative stress and/or
antioxidants in the vastus lateralis muscle after different training interventions in
patients with COPD (table 4).
Markers of oxidative and nitrosative stress
Measured markers of oxidative and nitrosative stress were lipid peroxidation, protein
carbonylation, protein nitration and nitric oxide synthase isoforms (table 4). Lipid
15
peroxidation did not change after HIIT in both COPD patients and healthy controls [33,
37]. Lipid peroxidation can produce reactive aldehydes, i.e. hydroxynonenal (HNE)
protein adducts, which also did not show significant change after combined aerobic and
resistance training in both COPD and healthy controls [28]. One study, however, did
report an increase of HNE protein adducts after aerobic training in both COPD and
healthy controls, showing a significant higher increase in COPD compared to healthy
controls [19]. Protein carbonylation was not changed in one MST, one aerobic training
and one HIIT study in both COPD and healthy controls [19, 35, 40]. Protein nitration did
not change after HIIT or MST in both COPD and healthy controls [29, 35, 40]. Protein
nitration, however, increased after HIIT in cachectic COPD patients and after aerobic
training in COPD patients with low and normal baseline fat-free mass index (FFMI) and
healthy controls [19, 29]. Nitric oxide isoform synthase mRNA expression indicated a
significantly higher eNOS (endothelial nitric oxide synthase) concentration after
resistance training combined with testosterone supplementation compared to no
training. mRNA expression of iNOS (inducible nitric oxide synthase) and nNOS
(neuronal nitric oxide synthase) did not change [25]. Nitric oxide isoform synthase
protein expression showed a significant increase in COPD patients with a low FFMI for
iNOS, while no change was reported for nNOS and eNOS in patients with a low or
normal FFMI and healthy controls after aerobic training [19]. Chavoshan et al., however,
reported a significant decrease of iNOS protein expression after resistance training with
testosterone supplementation and not after resistance training alone and no training.
Protein expression of eNOS showed an increase after resistance training with
testosterone supplementation compared to no training. Protein expression of nNOS
increased similarly, but also after resistance training alone [25].
16
Non-enzymatic antioxidants, enzymatic antioxidants and uncoupling proteins
The most frequently measured antioxidants, which reduce oxidative and nitrosative
stress, were glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) (table
4). Glutathione is classified as a non-enzymatic antioxidant that interrupts free radical
chain reactions. GSH, glutathione disulphide (GSSG) and total glutathione (GSH + GSSG)
concentrations did not show a significant change after HIIT in both patients and healthy
controls [33, 35]. Acute GSH levels after submaximal exercise, showed no significant
change in COPD patients, a significant 27% decrease in COPD patients with a low BMI
and a significant 89% increase in healthy controls after 8 weeks of HIIT [33, 37]. Acute
GSH synthesis after submaximal exercise was indicated by GSSG and mRNA expression
of gamma-glutamylcysteine synthetase (-GCS-HS). Whereas GSSG increased with 43%
in COPD patients, it showed no change in healthy controls after 8 weeks of HIIT [33]. -
GCS-HS mRNA expression showed conflicting results after HIIT, with one study finding
no change in both COPD and healthy controls after HIIT, while another study reported
an increase in COPD patients and not in healthy controls [33, 37]. SOD and CAT are
classified as enzymatic antioxidants that breakdown and remove free radicals. SOD, Mn-
SOD, Cu/Zn-SOD and SOD activity, but also CAT and CAT activity did not change after
different training interventions [19, 35, 40]. Uncoupling protein-3 (UCP3), which
protects against lipid peroxidation, showed no change after combined aerobic and
resistance training in both patients and healthy controls [28] (table 4).
Inflammation
Five studies measured markers of inflammation in the vastus lateralis muscle of COPD
patients after different training interventions (table 5). mRNA expression of
proinflammatory cytokines TNF- and IL-6 and protein expression of TNF- did not
17
change after HIIT [29, 30, 35, 36], while protein expression of TNF- soluble receptors I
and II did increase after HIIT [35]. Inflammatory cells NE+, measured 24h after the first
exercise bout and 24h after the last exercise bout (8 weeks later), decreased
significantly with 100% after resistance training in COPD patients and not in healthy
controls [22]. In contrast, inflammatory cells CD163+, measured likewise, did not show a
change after resistance training in COPD patients, while a significant decrease of 100%
was reported in healthy controls [22].

Correlations with functional capacity
All twenty-five studies also measured changes in exercise capacity and/or muscle
strength/endurance alongside structural and metabolic muscle characteristics following
the exercise-based intervention. However, only six out of twenty-five studies (24%)
reported correlations between a structural or metabolic muscle characteristic and a
functional exercise outcome measure after exercise-based training [17-19, 27, 29, 33,
38]. On a structural level, Dal Corso et al., reported a non-significant correlation between
change in type II fiber size and change in quadriceps peak torque after 6 weeks of HF-
NMES [38]. Concerning changes in capillary to fiber ratio, a positive correlation (r=0.51,
p<0.05) was found with changes in symptom limited VO 2 after combined aerobic and
resistance training [27]. On a metabolic level, Vogiatzis et al. reported a positive
correlation (r=0.65, p=0.034) between change in MGF mRNA expression and change in
Wpeak during incremental cycle ergometry after HIIT [29]. Aerobic training studies
showed correlations between change in mitochondrial enzyme activity and functional
capacity [17, 18]. Puente-Maestu et al. reported a positive correlation (r=0.63,
p=0.0013) between change in CS activity and change in endurance time of a submaximal
cycle test [17], while Maltais et al. reported positive correlations between change in CS
18
(r=0.83, p=0.009) and HADH (r=0.81, p=0.01) and change in arterial lactate acid
concentration for an identical work rate [18]. However, no correlations were found
between change in any mitochondrial enzyme activity and change in peak VO 2 [18].
Change in oxidized glutathione (GSSG) after HIIT was reported to be positively
correlated (r = 0.55, p < 0.02) with change in Wpeak after a incremental cycle ergometer
test [33].
19
Discussion
To the best of the authors knowledge, this is the first systematic review of the English-
language peer-reviewed literature that summarizes the changes in structural and
metabolic lower-limb muscle characteristics after exercise-based training interventions
in patients with COPD. Study design, study setting, and studied muscle markers varied
greatly between studies. Moreover, the exercise-based interventions (i.e. type,
frequency, intensity and duration) also differed significantly, which can explain at least
in part the heterogeneous response in structural and metabolic muscle characteristics.
Methodological considerations
Before interpreting the key results, some key methodological considerations need to be
taken into account.
First, only six out of twenty-five studies (24%) used a RCT design. The other nineteen
studies used a single group design with (n=9) or without a healthy control group (n=10)
undergoing the same intervention. The inclusion of a non-exercising COPD control group
in future RCTs may be unethical, as exercise-based interventions are generally very
beneficial for patients with COPD to improve exercise performance and health status [2].
A RCT in which an exercising group is compared by a non-exercising group, however
seems relevant to increase the level of evidence. A crossover of the initial non-exercising
COPD control group after a waiting period to the intervention seems a reasonable
solution.
20
Second, the rather low sample size (n<10 patients in three studies [20, 21, 34]), the
absence of proper eligibility criteria [24, 25, 31, 39], concealed allocation and intention
to treat in RCTs [24, 25, 31, 39, 40], and the overall inclusion of more male than female
patients, which is not in line with the latest epidemiological trends where COPD is also
increasingly diagnosed in females [45], might limit the validity of included studies.
Third, the moment of the post training muscle biopsies varied between < 1 to 7 days
after the last training session, which may induce variations in response of the outcome
measures. Only Rabinovich et al. [33, 36, 37], Menon et al. [22] and Constantin et al., [23]
obtained muscle biopsies immediately after exercise to also take the acute effect of
exercise into account. So, possible changes in the acute response of the muscle to an
exercise test following an exercise-based intervention remains a topic for future
research.
Fourth, we excluded exercise-based interventions in unstable COPD patients in this
systematic review because there are only two studies that have studied the effects of
training in unstable COPD patients [46, 47]. It is important to investigate in the future
how exercise training can improve muscle function in COPD patients during and after an
exacerbation, as quadriceps muscle function significantly reduces during an
exacerbation-related hospitalization with only partial recovery [48].
Fifth, ATP-ase staining and MyHC immunohistochemistry were most commonly used to
establish muscle fiber proportion. Out of the fourteen studies that measured structural
changes, nine studies used ATP-ase staining [3, 21, 24, 29-32, 38, 39], four studies used
MyHC immunohistochemistry [22, 26, 27, 40] and one study used MyHC gel
21
electrophoresis [28] to determine muscle fiber proportion. With MyHC
immunohistochemistry and MyHC gel electrophoresis hybrid fibers (I-IIa, IIa-IIx) can be
better detected and quantified compared to ATP-ase staining. As COPD patients show to
have more hybrid fibers compared to healthy controls due to fiber redistribution [49], it
may be more valuable to use MyHC immunohistochemistry and MyHC gel
electrophoresis to determine muscle fiber proportion in COPD patients.

Finally, it is also important to note that up or downregulation of proteins involved in the
muscle protein synthesis and breakdown pathways does not automatically translate in
muscle mass changes. To establish total muscle protein turnover, fractional synthetic
rate and fractional degradation rate of muscle protein need to be assessed which has not
yet been performed in COPD patients involved in exercise-based training. Thus, up or
downregulation of activation and signalling proteins can solely give an indication how
muscle protein is regulated. However, no conclusions can be made about the effect of
training on the net balance of muscle protein [50]. Similarly, changes in mRNA
expression do not automatically correspond to changes in protein expression. In several
studies in this systematic review mRNA expression was increased but protein
expression was not or vice versa, which can be due to failed mRNA to protein
translation, but methodological issues (time of biopsy, technique, ) can also play a role.
Thus measuring mRNA expression might be not as meaningful as the measurement of
protein expression in comprehending the effect of exercise training on muscle mass and
function in COPD patients.
Structural changes following exercise training
22
In healthy elderly subjects, moderate to high intensity aerobic training and resistance
training enlarges fiber size, enhances capillarization, and alters fiber type proportion in
favor of a more oxidative profile [51-54]. These observations provide a rationale for
exercise training as a means to counteract structural muscle abnormalities in patients
with COPD. The high-intensity interval training studies of the research group
of Vogiatzis et al. were the only studies where a significant decrease in type IIb fiber
proportion was observed compared to baseline following 10 weeks of HIIT (100% of

Wpeak), regardless of baseline nutritional status or GOLD stage, resulting in a less
glycolytic and more oxidative profile of the vastus lateralis muscle fibers. The shift in
fiber type was in line with an increase in exercise capacity, seen as increase in Wpeak
and VO 2 peak during an incremental cycle ergometer test, and 6-minute walking
distance [29-32]. Correlations between fiber proportion and functional capacity,
however, were not reported. Similar pilot data on fiber proportion after HIIT were
reported in chronic heart failure patients [55]. So, high-intensity interval exercise seems
a promising training intervention to significantly change lower-limb fiber proportion in
patients with COPD. Mean fiber size and capillary to fiber ratio increased significantly as
well after HIIT.
Concerning combined aerobic and resistance training, conflicting results are reported
about muscle fiber size [26, 27]. These results may be explained by differences in
training duration and intensity of the resistance training part, in favor of the longest (8
weeks) and the most intense (60 - 85% 1 RM) training program used in the study of
Costes et al. which showed an increase in mean fiber size, while Gouzi et al. did not (6
weeks at 40 % 1 RM) [26, 27]. In both studies, however, patients increased their
quadriceps strength after training. Evidence based research has stated that hypertrophy
23
of the muscle only starts contributing greatly to strength after 6 weeks of resistance
training [56] and the ACSM recommended intensity to induce hypertrophy is resistance
training at 70-85% of 1 RM [57]. Thus, the suggestion can be made that the study of
Gouzi et al. was too short in duration and too low in intensity to see increments in mean
fiber size, but was however sufficient to build up strength due to neural adaptation.
Changes in capillary to fiber ratio were consistent after combined aerobic and resistance
training and showed a significant increase in both COPD patients [26, 27] and healthy
controls, with the latter showing a higher increase [27]. These findings implicate that
the angiogenic training response is likely blunted in COPD patients after combined
aerobic and resistance training. Hypoxemic COPD patients even showed no increase in
capillary to fiber ratio and mean fiber size after combined aerobic and resistance
training [26], suggesting an almost absent angiogenic and anabolic training response.
HF-NMES training did not increase mean fiber size and capillary to fiber ratio in patients
with COPD [38, 39]. Findings about type I and II fiber size in COPD and healthy elderly
were contradictory [38, 58]. Vivodtzev et al. however reported an increase in mean fiber
size, but were not able to establish significance, this while significant increases in
quadriceps strength and endurance, and exercise capacity were observed. Differences in
results between HF-NMES studies might be due to the stimulus intensity of NMES as
illustrated in the systematic review of Sillen et al. [59]. The observation of no increase in
capillary to fiber ratio after HF-NMES is in contrast with a low frequency NMES (LF-
NMES) study in spinal-cord injury patients, where capillary to fiber ratio increased [60,
61]. The lack of change following HF-NMES may be due to the chosen stimulation
frequency, with HF-NMES comparable to resistance training and LF-NMES comparable
24
to aerobic training [62, 63]. Future research comparing the training effect of LF and HF-
NMES on capillary growth is warranted.
Changes in regulation of muscle protein synthesis and breakdown following
exercise training
Current knowledge on hypertrophy and atrophy signalling pathways is discussed in
detail in a review of Egerman and Glass [43].
Regulation of muscle protein synthesis
Solely taking protein expression into account, only IGF-I, MyoD and myostatin
expression appear affected by training. HIIT upregulated IGF-I and MyoD protein
expression significantly in COPD patients [29, 30], however not in cachectic COPD
patients [29]. So, the suggestion can be made that the anabolic response to exercise
training is altered in cachectic COPD patients. Resistance training with or without
testosterone supplementation showed as well an increase in IGF-I protein expression
[24], which is in line with findings that indicate that testosterone supplementation or
resistance training alone indeed increases the IGF-I expression in healthy elderly
subjects [64-68]. MyoD also seems to increase after resistance training, indicating an
increased regulation of cells to proliferate into muscle cells [23, 29, 30]. This is in line
with the observed decrease of myostatin protein expression after HIIT, indicating less
negative regulation of cell proliferation and differentiation [29]. This is conform findings
in heart failure patients [69]. Thus, exercise-based training appears to regulate IGF-I,
MyoD and myostatin in favor of upregulation of muscle protein synthesis and muscle
25
regeneration, which is in line with the established improvements in muscle strength and
functional exercise capacity after training [23, 24, 29, 30]. Unfortunately, statistical
correlations between protein expression and functional capacity are absent. It, however,
did not lead to increased expression of Akt and downstream hypertrophy mediators of
PI3K and Akt involved in the muscle protein synthesis signalling pathway after training
in COPD patients [23, 29, 39]. Phosphorylation/protein expression ratio of GSK-3 and
p70S6K, however, increased in healthy controls after resistance training [23], which
might indicate a blunted training response of the muscle protein synthesis signalling
pathway in COPD patients compared to healthy controls. Combined aerobic and
resistance training in hypoxemic patients even led to a decrease of phosphorylated Akt,
GSK-3 and p70S6K expression [26]. Thus, the suggestion can be made that the anabolic
response to exercise training might be altered even more in hypoxemic COPD patients,
however not resulting in different muscle strength and exercise capacity compared to
normoxemic patients [26]. Mechanisms involved with hypoxia are still largely unknown
and warrant future investigation.
Regulation of muscle protein breakdown
Resistance training and combined aerobic and resistance training did not change the
regulation of phosphorylated FOXO1 and FOXO3, of the disruption of myofilaments by
the autophagy/lysosomal pathway and of the expression of E3 ligases and 20S
proteasome of the ubiquitin mediated muscle proteolytic pathway in both COPD
patients and healthy controls [23, 24, 26]. MuRF-1 protein expression, an E3 ligase,
however, was decreased after aerobic training in chronic heart failure patients [70, 71].
Similar, protein expression of E3 ligases, MuRF-1 and Atrogin-1, was reported to be
significantly decreased after HIIT and HF-NMES in COPD patients [29, 39]. Cachectic
26
COPD patients, on the other hand, showed an upregulation of protein expression of
MuRF-1 and Atrogin-1 after HIIT [29], indicating that cachectic patients indeed appear
to have an increased muscle protein breakdown. This is conform Rutten et al., whom
reported increased muscle protein breakdown in cachectic COPD patients, measured as
increased fractional rate of myofibrillar breakdown, compared to non-cachectic patients
and healthy controls [72]. This is, however, not conform the study of Natanek et al.
where protein expression of MuRF-1 and Atrogin-1 in cachectic COPD patients was not
different compared with non-cachectic patients and healthy controls [73]. Exercise
capacity, however, showed an increase in Wpeak during an incremental cycle ergometer
test and in 6 minute walking distance compared to baseline in both cachectic and non-
cachectic patients, which did not differ between both groups [29]. This might suggest
that upregulated muscle protein breakdown does not automatically result in a
decreased exercise capacity in cachectic patients. Unfortunately, muscle strength was
not measured, which may be a better outcome measure in relation to the regulation of
muscle mass.
Changes in metabolic enzymes following exercise training
Mitochondrial (oxidative) enzymes are decreased in patients with COPD compared to
healthy subjects [7, 8]. Aerobic training, combined aerobic and resistance training, and
HIIT, significantly increased CS and/or HADH activity in COPD patients whom all
improved their maximal exercise capacity [17, 18, 26, 28, 34]. In contrast, positive
correlations between change in CS activity and change in submaximal exercise capacity
were found, instead of change in maximal exercise capacity [17, 18]. Thus, training with
an aerobic component appears to increase mitochondrial (oxidative) enzymes in COPD
to a similar extent as in healthy elderly subjects [51]. Combined aerobic and resistance
27
training in hypoxemic patients, however, did not increase CS activity [26]. The lack of
change in mitochondrial enzyme activity is not abnormal as it has been proven to be
unchanged (or even decreased) during chronic exercise in hypoxia [74, 75]. HF-NMES
did not significantly change mitochondrial (oxidative) enzyme activity [39]. In contrast,
NMES studies with healthy subjects, spinal-cord injury patients and chronic heart failure
patients did show an increase of oxidative enzyme activity, i.e. CS and HADH [60, 61, 76-
78]. It remains to be elucidated whether frequency and/or intensity of NMES influences

effects in terms of mitochondrial (oxidative) enzyme activity.
Glycolytic enzyme activity does not differ between healthy subjects and COPD at rest [8].
After exercise-based training, glycolytic enzyme activity did not change in COPD patients
[17, 18, 28, 39]. One study, however, indicated an increase in LDH activity in
normoxemic patients after combined aerobic and resistance training, suggesting an
increase in anaerobic metabolic capacity [26]. The inclusion of resistance training, 3 sets
of 8-12 repetitions at 60 85% of 1 RM, in the training protocol of Costes et al. [26]
might be a possible explanation for the augmentation of LDH activity.
Changes in oxidative and nitrosative stress, and antioxidants following exercise
training
Markers of oxidative and nitrosative stress, e.g. lipid peroxidation, protein carbonylation
and protein nitration, did not change after exercise-based training in COPD patients and
healthy controls, indicating that exercise does not aggravate oxidative stress [19, 28, 29,
33, 35, 37, 40]. Resistance training in combination with testosterone supplementation
even seems to decrease markers of nitrosative stress, shown as decreased protein
expression of iNOS and significantly increased protein expression of eNOS and nNOS,
28
indicating less inflammation related to nitrosative stress and improved endothelial and
neuronal function [25]. It should be noted that one aerobic training study reported an
increase of markers of oxidative and nitrosative stress after only 3 weeks (5x/w) of
training in COPD patients and healthy controls, with patients showing a higher increase
compared to healthy controls [19]. Interestingly, the duration of this training program is
shorter compared to the other studies [19]. Acute exercise has proven to induce
oxidative stress in patients with COPD [79], thus it is possible that a 3-week intensive
training program is not long enough to counteract acute oxidative stress caused by
exercise. Several measurements of oxidative and nitrosative stress at different time
points during a longer training program would be recommended in the future to gain a
deeper understanding of the effect of training on markers of oxidative stress and
nitrosative stress. Training in patients with low FFMI and/or BMI, also induces oxidative
and nitrosative stress, based on unfavorable changes in antioxidants (GSH), iNOS and
protein nitration compared to patients with normal FFMI/BMI and healthy controls [19,
29, 37]. Thus indicating that cachectic patients appear to be more vulnerable to training
induced oxidative and nitrosative stress compared to non-cachectic patients. This
vulnerability however does not lead to differences in functional exercise capacity,
between cachectic and non-cachectic patients after training.
Enzymatic and non-enzymatic antioxidants measured at rest did not change after
aerobic training [19] and HIIT [33, 35, 37] in patients with COPD. Even more, a blunted
SOD response at rest was seen in patients with COPD after training, with healthy
subjects managing to significantly increase SOD, while COPD patients could not [19, 35].
Rabinovich et al. also showed that the acute muscle GSH and total glutathione (GSH +
GSSG) response to submaximal exercise after HIIT was enhanced compared to the acute
29
response to submaximal exercise before training in healthy controls but not in COPD
patients [33, 37]. Thus, the anti-oxidant response after submaximal exercise seems
blunted as well in COPD patients, indicating a higher vulnerability to oxidative stress
[33, 37].
Changes in inflammation following exercise training

COPD is characterized by low-grade systemic inflammation [80] resulting in an elevation
of circulatory inflammatory mediators, e.g. pro-inflammatory cytokines like TNF-.
However, it is debatable whether TNF- levels are elevated in the peripheral muscles
[81-84]. The effect of aerobic training and HIIT, does not appear to significantly change
mRNA and protein expression of TNF- [29, 30, 35, 36]. Thus, physical capacity of COPD
patients seems to improve without increasing inflammation levels after training. Other
inflammatory cells, i.e. NE+ (neutrophils), measured within 24 hours after exercise, did
even tend to decrease after 8 weeks of resistance training, suggesting an anti-
inflammatory effect of resistance training [22]. Future research focusing on the possible
anti-inflammatory effect of different muscle-focused training strategies is however
suggested.
Expert commentary
Exercise training is the cornerstone of pulmonary rehabilitation and the development of
individually tailored exercise-based training interventions for patients with COPD is an
ongoing challenge. The understanding of the effect of different training interventions on
lower-limb muscle characteristics provides clinicians with more insight to optimize
their rehabilitation programs. Indeed, it may partially explain why the response to
30
pulmonary rehabilitation is differential in patients with COPD [85]. Intensity and
duration of exercise-based training programs seem to be very important factors when
developing a training program. Also, less evidence-based but promising training
modalities like high intensity interval training, neuromuscular electrical stimulation and
magnetic stimulation should be explored more in the future.
Five-year view
It is striking that the amount of well-designed studies exploring training effects by using
lower-limb muscle biopsies is rather limited. The effectiveness of commonly used
interventions like aerobic and resistance training in terms of exercise tolerance and
quality of life is clearly documented. This conflicts with our lack of knowledge on what is
really changing within the lower-limb muscles underlying these beneficial effects, in
particular on exercise tolerance. In the next few years, adequately powered randomized
controlled trials comparing different exercise-based interventions, which explore the
local muscle effects in more depth, should be implemented. A better knowledge on
specific muscle adaptations following different training modalities enhances the ability
to make individually tailored choices in light of exercise training.
Key issues
- Lower-limb muscle dysfunction in patients with COPD is associated with a
decreased oxidative capacity of the muscle and a loss of muscle mass.
- Structural changes, i.e. fiber proportion, fiber size and capillary to fiber ratio,
tend to increase after combined aerobic and resistance training, but
predominantly with very good results after HIIT. This, however, needs to be
confirmed in randomized controlled studies.

31
- Studies measuring the regulation of muscle protein synthesis and breakdown
should perform netto protein turnover measurements after exercise-based
training programs to understand muscle protein synthesis and breakdown more
profound. Correlations with functional outcomes measures such as muscle
strength and muscle mass would also be recommended.
- Exercise-based training does not seem to affect markers of oxidative and
nitrosative stress, and inflammation after training. Future studies should

measure oxidative and nitrosative stress and inflammation markers at different
points in time during and after an exercise-based training program. This will give
us more insight in how oxidative and nitrosative stress, and inflammation
mechanisms work in the muscles. Future research should also explore the ability
of exercise-based training to decrease oxidative and nitrosative stress, and
inflammation.
- Blunted antioxidant training responses at rest and after submaximal exercise
were established. It would be interesting to investigate in future research how
antioxidant supplements could have an impact on this blunted responses.
- Hypoxia appears to blunt increases in mean fiber size, capillary to fiber ratio,
phosphorylated Akt, downstream effectors of Akt and mitochondrial enzyme
activity after exercise-based training compared to normoxemic COPD patients.
Involved mechanisms need to be explored more in the future.
- Cachexia seems to blunt increases in protein expression of IGF-I and MyoD, to
increase MuRF1 and Atrogin1 protein expression and to increase vulnerability to
oxidative and nitrosative stress after exercise-based training compared to non-
cachectic COPD patients. Involved mechanisms need to be explored in future
research.
32
- The effect of NMES and MST protocols should be explored more in the future
with a focus on investigating the effects of different frequencies and intensities
on structural and metabolic characteristics.
- Overall, future research should focus on developing large-scale RCTs that
compare the effect of different training modalities on structural and metabolic
characteristics of lower-limb muscles of patients with COPD.
Financial and competing interests disclosure

The authors were supported by a BOF bursary from the University of Hasselt (15DOC12BOF). The authors have
no other relevant affiliations or financial involvement with any organization or entity with a financial interest in
or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
33
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39
Identification Articles identified through
database searching:
Pubmed and PEDro
(n = 9503)
Titles screened Articles excluded

(n = 9503) (n = 8462)
Screening
Abstracts screened Articles excluded

(n = 1041) (n = 901)
Eligibility
Full-text articles assessed for Full-text articles

eligibility excluded
(n = 140) (n = 115)
Studies included in systematic

Inclusion
review
(n = 25)
Figure 1: Study flowchart from identification of articles to final inclusion (based on the Prisma flowchart template)
40
41
Table 1: Structural changes of the vastus lateralis muscle after different training interventions in patients with COPD
(ns = not significant; RCT = randomized controlled trail; MyHC = myosin heavy chain; RM = repetition maximum; VT = ventilatory threshold; FEV1 = forced expired volume in 1 second)
Author, year of N (n) Mean (SD) FEV 1 Mean (SD) age (y) Study design Study intervention Study duration + Outcome measures Significance difference Significant change pre Significant difference
publication (%predicted) setting within groups post to post (% baseline) between groups post
training training
Aerobic training
Whittom et al., 11 COPD COPD: 37 (11) COPD: 65 (8) Single group pretest-posttest study 30 min cycle ergometer at 12 weeks Fiber type proportion ns - -
1998 (3) 9 age matched healthy Control: 104 (9) Control: 65 (5) (healthy controls only baseline) 80% Wpeak, upper (3x/w) Fiber size type I p < 0.0005 31% -
controls extremity exercise, self- Fiber size type IIa p < 0.05 29% -
paced walking, stretching Fiber size type IIa/b ns - -
and relaxing Fiber size type IIb ns - -

Capillary to fiber ns - -
# Capillary contact type I p < 0.05 34% -
# Capillary contact type IIa p < 0.005 32% -
# Capillary contact type IIa/b ns - -
# Capillary contact type IIb ns - -
# Capillary contact/fiber size ns - -
Guzun et al., 2012 8 COPD COPD 1.53 (0.16)L COPD: 61.63 (4.2) Non-controlled intervention study 45 min: cyclo ergometer 12 weeks Fiber type proportion ns both groups - ns between groups
(21) 8 age and gender Control: 3.33 (0.2)L Control: 58.7 (3.7) with subgroup analyses. Same at 50-80% Wpeak (3x/w) Fiber size type I ns both groups - ns between groups
matched healthy (absolute FEV 1 values) intervention for both groups. Fiber size type II ns both groups - ns between groups
controls Outpatient
homebased
Resistance training
Menon et al., 12 COPD COPD: 46.4 (5.9) COPD: 66.7 (2.0) Non-controlled intervention Bilateral, lower limb, high 8 weeks (3x/w) Fiber size type I ns both groups - not reported
2012 (22) 7 age-matched healthy Control: 103.4 (6.4) Control: 66.7 (1.9) study with subgroup analyses. intensity isokinetic Fiber size type II COPD (p = 0.03) 25.7% not reported
controls (C) Same intervention for both resistance training (5 sets Outpatient C (p = 0.03) 15.4%
groups. of 30 max. isokinetic knee
contractions, angular
velocity 180/s)
Lewis et al., 2007 40 COPD divided in 4 P: 38.8 (12.4) P: 68.6 (8.6) RCT 3 sets of different 10 weeks (3x/w) Muscle fiber density TR (p < 0.05) 11.9% TR > P (p < 0.05)
(24) groups: PR: 43.7 (15.9) PR: 67.6 (7.2) resistance training (# fibers/unit area of muscle) T (p < 0.05) 12.7% T > P (p < 0.05)
P = placebo (11) T: 37.2 (10.8) T: 68.0 (10.8) exercises: seated leg press, Outpatient PR (p < 0.05) 12.8% PR > P (p < 0.05)
PR = placebo + resistance TR: 44.1 (11.0) TR: 67.6 (7.4) seated leg Fiber type proportion ns all groups - not reported
training (8) curl, seated leg extension, Fiber size type I ns all groups - ns between groups
T = testosterone (11) standing calf raise, and Fiber size type IIa ns all group - ns between groups
TR = testosterone + seated ankle Fiber size type IIx ns all groups - ns between groups
resistance training (10) dorsiflexion at 60% 1 RM
(45 min)
Testosterone: 100 mg/w

Combined aerobic and resistance training
Costes et al., 23 COPD: 15 N: 42 (3) N: 60.5 (1.9) Non-controlled intervention Endurance: bicycle exercise 8 weeks (3x/w) Fiber type proportion ns both groups - ns between groups
42
2015 (26) normoxemic (N), 8 H: 34 (4) H: 60.4 (2.4) study with subgroup analyses. (20-30 min), treadmill Mean fiber size N (p < 0.05) ns between groups
hypoxemic (H) Same intervention for both exercise (10-15 min) at Outpatient ns H -
groups. intensity of heart rate at VT Capillary to fiber ratio N (p < 0.05) 16% N > H (p < 0.05)
or 60% Wpeak. Resistance ns H -
exercise upper and lower Capillary to fiber ratio ns both groups - ns between groups
limbs: 3 sets of 8-12 reps at normalized for fiber size
60 85% of maximal
isometric force.
Gouzi et al., 2013 24 COPD COPD: 45.6 (17.5) COPD: 60.8 (8.0) Non-controlled intervention Supervised training: 45 min 6 weeks Proportion type I ns COPD - not reported
(27) 23 age-matched Control: 106.0 (12.9) Control: 61.5 (5.7) study with subgroup analyses. aerobic exercise at heart (3-4x/w) C (p < 0.01)
sedentary healthy Same intervention for both rate corresponding to the Proportion type I-IIa ns both groups - not reported
controls (C) groups. ventilatory or dyspnoea Outpatient Proportion type IIa ns both groups - not reported
threshold. Every other Proportion type IIa-IIx ns both groups - not reported
sessions 30 min of Proportion type IIx ns COPD - not reported
resistance training at 40% C (p = 0.001)
1RM. Mean fiber size COPD (p < 0.05) 11% not reported
ns C -
Fiber size type I COPD (p < 0.05) 11% not reported
ns C -
Fiber size type IIa COPD (p < 0.05) 14% not reported
ns C -
Capillary to fiber ratio COPD (p < 0.001) 16% C > COPD (p < 0.01)
C (p < 0.001) 37%
Capillary density COPD (p < 0.01) 29% ns between groups
C (p < 0.01) 9%
VEGF-A protein ns both groups - not reported
TSP-1 protein COPD (p < 0.05) 44% not reported
ns C -
VEGF-A/TSP-1 COPD (p < 0.05) 65% not reported
C (p < 0.05) 35%
Gosker et al., 13 COPD COPD: 37.1 (11.8) COPD: 61 (12) Single group pretest-posttest 2 x 20 min submaximal 8 weeks Proportion MyHCI (area) ns - -
2006 (28) 7 age-matched healthy Control: 119 (22) Control: 64 (3) study (healthy controls only cycling, 20 min treadmill, (5x/w) Proportion MyHCIIa (area) ns - -
controls baseline) 30 min gymnastics, Proportion MyHCIIx (area) ns - -
unsupported arm exercise Outpatient
training
High intensity interval training
Vogiatzis et al., 15 COPD COPD: 35.7 (16.4) COPD: 66 (7) Single group pretest-posttest High intensity exercise 10 weeks Proportion type I ns - -
2007 (30) 10 age-matched healthy Control: 94.7 (5.4) Control: 61 (5) study (healthy controls only training on cycle (3x/w) Proportion type IIa ns - -
controls baseline) ergometer: constant load Proportion type IIb p = 0.001 14% 8% (43% ) -
at 60% Wpeak (30 min) or Outpatient Fiber size type I p < 0.05 12% -
43
intervals of 30s work 30s Fiber size type IIa p < 0.05 12% -
rest at 100% Wpeak (45 Fiber size type IIb p < 0.05 14% -
min) Mean fiber size p = 0.001 13% -
Vogiatzis et al., 29 COPD: 19 non- NC: 44.1 (4.8) NC: 67 (2) Non-controlled intervention Cycle ergometer: intensity 10 weeks Proportion type I NC (p < 0.001) 32.0% 38.7% NC > C (p < 0.05)
2010 (29) cachectic (NC), 10 C: 37.5 (6.1) C: 63 (2) study with subgroup analyses. 100% Wpeak, 30s work - (3x/w) (21% )
cachectic (C) Same intervention for both 30s rest for 45 min. ns C -
groups. Outpatient Proportion type IIa ns NC - C > NC (p < 0.05)

C (p = 0.012) 50.4% 58.0% (15%
)
Proportion type IIb NC (p < 0.005) 15.2% 9.3% (63% ns between groups
)
C (p < 0.005) 15.5% 11.1% (28%
)
Fiber size type I NC (p = 0.001) 14% NC > C (p < 0.05)
ns C -
Fiber size type IIa ns NC - ns between groups
C (p < 0.01) 11%
Fiber size type IIb NC (p < 0.01) 9% ns between groups
C (p < 0.01) 12%
Mean fiber size NC (p < 0.001) 21% NC > C (p < 0.039)
C (p = 0.003) 12%
Capillary to fiber ratio NC (p < 0.02) 11% ns between groups
C (p < 0.02) 7%
Vogiatzis et al., 46 COPD: STAGE II (14), STAGE II: 67 (2) STAGE II: 69 (2) Non-controlled intervention Cycling: 30 seconds 10 weeks Proportion type I II & IV (p < 0.01) ns between groups
2011 (32) STAGE III (18), STAGE IV STAGE III: 39 (1) STAGE III: 69 (2) study with subgroup analyses. alternated with 30 seconds (3x/w) ns III -
(14). STAGE IV: 21 (1) STAGE IV: 60 (2) (healthy controls only baseline) rest at 80 100% Wpeak Proportion type IIa III (p < 0.01) ns between groups
8 age-matched healthy Control: 100 (5) Control: 60 (2) rate for 45 min. Outpatient ns II & IV -
controls. Proportion type IIb II IV (p < 0.01) ns between groups
Mean fiber size II IV (p < 0.01) ns between groups
Fiber size type I II IV (p < 0.01) ns between groups
Fiber size type IIa II IV (p < 0.01) ns between groups
Fiber size type IIb II IV (p < 0.01) ns between groups
Capillary to fiber ratio II IV (p < 0.001) ns between groups
Capillary to fiber size II IV (p < 0.001) ns between groups
Vogiatzis et al., 19 COPD: 10 interval IE: 44 (6) IE: 64 (3) Randomized, controlled, parallel, IE group: cycle ergometer: 10 weeks Proportion type I ns both groups - ns between groups
2005 (31) exercise (IE), 9 CLE: 39 (6) CLE: 67 (2) two group study intensity 100 - 140% (3x/w) Proportion type IIa ns both groups - ns between groups
continuous-load exercise Wpeak. 30s work - 30s rest Proportion type IIb IE (p < 0.001) 13% 7% (46% ) ns between groups
(CLE) for 45 min. Outpatient CLE (p = 0.02) 13% 9% (31% )
CLE group: cycle Fiber size type I IE (p = 0.004) 24% ns between groups
ergometer: intensity 60 - CLE (p = 0.012) 10%
44
80% Wpeak for 30 min. Fiber size type IIa IE (p = 0.008) 30% ns between groups
CLE (p = 0.021) 10%
Fiber size type IIb ns IE - ns between groups
CLE (p = 0.001) 13%
Capillary to fiber ratio IE (p = 0.013) 10% ns between groups
CLE (p = 0.024) 12%
NMES and magnetic stimulation

Dal Corso et al., 17 COPD: 9 NMES before All patients: 49.6 (13.4) All patients: 65.9 (6.8) Prospective, cross-over, single- NMES (50 Hz, 400 s, 10-25 6 weeks (5x/w) Fiber type proportion ns - -
2007 (38) SHAM, 8 SHAM before blinded, randomized controlled mA, on-off cycle: 2s-10s for Fiber size type I p < 0.05 9.8% -
NMES trial (muscle biopsy only pre and 15 min/leg. (intensity and Outpatient - Fiber size type II p < 0.05 12.5% -
post NMES) duration increased home-based Fiber size type I & II ns - -
progressively). Capillary to fiber ratio ns - -
SHAM (10 Hz, 50 s, 10 mA)
Vivodtzev et al., 20 COPD: 12 NMES, 8 NMES: 34 (3) NMES: 70 (1) Randomized, double-blind, NMES: 35 min quad, 25 min 6weeks (5x/w) Fiber type proportion (#) ns both groups - ns between groups
2012 (39) SHAM SHAM: 30 (4) SHAM: 68 (3) controlled, parallel group study calf (50 Hz, 400 s, 6s/16s Capillary to fiber ratio ns both groups - ns between groups
cycle). Outpatient Fiber size type I ns both groups - ns between groups
SHAM: 35 min quad, 25 min home-based Fiber size type IIa ns both groups - ns between groups
calf (5 Hz, 100 s). Fiber size type IIb ns both groups - ns between groups
Mean fiber size ns both groups - ns between groups
Bustamante et 15 COPD: 10 magnetic MST: 31 (10) MST: 59 (8) Prospective randomized Magnetically stimulated 8 weeks (3x/w) Fiber type proportion ns both groups - not reported
al., 2008 (40) stimulation training Control: 27(6) Control: 68 (10) controlled study quadriceps in both legs: 15 Fiber size type I MST (p = 0.007) 36% not reported
(MST), min/d, 40-70% max. output Outpatient ns C -
5 control (C) of stimulator as tolerated, Fiber size type II ns both groups - not reported
15-18 Hz.
Table 2: Changes in regulation of muscle protein synthesis and breakdown of the vastus lateralis muscle after different training interventions in patients with COPD
(ns = not significant; KLF-10 = Kruppel-like factor 10; MAPK-9 = mitogen activated protein kinase 9; MAPKAPK-3= MAPK-activated protein kinase 3; UBE2GI = ubiquitin conjugating enzyme E2G 1; RAD 23B = RAD23 homolog B; USP 15 = ubiquitin specific protease 15; MGF = mechano growth
factor; IGF = insulin growth factor; MuRF-1 = muscle ring finger protein-1; MAFbx = muscle atrophy F-box; NEDD4 = neural precursor cell expressed developmentally down-regulated protein-4; MyoD = myogenic differentiation 1; IGF-BP= IGF binding factor; ZNF = zinc finger protein; Akt =
protein kinase B; GSK = glycogen synthase kinase; p70S6K = p70S6 kinase; 4EBP-1 = eukaryotic translation initiation factor 4E binding protein 1; REDD1 = DNA damage-inducible transcript 4 protein; FOXO = forkhead box O; RUNX1 = runt-related transcription factor; PAX 7 = paired box
protein 7; LC3 = microtubule-associated protein light chain 3; MyHC = myosin heavy chain; RM = repetition maximum; RCT = randomized controlled trial; FEV1 = forced expired volume in 1 second)
Author, year of N (n) Mean (SD) FEV 1 Mean (SD) age (y) Study design Study intervention Study duration + Outcome measures Significance difference Significant Significant difference
publication (%predicted) setting within groups post change pre to between groups post
training post (% training
baseline)
45
Aerobic training
Rodom-Aizik et 6 COPD COPD: 38.7 (3.2) COPD: 72 (2) Non-controlled 45 min of cycle ergometer at 12 weeks (3x/w) mRNA expression
al., 2007 (20) 5 healthy, age- Control: 108.4 (8.3) Control: 70 (2) intervention study 80% of individual maximal KLF-10 COPD (p = 0.037) not reported
matched controls (C) with subgroup workload. Outpatient ns C -
analyses. Same MAPK-9 COPD (p = 0.041) not reported
intervention for both ns C -
groups. MAPKAPK-3 COPD (p = 0.014) not reported

ns C -
UBE2GI COPD (p = 0.022) not reported
ns C -
RAD23B COPD (p = 0.048) not reported
ns C -
USP15 COPD (p = 0.007) not reported
ns C -
Resistance training
Lewis et al., 2007 40 COPD divided in 4 P: 38.8 (12.4) P: 68.6 (8.6) RCT 3 sets of different resistance 10 weeks (3x/w) mRNA expression
(24) groups: PR: 43.7 (15.9) PR: 67.6 (7.2) training exercises seated leg Myogenin not reported - TR & T > P (p < 0.05)
P = placebo (11) T: 37.2 (10.8) T: 68.0 (10.8) press, seated leg curl, seated leg MyoD not reported - ns between groups
PR = placebo + TR: 44.1 (11.0) TR: 67.6 (7.4) extension, standing calf raise Outpatient IGF-IEa not reported - TR > T, PR & P (p < 0.05)
resistance training (8) and seated ankle dorsiflexion at IGF-IEb not reported - ns between groups
T = testosterone (11) 60% 1 RM (45 min) IGF-IEc not reported - TR & T > PR & P (p < 0.05)
TR = testosterone + IGF-II not reported - TR > T, PR & P (p < 0.05)
resistance training Testosteron: 100 mg/w IGFBP-3 not reported - ns between groups
(10) IGFBP-4 not reported - TR > T, PR & P (p < 0.05)
IGFBP-5 not reported - ns between groups
IGFBP-6 not reported - ns between groups
Myostatin not reported - ns between groups
MAFbx not reported - ns between groups
Protein expression
IGF-I TR (p < 0.001) 90% TR > T, PR & P (p < 0.05)
T (p < 0.05) 30%
PR (p < 0.05) 20%
ns P -
IGF-II ns all groups - ns between groups
Constantin et al., 59 COPD: 32 training + TS: 47.7 (3.3) TS: 68.9 (1.7) RCT Knee extensor training: 5 sets of 8 weeks (3x/w) mRNA expression
2013 (23) supplementation (TS), TP: 45.8 (3.2) TP: 66.9 (1.7) 30 maximal knee extensions at Myogenin TP (p < 0.01) not reported
27 training + placebo C: 105.0 (4.7) C: 66.1 (1.0) angular velocity of 180/s. Outpatient ns TS & C -
(TP) MyoD ns all groups - not reported
Nutritional supplementation: Myostatin ns all groups - not reported
21 age-matched 19g protein and 49g glucose MURF-1 ns all groups - ns TS vs. TP
46
healthy controls who polymer carbohydrate in 500ml MAFbx ns all groups - ns TS vs. TP
receive training + of water after each session Calpain ns all groups - ns TS vs. TP
placebo (C) 20S proteasome TS (p < 0.01) ns TS vs. TP
TP (p < 0.05)
ns C -
ZNF216 ns all groups - ns TS vs. TP
Akt1 ns all groups - not reported

GSK3 ns all groups - not reported
GSK3 ns all groups - not reported
p70S6K ns all groups - not reported
4EBP1 ns all groups - not reported
Redd1 ns all groups - not reported
FOXO1 ns all groups - not reported
RUNX1 TS & C (p < 0.05) not reported
TP (p < 0.01)
Protein expression
Myogenin ns all groups - ns TS vs. TP
MyoD TS & TP (p < 0.05) ns TS vs. TP
C (p < 0.01)
Myostatin ns all groups - ns TS vs. TP
MURF-1 ns all groups - ns TS vs. TP
MAFbx ns all groups - ns TS vs. TP
Calpain ns all groups - ns TS vs. TP
20S proteasome ns TS & TP - ns TS vs. TP
C (p < 0.05)
PAkt1/Akt1 ns all groups - ns TS vs. TP
PGSK3/GSK3 ns TS & TP - ns TS vs. TP
C (p < 0.05)
PGSK3/GSK3 ns all groups - ns TS vs. TP
Pp70S6K/p70S6K ns TS & TP - ns TS vs. TP
C (p < 0.05)
P4EBP1/4EBP1 ns all groups - ns TS vs. TP
Redd1 ns all groups - ns TS vs. TP
PFOXO1/FOXO1 ns all groups - not reported
PFOXO3/FOXO3 ns all groups - not reported
Menon et al., 12 COPD COPD: 46.4 (5.9) COPD: 66.7 (2.0) Non-controlled Bilateral, lower limb, high 8 weeks PAX 7 (satellite cells) ns both groups - not reported
2012 (22) 7 age-matched healthy Control: 103.4 (6.4) Control: 66.7 (1.9) intervention study intensity isokinetic resistance (3x/w)
controls with subgroup training (5 sets of 30 max.
analyses. Same isokinetic knee contractions, Outpatient
47
intervention for both angular velocity 180/s)
groups.
Costes et al., 23 COPD: 15 N: 42 (3) N: 60.5 (1.9) Non-controlled Endurance: bicycle exercise (20- 8 weeks mRNA expression
2015 (26) normoxemic (N), 8 H: 34 (4) H: 60.4 (2.4) intervention study 30 min), treadmill exercise (10- (3x/w) IGF-I ns both groups - ns between groups
hypoxemic (H) with subgroup 15 min) at intensity of heart rate Myostatin ns both groups - ns between groups
analyses. Same at VT or 60 % Wpeak. Outpatient MURF ns both groups - ns between groups

intervention for both Resistance exercise upper and Atrogin-1 ns both groups - ns between groups
groups. lower limbs: 3 sets of 8-12 reps NEDD4 ns both groups - ns between groups
at 60 - 85% of maximal Beclin ns both groups - ns between groups
isometric force. Bnip ns both groups - ns between groups
Gabarapl ns both groups - ns between groups
LC3 ns both groups - ns between groups
Enzyme activity
Cathepsin B+L enzyme ns both groups - ns between groups
activity
Chymotrypsin-like enzyme ns both groups - ns between groups
activity of
20 S proteasome
Protein expression
PAkt ns N - not reported
H (p < 0.05)
PGSK-3 ns N - not reported
H (p < 0.05)
Pp70S6K ns N - not reported
H (p < 0.05)
Akt ns both groups - ns between groups
GSK-3 ns both groups - ns between groups
p70S6K ns both groups - ns between groups
High-intensity interval training
Vogiatzis et al., 29 COPD: 19 non- NC: 44.1 (4.8) NC: 67 (2) Non-controlled Cycle ergometer: intensity 100 10 weeks mRNA expression
2010 (29) cachectic (NC), 10 C: 37.5 (6.1) C: 63 (2) intervention study % Wpeak., 30s work - 30s rest (3x/w) IGF-I NC (p < 0.02) 79% ns between groups
cachectic (C) with subgroup for 45 min. C (p < 0.02) 88%
analyses. Same Outpatient MGF NC (p < 0.05) 48% NC < C (p = 0.027)
intervention for both C (p < 0.05) 90%
groups. MyoD NC (p < 0.05) 69% NC > C ( p < 0.05)
ns C -
Myostatin NC (p < 0.05) 25% NC <. C (p < 0.05)
ns C -
48
Protein expression
IGF-I NC (p < 0.05) NC > C (p < 0.05)
ns C -
MyoD NC (p < 0.05) NC > C (p < 0.05)
ns C -
Myostatin NC (p < 0.05) ns between groups

C (p < 0.05)
PAkt/totalAkt ns NC & C - NC < C (p < 0.05)
PIB-/IB- NC & C (p < 0.05) NC < C (p < 0.05)
Atrogin-1 NC (p < 0.05) NC C (p < 0.05)
C (p < 0.05)
MURF-1 NC (p < 0.05) NC C (p < 0.05)
C (p < 0.05)
Vogiatzis et al., 15 COPD COPD: 35.7 (16.4) COPD: 66 (7) Single group pretest- High intensity exercise training 10 weeks mRNA expression
2007 (30) 10 age-matched Control: 94.7 (5.4) Control: 61 (5) posttest study on cycle ergometer: constant (3x/w) IGF-I p = 0.044 67% -
healthy controls (healthy controls load 60% Wpeak (30 min) or MGF p = 0.002 67% -
only baseline) intervals of 30s work 30s rest Outpatient MyoD p = 0.001 116% -
100% Wpeak (45 min)
Protein expression
IGF-I p = 0.046 72% -
MyoD p = 0.012 67% -
NMES
Vivodtzev et al., 17 COPD: 10 NMES, 7 NMES: 34 (3) NMES: 70 (1) Randomized, double- NMES: 35 min quad, 25 min calf 6weeks (5x/w) Protein expression
2012 (39) SHAM SHAM: 30 (4) SHAM: 68 (3) blind, controlled, (50 Hz, 400 s, 6s/16s cycle). Pp70S6K ns both groups - NMES > SHAM (p<0.05)
parallel group study SHAM: 35 min quad, 25 min calf Outpatient - home- PAkt/totalAkt ns both groups - ns between groups
(5 Hz, 100 s). based PGSK-3 ns both groups - ns between groups
P4EBP-1 ns both groups - ns between groups
Atrogin-1 NMES (p = 0.01) ns between groups
ns SHAM -
49
Table 3: Changes in metabolic enzymes of the quadriceps muscle after different training interventions in patients with COPD
(ns = not significant; CS = citrate synthase; HADH: hydroxyacyl-coenzyme A dehydrogenase; LDH = lactate dehydrogenase; PFK = phosphofructokinase; CK = creatine kinase; HK = hexokinase; COX = cytochrome oxidase C assembly protein; GlyP = glycogen phosphorylase; FEV1 = forced
expired volume in 1 second; VT = ventilatory threshold)
Author, year of N (n) Mean (SD) FEV 1 Mean (SD) age (y) Study design Study intervention Study duration + Outcome measures Significance difference Significant change Significant difference
publication (%predicted) setting within groups post pre to post (% between groups post
training baseline) training
50
Aerobic training
Puente-Maestu et 21 COPD 40.0 (6.0) 63.0 (9.8) Single group pretest 45 min/day cycle ergometer at 70% Wpeak 6 weeks (3x/w) CS activity p = 0.01 47% -
al., 2003 (17) posttest study HADH activity ns - -
Outpatient LDH activity ns - -
PFK activity ns - -
CK activity p = 0.04 11% -
Maltais et al., 11 COPD 36 (11) 65 (7) Single group pretest Aerobic training: cycle ergometer 30 min at 12 weeks CS activity p < 0.05 16% -
1996 (18) posttest study 80% VO 2 max. Upper extremity exercises, (3x/w) HADH activity p < 0.01 40% -
self-paced walking, stretching and relaxing LDH activity ns - -
Outpatient PFK activity ns - -
HK activity ns - -
Rodom-Aizik et 6 COPD COPD: 38.7 (3.2) COPD: 72 (2) Non-controlled 45 min of cycle ergometer at 80% of 12 weeks (3x/w) mRNA expression
al., 2007 (20) 5 healthy, age-matched Control: 108.4 (8.3) Control: 70 (2) intervention study individual maximal workload. COX 11 COPD (p = 0.014) not reported
controls with subgroup Outpatient ns C -
analyses. Same COX 15 COPD ( p = 0.006) not reported
intervention for both ns C -
groups.
Costes et al., 23 COPD: 15 N: 42 (3) N: 60.5 (1.9) Non-controlled Endurance: bicycle exercise (20-30 min), 8 weeks (3x/w) CS activity N (p < 0.05) ns between groups
2015 (26) normoxemic (N), 8 H: 34 (4) H: 60.4 (2.4) intervention study treadmill exercise (10-15 min) at intensity of ns H -
hypoxemic (H) with subgroup heart rate at VT or 60% Wpeak. Resistance Outpatient LDH activity N (p < 0.05) ns between groups
analyses. Same exercise upper and lower limbs: 3 sets of 8- ns H -
intervention for both 12 reps at 60 - 85% of maximal isometric
groups. force.
Gosker et al., 13 COPD COPD: 37.1 (11.8) COPD: 61 (12) Single group pretest- 2 x 20 min submaximal cycling, 20 min 8 weeks CS activity p < 0.05 30% -
2006 (28) 7 age-matched healthy Control: 119 (22) Control: 64 (3) posttest study treadmill, 30 min gymnastics, unsupported (5x/w) PFK activity ns - -
controls (healthy controls arm exercise training GlyP activity ns - -
only baseline) Outpatient HAD activity ns - -
Bronstad et al., 7 COPD COPD: 45.5 (9.8) COPD: 67.6 (7.2) Single group pretest- Knee-extensor protocol: 5 min warm up 6 weeks CS activity p = 0.01 28% -
2012 (34) 5 age-matched controls Control: 93.3 (13.6) Control: 70.0 (4.6) posttest study without load - 4 intervals of 4 min at 90% (3x/w) Mitochondrial respiration p = 0.013 44% -
(healthy controls Wpeak - 2 min active unloaded kicking (60 Basal respiration ns - -
only baseline) kicks a minute). Legs trained separately. Outpatient Maximal activity complex II ns - -
Maximal activity complex IV ns - -
NMES
Vivodtzev et al., 17 COPD: 10 NMES, 7 NMES: 34 (3) NMES: 70 (1) Randomized, double- NMES: 35 min quad, 25 min calf (50 Hz, 400 6 weeks (5x/w) CS activity ns both groups - ns between groups
2012 (39) SHAM SHAM: 30 (4) SHAM: 68 (3) blind, controlled, s, 6s/16s cycle). HADH activity ns both groups - ns between groups
parallel group study SHAM: 35 min quad, 25 min calf (5 Hz, 100 Outpatient LDH activity ns both groups - ns between groups
s). home-based
51
Table 4: Changes in markers of oxidative and nitrosative stress and in antioxidants of the quadriceps muscle after different training interventions in patients with COPD
(ns = not significant; FEV1 = forced expired volume in 1 second; FFMI = fat-free mass index; BMI = body mass index; GSH = glutathione; GSSG = glutathione disulphide; GCS-HS= -glutamylcysteine synthethase heavy subunit; SOD = superoxide dismutase; HNE = 4-hydroxynonenal; iNOS = inducible nitric oxide synthase;
nNOS = neuronal nitric oxide synthase; eNOS = endothelial nitric oxide synthase; UCP3 = uncoupling protein-3; RM = repetition maximum; RCT = randomized controlled trial)
Author, year of N (n) Mean (SD) FEV1 Mean (SD) age (y) Study design Study intervention Study duration + Outcome measures Significance difference Significant Significant difference
publication (%predicted) setting within groups post training change pre to between groups post
post (% baseline) training
52
Aerobic training
Barreiro et al., 15 COPD: 8 normal FFMI N: 47 (19) N: 63 (6) Non-controlled 1 hour cycling ergometer 3 weeks (5x/w) HNE-protein adducts N (p < 0.001) ns N vs. L
2009 (19) (N), 7 low FFMI (L) L: 33 (16) L: 61 (9) intervention study L (p = 0.05) L > C (p = 0.027)
Control: 95 (15) Control: 62 (6) with subgroup Outpatient C (p = 0.001) N > C (p = 0.023)
7 age-matched healthy analyses. Same Protein carbonylation ns all groups - N < L (p = 0.014)
controls (C) intervention for all L > C (p = 0.014)
groups. ns N vs. C
Total SOD ns N & L - N < L (p = 0.03)
C (p = 0.043) L > C (p = 0.006)
N > C (p = 0.05)
Mn-SOD ns all groups - N < L (p = 0.01)
L > C (p = 0.046)
ns N vs. C
Tyrosine nitration N (p < 0.001) ns N vs. L
L (p < 0.001) L > C (p = 0.031)
C (p = 0.02) N > C (p = 0.031)
iNOS L (p = 0.035) ns N vs. L
ns N - L > C (p = 0.041)
ns C N > C (p= 0.034)
eNOS ns L & C - ns between groups
N (p = 0.033)
nNOS ns all groups - ns between groups

Catalase ns all groups - ns between groups
Catalase activity ns all groups - ns between groups
Resistance training
Chavoshan et al., 40 COPD: divided over 4 P: 38.8 (12.4) P: 68.6 (8.6) Randomized placebo Resistance training: leg press, leg 10 weeks (3x/w) mRNA expression:
2012 (25) groups: PR: 37.2 (10.8) PR: 68.0 (10.8) controlled trial: curl, leg extension, calf raise, ankle eNOS not reported - TR > P & T (p < 0.001)
P = placebo (11) T: 43.7 (15.9) T: 67.6 (7.2) Randomization dorsiflexion (3 sets of 8-12 reps at Outpatient nNOS not reported - ns between groups
PR = placebo + resistance TR: 44.1 (11.0) TR: 67.6 (7.4) stratified based on 60-80% 1 RM). iNOS not reported - ns between groups
training (8) age and FEV 1 Protein expression:
T = testosterone (11) Testosterone supplementation: eNOS TR & T (p < 0.05) TR > P (p = 0.008)
TR = testosterone 100 mg/w ns PR & P -
+ resistance training (10) nNOS TR, T & PR TR, T & PR > P (p< 0.001)
(p < 0.05)
ns P -
iNOS TR (p = 0.012) ns between groups
ns T, PR & P -
53
Gosker et al., 13 COPD COPD: 37.1 (11.8) COPD: 64 (12) Single group pretest- 2 x 20 min submaximal cycling, 20 8 weeks HNE-protein adducts ns - -
2006 (31) 7 age-matched healthy Control: 119 (22) Control: 64 (3) posttest study min treadmill, 30 min gymnastics, (5x/w) UCP3 ns - -
controls (healthy controls unsupported arm exercise training
only baseline) Outpatient

Vogiatzis et al., 29 COPD: 19 non-cachectic NC: 44.1 (4.8) NC: 67 (2) Non-controlled Cycle ergometer: intensity 10 weeks Protein nitration ns NC - ns between groups
2010 (29) (NC), 10 cachectic (C) C: 37.5 (6.1) C: 63 (2) intervention study with 100% Wpeak, 30s work - 30s (3x/w) C (p < 0.05)
subgroup analyses. rest for 45 min.
Same intervention for Outpatient
both groups.
Rabinovich et al., 17 COPD COPD: 38 (4) COPD: 66 (1.3) Non-controlled Small blocks of 2 - 5 min of high 8 weeks (5x/w) GSH ns COPD - not reported
2001 (33) 5 age-matched healthy Control: 105 (11) Control: 62 (1.7) intervention study with intensity continuous cycling for C (p < 0.01) 89%
controls (C) subgroup analyses. 30 min. at 90% Wpeak at the Outpatient GSSG COPD (p = 0.05) 43% not reported
Same intervention for end of training program. ns C -
both groups. Total glutathione: GSH + ns COPD - not reported
GSSG C (p < 0.05) 83%
Redox status GSH ns both groups - not reported
Redox status GSSG ns both groups - not reported
Redox status total glutathione ns both groups - not reported
Lipid peroxidation
GCS-HS mRNA expression ns both groups - not reported
COPD (p < 0.05) not reported
ns C -
Rabinovich et al., 20 COPD: 11 BMI normal BMI N : 41 (5.0) BMI N : 67 (1.6) Non-controlled Small blocks of 2 - 5 min of high 8 weeks Lipid peroxidation ns all groups - not reported
2006 (37) (BMI N ), 9 BMI low (BMI L ) BMI L : 30 (3.8) BMI L : 66 (2.1) intervention study with intensity continuous cycling for Muscle GSH ns BMI N - BMI N > BMI L (p < 0.05)
Control: 102 (9.0) Control: 62 (2.8) subgroup analyses. 30 min. at 90% Wpeak at the Outpatient BMI L (p < 0.05) 27% BMI L < C (p < 0.05)
5 age-matched healthy Same intervention for end of training program. C (p < 0.01) 89%
sedentary controls (C) all groups. GCS-HS mRNA expression ns all groups - BMI L > C (p < 0.05)
BMI N > C (p < 0.05)
Rodriguez et al., 18 COPD COPD: 46 (12) COPD: 68 (7) Non-controlled Interval training at > 70% 8 weeks (5x/w) Protein carbonylation ns both groups - not reported
2012 (35) 12 age-matched healthy Control: 107 (14) Control: 65 (9) intervention study with Wpeak with progressive Protein nitration ns both groups - not reported
controls subgroup analyses. increases to 100% Wpeak on Outpatient SOD content ns COPD - not reported
Same intervention for cycle ergometer for 1 hour. C (p = 0.037) 25%
both groups. Total SOD activity ns both groups - not reported
Muscle GSH ns both groups - not reported
Catalase content ns both groups - not reported
Catalase activity ns both groups - not reported
54
Magnetic stimulation-
Bustamante et 15 COPD: 10 magnetic MST: 31 (10) MST: 59 (8) Prospective Magnetically stimulated 8 weeks (3x/w) Protein carbonylation ns both groups - not reported
al., 2008 (40) stimulation training (MST), Control: 27(6) Control: 68 (10) randomized quadriceps in both legs: 15 min/d, Protein nitration ns both groups - not reported
5 control controlled study 40 - 70% max. output of stimulator Outpatient Mn-SOD content ns both groups - not reported
as tolerated, 15-18 Hz. Mn-SOD activity ns both groups - not reported
Catalase content ns both groups - not reported
Catalase activity ns both groups - not reported
55
Table 5: Changes in markers of inflammation in the vastus lateralis muscle after different training interventions in patients with COPD
(ns = not significant; NE+ = neutrophil; CD163+ = tumor associated macrophage; TNF- = tumor necrosis factor alpha; IL-6 = interleukin-6; FEV1 = forced expired volume in 1 second)
Author, year of N (n) Mean (SD) FEV 1 Mean (SD) age (y) Study design Study intervention Study duration + Outcome measures Significance Significant Significant difference
publication (%predicted) setting difference within change pre to between groups post
groups post training post (% training
baseline)
Resistance training
Menon et al., 2012 (22) 12 COPD COPD: 46.4 (5.9) COPD: 66.7 (2.0) Non-controlled Bilateral, lower limb, 8 weeks (3x/w) NE+ COPD (p < 0.05) 100% not reported
56
7 age-matched healthy Control: 103.4 (6.4) Control: 66.7 (1.9) intervention study high intensity ns C -
controls (C) with subgroup isokinetic resistance Outpatient CD163+ ns COPD - not reported
analyses. Same training (5 sets of 30 C (p < 0.05) 100%
intervention for both max. isokinetic knee
groups. contractions, angular
velocity 180/s)

Vogiatzis et al., 2007 15 COPD COPD: 35.7 (16.4) COPD: 66 (7) Single group pretest- High intensity exercise 10 weeks mRNA expression
(30) 10 age-matched healthy Control: 94.7 (5.4) Control: 61 (5) posttest study (healthy training on cycle (3x/w) TNF- ns - -
controls controls only baseline) ergometer: constant IL-6 ns - -
load at 60% Wpeak (30 Outpatient
min) or intervals of 30s Protein expression
work 30s rest at 100% TNF- ns - -
Wpeak (45 min)
Vogiatzis et al., 2010 29 COPD: 19 non- NC: 44.1 (4.8) NC: 67 (2) Non-controlled Cycle ergometer: 10 weeks mRNA expression
(29) cachectic (NC), 10 C: 37.5 (6.1) C: 63 (2) intervention study with intensity 100% of (3x/w) TNF- ns both groups - C > NC (p < 0.05)
cachectic (C) subgroup analyses. Wpeak, 30s work - 30s
Same intervention for rest for 45 min. Outpatient Protein expression
both groups. TNF- ns both groups - ns between groups
Rodriguez et al., 2012 18 COPD COPD: 46 (12) COPD: 68 (7) Non-controlled Interval training at > 8 weeks (5x/w) Protein expression
(35) 12 age-matched healthy Control: 107 (14) Control: 65 (9) intervention study with 70% Wpeak with TNF- ns both groups - ns between groups
controls (C) subgroup analyses. progressive increases to Outpatient TNF- soluble receptor I COPD (p = 0.004) ns between groups
Same intervention for 100% Wpeak on cycle ns C -
both groups. ergometer for 1 hour. TNF- soluble receptor II COPD (p = 0.017) ns between groups
ns C -
Rabinovich et al., 2003 11 COPD COPD: 59 (3.5) COPD:65 (1.4) Non-controlled 60 min of cycling 8 weeks (5x/w- mRNA expression
(36) 6 age and gender Control: 108 (6.5) Control: 63 (1.9) intervention study with divided in intervals of TNF- ns both groups - not reported
matched healthy subgroup analyses. high intensity cycling of Outpatients
sedentary controls Same intervention for 2 5 minutes at 90%
both groups. Wpeak.
57

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Expert Review of Respiratory Medicine

ISSN: 1747-6348 (Print) 1747-6356 (Online) Journal homepage: http://www.tandfonline.com/loi/ierx20

Changes in structural and metabolic muscle

To link to this article: http://dx.doi.org/10.1586/17476348.2016.1157472

Accepted author version posted online: 22

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Journal: Expert Review of Respiratory Medicine

based interventions in patients with COPD: a systematic review

Jana De Brandt, MSc 1 Corressponding author: jana.debrandt@uhasselt.be

Martijn A. Spruit, PhD, PT 12

Wim Derave, PhD 3

Dominique Hansen, PhD, PT 1

Lowie E.G.W. Vanfleteren, PhD, MD 2

Chris Burtin, PhD, PT 1

1 REVAL - Rehabilitation Research Center, BIOMED - Biomedical Research Institute,

Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium

Failure, Horn, The Netherlands.

3 Dept. of Movement and Sports Sciences, Ghent University, Ghent, Belgium

muscle oxidative capacity and muscle mass. Exercise-based training is expected to

attenuate lower-limb intramuscular characteristics, but a detailed systematic approach

databases were searched. Twenty-five studies that implemented an exercise-based

structure, muscle protein turnover regulation, mitochondrial enzyme activity, oxidative

and nitrosative stress, and inflammation after exercise-based training interventions.

observed heterogeneous response in muscle characteristics. Gaps in the current

enhance our knowledge on exercise training effects in patients with COPD.

quadriceps muscle, skeletal muscle, muscle morphology

Chronic Obstructive Pulmonary Disease (COPD) is a chronic lung disease characterized

extra-pulmonary features, such as an impaired lower-limb muscle function [2].

Structural and metabolic muscle alterations result in a decreased lower-limb muscle

oxidative capacity in patients with COPD when compared to healthy age-matched

[10]. Lower-limb muscle dysfunction clearly contributes to the observed exercise

intolerance and exercise-induced symptoms of dyspnea and fatigue in patients with

health status, more hospitalizations, and worse survival [9].

the observed decrease in lower-limb strength is proportional to the decrease in muscle

to reverse or at least stabilize the muscular changes in patients with COPD.

comprehensive care of patients with COPD [2]. Indeed, international

statements/guidelines state that exercise training is the best available non-

pharmacological therapy to improve lower-limb muscle function in patients with COPD

detailed critical appraisal of the peer-reviewed literature aiming to determine the

impact of a wide range of exercise-based therapies on structural and metabolic muscle

characteristics in patients with COPD.

In- and exclusion criteria

metabolic muscular characteristics in the lower-limb muscles in patients with COPD

reported changes in muscle strength and/or endurance capacity after a training

outcome used. Only studies published in English were included.

COPD AND (exercise OR exercise training OR rehabilitation OR pulmonary rehabilitation

OR physical activity OR aerobic training OR endurance training OR resistance training

OR strength training OR cycling OR walking). The search strategy was adapted to

Results were compared, discrepancies between reviewers were discussed and a

(percentages of baseline) between pre and post measurements of outcome measures

tables 1 to 5, according to outcome measure.

whereof 115 articles were excluded. Twenty-five exercise-based intervention studies

nine high-intensity interval training (HIIT) [29-37], two neuromuscular electrical

Fiber type proportion

training study reported differences in fiber type proportion changes according to

IIb/x fiber proportion was significantly decreased in patients of GOLD stages II to IV

Capillary to fiber ratio and markers of angiogenesis

Hypoxemic patients showed no significant change in capillary to fiber ratio after

VEGF-A/TSP-1 ratio in patients and healthy controls, respectively, after combined

aerobic and resistance training [27].

Regulation of muscle protein synthesis and breakdown