Exercise Training in Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis

Abstract

Objective:
To evaluate the effects and safety of exercise training, and to determine the most effective exercise intervention for people with Duchenne muscular dystrophy. Exercise training was compared with no training, placebo or alternative exercise training. Primary outcomes were functioning and health-related quality of life. Secondary outcomes were muscular strength, endurance and lung function. Data sources: A systematic literature search was conducted in Medline, EMBASE, CINAHL, Cochrane Central, PEDro and Scopus. Study selection and data extraction: Screening, data extraction, risk of bias and quality assessment were carried out. Risk of bias was assessed using the Cochrane Collaborations risk of bias tools. The certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation.

Data synthesis:
Twelve studies with 282 participants were included. A narrative synthesis showed limited or no improvements in functioning compared with controls. Health-related quality of life was assessed in only 1 study. A meta-analysis showed a significant difference in muscular strength and endurance in favour of exercise training compared with no training and placebo. However, the certainty of evidence was very low.

Conclusion:
Exercise training may be beneficial in Duchenne muscular dystrophy, but the evidence remains uncertain. Further research is needed on exercise training to promote functioning and health-related quality of life in Duchenne muscular dystrophy.

Full text

JRM JRM
Journal of Rehabilitation Medicine
JRM Journal of Rehabilitation Medicine
REVIEW ARTICLE
J Rehabil Med 2021; 53: jrm0000X
doi: 10.2340/jrm.v53.985
This is an open access article under the CC BY-NC license. www.medicaljournals.se/jrm
Foundation of Rehabilitation Information
EXERCISE TRAINING IN DUCHENNE MUSCULAR DYSTROPHY: A SYSTEMATIC
REVIEW AND META-ANALYSIS
Stian HAMMER, PT, MSc
1,2
, Michel TOUSSAINT, PT, PhD
3
,
Maria VOLLSÆTER, MD, PhD
4,5,6
, Marianne NESBJØRG
TVEDT, ML, MSc
7
, Ola DRANGE RØKSUND, PT, PhD
2,4
, Gregory REYCHLER, PT, PhD
8
, Hans LUND, PT, PhD
9
and
Tiina
ANDERSEN, PT, PhD
1,2,5
From the
1
Department of Physiotherapy, Haukeland University Hospital,
2
The Faculty of Health and Social Sciences, Western Norway
University of Applied Science, Bergen, Norway,
3
Centre de Référence Neuromusculaire, Department of Neurology, Cliniques Universitaires
de Bruxelles, Hôpital Erasme, Université libre de Bruxelles (ULB) , Brussels, Belgium,
4
Department of Paediatrics, Haukeland University
Hospital,
5
Norwegian Advisory Unit on Home Mechanical Ventilation,
Department of Thoracic Medicine, Haukeland University Hospital,
6
Department of Clinical Science, University of Bergen, Bergen,
7
University Library, Western Norway University of Applied Science,
Haugesund, Norway,
8
Department of Physical Medicine and Rehabilitation, Cliniques Universitaires Saint-Luc, Brussels, Belgium and
9
Section of Evidence-Based Practice, Western Norway University of Applied Science, Bergen, Norway
LAY ABSTRACT
The aim of this study was to examine the effects of all
types of exercise training compared with no training,
placebo or alternative exercise training programmes in
people with Duchenne muscular dystrophy. The primary
outcomes were functioning and health-related quality of
life. Secondary outcomes were muscular strength and
endurance. A further aim was to evaluate safety and, if
possible, to nd the most effective exercise training in-
tervention. This review investigates existing research on
this topic. The results have been systematically gathered
and analysed, to give a broader view of what effect exer-
cise training may have for people with Duchenne muscu-
lar dystrophy. The results suggest that exercise training
preserves functioning, and benets muscular strength
and endurance. The study was not able to identify the
best type of exercise training and prescriptions to use in
Duchenne muscular dystrophy. The validity of the results
was reduced by the low number of studies included, the
low quality of the studies, and diversity in both the inter-
ventions and outcome measures used. The results should
therefore be interpreted with caution.
Objective: To evaluate the effects and safety of ex-
ercise training, and to determine the most effecti-
ve exercise intervention for people with Duchenne
muscular dystrophy. Exercise training was compa-
red with no training, placebo or alternative exercise
training. Primary outcomes were functioning and
health-related quality of life. Secondary outcomes
were muscular strength, endurance and lung fun-
ction.
Data sources: A systematic literature search was
conducted in Medline, EMBASE, CINAHL, Cochrane
Central, PEDro and Scopus.
Study selection and data extraction: Screening,
data extraction, risk of bias and quality assessment
were carried out. Risk of bias was assessed using
the Cochrane Collaborations risk of bias tools. The
certainty of evidence was assessed using Grading
of Recommendations Assessment, Development and
Evaluation.
Data synthesis: Twelve studies with 282 participants
were included. A narrative synthesis showed limited
or no improvements in functioning compared with
controls. Health-related quality of life was assessed
in only one study. A meta-analysis showed a sig-
nicant difference in muscular strength and endu-
rance in favour of exercise training compared with
no training and placebo. However, the certainty of
evidence was very low.
Conclusion: Exercise training may be benecial
in Duchenne muscular dystrophy, but the eviden-
ce remains uncertain. Further research is needed
on exercise training to promote functioning and
health-related quality of life in Duchenne muscular
dystrophy.
Key words: Duchenne muscular dystrophy; exercise train-
ing; respiratory muscle training; rehabilitation; physioth-
erapy.
Accepted Nov 12, 2021; Epub ahead of print Dec 14, 2021
J Rehabil Med 2021; 53: jrm002XX
Correspondence address: Stian Hammer, Department of Physioth-
erapy, Haukeland University Hospital, Post Box 1400, 5021 Bergen,
Norway. E-mail: stian.hammer@helse-bergen.no
Duchenne muscular dystrophy (DMD) is one
of the most common inherited neuromuscular
disorders (NMDs) in children, with an incidence of
1 in 3,500–5,000 newborn boys. DMD presents with
early-life onset of progressive muscle weakness,
associated motor delay, and loss of ambulation, due
to absence of the structural protein dystrophin (1).
Most boys become wheelchair-dependent by the
age of 12 years. Thereafter, a gradual loss of arm
function develops, with an increasing need for per-
sonal assistance to perform daily functions (1). DMD
strongly affects longevity (2). Despite new and
promising drugs, there are no curative treatments
(3). Corticosteroids delay the loss of ambulation,
preserve upper limb function and respiration (4),
and combined with ventilation, the median survival
of patients with DMD has increased to more than
into their 30s (5).

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S. Hammer et al.p. 2 of 13
Regular physical activity is essential to maintain
health, functioning, quality of life and social participa-
tion (6). Exercise training is dened as a structured
physical activity prescribed by the type, intensity, du-
ration and frequency in order to improve functions of
the cardiorespiratory, muscular and nervous system (7).
For persons with DMD, there is uncertainty considering
what type, level and intensity of exercise training are
most benecial. Regular submaximal exercise may
maintain muscular strength and prevent secondary
disuse atrophy (1, 8, 9). Intensive eccentric muscle exer-
cise, where the muscle is both activated and lengthened,
in addition to high-resistance exercise, may exacerbate
muscle damage and should be avoided (10). Lack of
dystrophin may lead to contraction-induced injuries,
with ongoing cycles of degeneration and inammation,
impaired muscle tissue repair and the replacement of
muscle bres by fat and connective tissue (11).
Four systematic reviews and one meta-analysis
have considered exercise interventions in mixed NMD
populations (12–15), only one has focused on DMD,
including solely inspiratory muscle training (15). There
are no clear guidelines for exercise training in DMD.
Both boys, parents and physiotherapists require exer-
cise training that is safe and benecial. According to the
World Health Organization’s (WHO) framework, the
International Classication of Functioning, Disability
and Health (ICF), the term “functioning” is dened as
measures of body functions and structures, in addition
to activity and participation level (including interaction
in the context of environmental and personal factors)
(16). Health-related quality of life (HRQoL) is a
broad-ranging concept affected in a complex way by
a person’s physical health, psychological state, level
of independence, social relationships, and relationship
with salient features of their environment (17), and
may be dened as subjective perceived enjoyment and
well-being (18).
The aim of this systematic review was to investigate
the effects of exercise training to improve functioning or
decrease disability in persons with DMD. The primary
outcomes were functioning and HRQoL, and secondary
outcomes were surrogate measures for functioning, such
as muscular strength, endurance or lung function. Further,
we aimed to evaluate safety of the included exercise
training interventions in DMD, and if possible, to search
for the most effective exercise training intervention.
METHODS
The review protocol was registered in PROSPERO in January
2020 (CRD42020149068). The reporting of this systematic
review followed the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) statement.
Eligibility criteria
Study design. Randomized controlled trials (RCT), cross-over
trials, quasi-RCTs and clinical controlled trials were included,
regardless of publication year or language of publication.
Participants. Studies with participants with a dened DMD
diagnosis (1) were included regardless of age. Studies of mixed
NMD populations without separate results for DMD participants
were excluded.
Interventions. Exercise training was the main intervention,
including active voluntary, active assisted, endurance or mus-
cular strength training. Exclusion criteria were: studies with
whole-body vibration, facial exercises, yoga, qigong, tai chi,
passive stretching or range of motion exercises, use of splints
or orthoses, and studies using virtual reality to promote motor
learning or task skills.
Comparisons. Studies with control groups using non-exercise,
usual care, sham or alternative exercise training, were included.
Control groups with pharmacological, surgical or electrothera-
peutical interventions, or within-participants design using the
non-exercised limb as control were excluded.
Outcomes. Primary outcomes were functioning (ICF activity and
participation level, e.g. standardized functional assessments or
use of questionnaires) and HRQoL (generic or disease specic
validated questionnaires). Secondary outcomes were muscular
strength (static or dynamic), endurance (oxygen consumption,
work capacity) or lung function (ICF body functions and structu-
re level). Furthermore, from the included studies, reported safety
of exercise training interventions were of interest. Outcomes of
interest were change between baseline and end of intervention.
Search strategy
A systematic search was performed (SH and MNT) in the fol-
lowing databases: Embase, MEDLINE, CINAHL, Cochrane
Central, PEDro and Scopus, applying available thesaurus
terms/subject headings and text words. The term “Duchenne”
was combined with “physical activity” and/or “exercise”. The
search strategy was reviewed by 2 medical science librarians and
adjusted accordingly. The search was performed on 26 February
2021, in addition to searches in other sources (see Appendix SI).
Reference lists of included studies and earlier similar systematic
reviews were checked for other potentially eligible studies.
Study selection
After removal of duplicates, titles and abstracts were screened
independently by 2 authors (SH and MT). Full-text versions
were reviewed by the same authors. Disagreements were resol-
ved through discussion or by a third author (GR).
Data collection
The extracted data were transferred to predened summary tables
(SH and MT), and transferred to Review Manager (RevMan)
[computer program] Version 5.4, The Cochrane Collaboration 2020
by (SH). Data were double-checked for correct entry (MT). Ex-
tracted data included: methods (study design, duration of the study
and the intervention, study locations, study settings); participants
(number, mean age, age range, diagnosis criteria, functional level,
inclusion criteria, exclusion criteria, withdrawals); interventions
(intervention, comparison, co-interventions); outcomes (primary
and secondary outcomes specied and collected, time points, va-
medicaljournalssweden.se/jrm

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Exercise training in Duchenne muscular dystrophy p. 3 of 13
was considered statistically signicant. Subgroup analysis was
performed by type and duration of the exercise training for each of
these outcomes. Data analysis was performed by use of RevMan
Software version 5.4. In cases with heterogeneity of outcome
measures or limited reporting of data on separate arms of inter-
ventions in the included studies, data were narratively synthesi-
zed. A preliminary synthesis was performed, data relationships
were searched, a theory was developed for how the intervention
worked, and the robustness of synthesis was assessed (23).
RESULTS
Study selection
The search identied 3,466 references from 6 databases
and 86 references from other sources. After screening,
25 were assessed as full-text articles. Amongst these,
we identied two study reports of the same study (25,
30). Hence, the nal sample included 12 studies for
qualitative analysis (8, 24–35) (Fig.1).
Study characteristics
All 12 studies were conducted in the Western world
between 1966 and 2018. In general, the studies were
diverse with respect to design, type and duration of
exercise intervention, number of participants, outcome
assessments and outcomes of interest. Characteristics
and summary of ndings of included studies are des-
cribed in Table I.
lues and changes in baseline and end of intervention completion)
and notes (funding for trial, declared conicts of interests by trial
authors, adverse events, review authors comments or free report
of outcome measures and results).
Risk of bias assessment
The risk of bias (ROB) of the included studies was assessed
independently (SH and MNT) using the Cochrane Collaboration
“Risk of Bias 2” tool (ROB2) (19) for included RCTs and RCT
cross-over trials. The Risk of Bias In Non-randomized Studies
– of Interventions (ROBINS-I) tool (20) was used for clinical
controlled trials. The studies were not blinded to the reviewer
(SH, MNT and MT). Disagreements were resolved through
discussion or by a third author (HL). The certainty of evidence
was assessed using GRADEpro Guideline Development Tool
(SH and HL) (21).
Data synthesis and analysis
Three comparisons were made; (i) exercise training vs no exer-
cise training; (ii) exercise training vs placebo; and (iii) exercise
training vs alternative exercise training. When reporting results
from multiple time-points, data closest to the end of the exercise
intervention were included. In cross-over trials, effect size was
extracted from the rst cross-over. In studies with missing data,
corresponding authors were contacted. A random effect meta-
analysis was conducted, based on the variation of participants,
settings, interventions and outcomes. The outcomes were cal-
culated by standardized mean differences (SMDs). SMD effect is
characterized as small when less than 0.2, moderate when between
0.21 and 0.8, and large when more than 0.8 (22). Heterogeneity
was assessed by the χ2 test and I-squared statistic, p-value < 0.1
Fig. 1. Flow chart of identied, screened, excluded and included articles. DMD: Duchenne muscular dystrophy.
Records after duplicates removed
(n=2,327)
Records screened
(n=2,327)
Records excluded
(n=2,302)
Full-text articles assessed for
eligibility
(n=25)
Studies included in quantitative
synthesis (meta-analysis)
(n=7)
Additional records identified
through other sources
(n=86)
Records identified through
database searching
(n=3,466)
Studies included in qualitative
synthesis
(n=12)
Full-text articles excluded with
reasons (n=12)
Study design (n=7)
Intervention (n=2)
Insufficient data (n=2)
Did not provide original data
for DMD (n=1)
Screening noitacifitnedI
Included
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Table I. Characteristics of included studies (n = 12)
Author, year (reference)
Country
Study design
Sample size
Total, IG and CG. Mean age (SD)
or range
And
Participants functioning
Exercise training
intervention
for the IG
Frequency, Intensity,
Time, Setting, Duration
Intervention for the CG
(Comparison)
Frequency, Intensity, Time,
Setting, Duration
Outcome
Measures
Alemdaruglo et al. 2015 (24)
Turkey
RCT
N = 24
IG (n = 12)
9.5 (1.38) years
IG (n = 12)
9.33 (1.37) years
All ambulant, able to sit 1 hour
independently, steroid use for more
than 6 months
Arm cycling
F:3 days/week
I:50% of max
difculty
T:40 minutes
S: Hospital, supervised
by PT
D: 8 weeks
UE ROM exercises
F: 5 days/week
I:5-10 reps depending on
individual fatigue
T:40 minutes
S:Home, supervised by family
D: 8 weeks
Functioning
AERA. Standing from
supine. T-shirt donning/
Removing
NSAA
Quality-of-life
NA
Strength
Isometric strength by HDD
UE. Grip Strength.
Endurance
A6MCT
Heutinck et al. 2018 (26)
Netherland
RCT
N = 19
IG (n = 9)
12.9 (2.8) years
CG (n = 10)
12.6 (3.4) years
Ambulatory and wheelchair
dependent, able to lift their hands to
the head by use of elbow exion or
compensate. 100% in IG and 60% in
CG used steroids.
Gravity compensated
UE training with use of
3D Sony PlayStation
videogame
F:5 days/week
I:n/a
T: 15 minutes
S: Home, supervised at
start and after 10 weeks,
otherwise independently
D: 30 weeks
Usual care
Functioning
PUL, MFM ROM
Abilhand-plus
(questionnaire children/
parents)
Quality-of-life
Kidscreen 52
Global Health (Children and
parents questionnaires)
Strength
Isometric strength by HDD
UE. MVC
Endurance
A6MCT
Houser et al. 1971 (27)
USA
CCT
N = 14
IG (n = 7)
8.5-14.11 years
CG (n = 7)
8.5-15.6 years
All the participants were wheelchair
dependent
Breathing exercises and PT
program
F: 5 days/week
I: 10 and 18 cm H20 CPAP
during 12 deep insp, 4-5
cough cycles, 6 forced
expirations
T: n/a
S: School, supervised
by PT.
D: 12 weeks
PT program
F:5 days/week
I: n/a
T: n/a
S: School, supervised by PT.
D: 12 weeks
Functioning
FVC, FEV1, FEF25-75, PERF
Quality-of-life
n/a
Strength
n/a
Endurance
M
Jansen et al. 2013 (8)
Netherland
RCT
N = 30 (29 analyzed)
IG (n = 17)
10.8 (2.4) years
CG (n = 13)
10.5 (2.8) years
Ambulatory (n = 18) and wheelchair
dependent (n = 12).
23 of participants used steroids. All
were able to lift both arms to the
head, but unable to use wheel chair
> 500 meters.
Active assisted UE and
LE cycling (KTP kinetic
ergometer).
F: 5 days/week
I:65 revolutions per
minute/< 6 OMNI scale)
T: 15 minutes legs, 15
minutes arms.
S: Home supervised by
parents or PT.
D: 24 weeks
Usual care Functioning
MFM, ROM PEDI (self-care
questionnaire).
Quality-of-life
n/a
Strength
MRC
Endurance
A6MCT
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Exercise training in Duchenne muscular dystrophy p. 5 of 13
Table I. Conts.
Author, year (reference)
Country
Study design
Sample size
Total, IG and CG. Mean age (SD)
or range
And
Participants functioning
Exercise training
intervention
for the IG
Frequency, Intensity,
Time, Setting, Duration
Intervention for the CG
(Comparison)
Frequency, Intensity, Time,
Setting, Duration
Outcome
Measures
Martin et al. 1986 (28)
Australia
RCT cross-over
N= 18 (17 analyzed, one died)
14.2 (7-20) years
IG (n = 9)
CG (n = 9)
Wheelchair dependent (n = 17),
ambulatory (n = 1)
Respiratory strength and
endurance training by use
of circuit respiration device
(ow limiting resistance).
F: 5 days/week
I: Endurance;
Ventilate until exhaustion
within 3 minutes, 20% over
VC rage in one sequence.
Strength: Maximal
inspiratory/expiratory
manoeuvers in 3-5 seconds
S: supervised at school
D: 8 weeks
Usual care Functioning
VC
Quality-of-life
n/a
Strength
PeMax and
PiMax
Endurance
Pe time and
Pi time
Radillo et al. 1989 (29)
United Kingdom
RCT cross-over
N = 22 (20 analyzed)
11.6 (9-14) years
n/a
Inspiratory muscle training
(Triow II)
F: 5 days/week
I: 20 inspirations with
increased resistance ow
T: n/a
S: School, supervised by PT
D: 18 days
Placebo
Forced expirations (Peak
expiratory ow meter).
F: 5 days/week
I: 10 expirations
T: n/a
S: School, supervised by PT
D: 18 days
Functioning
FVC, FEV1, PERF
Quality-of-life
n/a
Strength
PiMax
Endurance
n/a
Scott et al. 1989 (30)
United Kingdom
RCT
N = 18
6.9 (1.17) years
(5-9) years
IG (n = 9)
CG (n = 11)
All were fully ambulatory, with
anticipated compliance to the
intervention.
LE exercise program and
passive stretching.
F: 7 days/week
I: Manual resistance (n/a)
T: 15 minutes
S: Home, supervised by the
parents
D: 6 months
Series of oral instructed free
exercises for the LE and
passive stretching.
F: 7 days/week
I: n/a
T: 15 minutes
S: Home, supervised by the
parents
D: 6 months
Functioning
Locomotor ability, ROM
ankle dorsiexion. Vignos
Scale,
8.4 and 45 meter timed
test.
Quality-of-life
n/a
Strength
MRC, Myometric and torque
force output
Endurance
n/a
Stern et al. 1989 (31)
Australia
RCT cross-over
N = 18 (12 analyzed, four died).
15 (range 10.4 – 23.4) years
IG (n = 7)
CG (n = 11)
Ambulatory (n = 2) and wheelchair
dependent (n = 2).
Inspiratory muscle training
with ow resistance to play
a video game with visual
audio feedback.
F: 5 days/week
I: Exceed a pre-set level of
resistance, 6.25, 4.76, 3.18
or 2.38 mm restrictors.
S: School, supervised
D: 6 months IP, 12 months
S P.
Usual care Functioning
FVC (% pred)
Quality-of-life
n/a
Strength
PeMax
(% pred), PiMax (% pred)
Endurance
Endurance (mmHg)
Topin et al. 2002 (32)
France
RCT
N = 16
IG (n = 8)
14.7 (4.5) years
CG (n = 8)
12.63 (1.8) years
All were wheelchair dependent,
clinically stable and free of
medication and dyspnea
Inspiratory resistive muscle
training (Triow)
F: 2times/5 days
I: 30% of PiMax
T: 10 minutes
S: Home, supervised by
parents,
D: 6 weeks
Placebo
Inspiratory muscle training
(Triow)
F:2times/5 days
I: 5% of PiMax
T: 10 minutes
S: Home, supervised by
parents
D: 6 weeks
Functioning
VC, FRC, TLC, FEV1, FEV1/
FVC
Quality-of-life
n/a
Strength
PiMax/MIP
Endurance
Tlim
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Table I. Conts.
Author, year (reference)
Country
Study design
Sample size
Total, IG and CG. Mean age (SD)
or range
And
Participants functioning
Exercise training
intervention
for the IG
Frequency, Intensity,
Time, Setting, Duration
Intervention for the CG
(Comparison)
Frequency, Intensity, Time,
Setting, Duration
Outcome
Measures
Vignos et al. 1966 (33)
USA
CCT
N = 28
IG (n = 14) 7.4 years
CG (n = 14) 7.7 years
Fully ambulating with good functional
status
Resistance muscle training
(active/active assisted)
of LE, UE and abdominal
muscles.
F: 7 days/week rst 6
months, 3-5 days/week
next 6 months
I: 10 reps with maximal
resistance/lowest degree
of assistance by antigravity
pulley.
T: 30 minutes
S: Home, initial supervised
by PT.
D: 12 months
Usual care Functioning
Timed tests by
Stair climbing, rising from
oor, rising from chair, 23
feet walking.
Quality-of-life
n/a
Strength
Overall muscle strength
%-of normal (MRC). Weight
lifted in each exercise.
Endurance
n/a
Wanke et al. 1994 (34)
Australia
RCT
N = 30 (22 analyzed)
IG (n = 15)
13.6 (4.5) years
CG (n = 15)
14.5 (3.8) years
Both ambulatory (n = 7) and
wheelchair depended (n = 23).
Inspiratory muscle training
with special constructed
training device.
F: 2 times/day
5 days/week
I: Endurance;
10 cycles of 1-minute
duration with variable
resistance, 20 second rest.
Strength;
10 maximal inspirations.
T:n/a
S: Home, supervised by
clinicians or parents
D: 6 months
Usual care Functioning
VC, FEV1, 12 s MVV
Quality-of-life
n/a
Strength
PesMax, Pdi
Endurance
Endurance time (Te)
Zileili et al. 1999 (35)
Turkey
CCT
N=45
IG (n=24)
12.08 (1.79) years
CG (n=21)
23.43 (2.04) years
Participants with early scoliosis, able
to cooperate and without affected
respiration and use of respiratory
assistive devices
Breathing exercises and a
PT program as CG.
F: 3 times/day
7 days/week
I: 10 reps
a) isolated chest breathing
b) respiratory exercise
combined with other
exercises
c) Breathing cycles with
Triow device
T: n/a
S: Home, supervised by
parents
D: 4 weeks
PT program
F: 2 times/day
7 days/week
I: 10 reps active or active
assisted UE and LE exercises
isotonic exercise for
abdominal muscles. Passive
stretching of LE (hip, exors,
hamstrings, tensor facia
latae, gastro soleus, lumbar
extensors)
T: n/a
S: Home, supervised and help
from parents
D: 4 weeks
Functioning
VC, FVC, FEV1, Mobility
of thorax (circumference
measured at maximal
inspiration (FVC level),
neutral (functional
residual capacity- level)
and maximal expiration
(residual volume-level) at
three dened anatomical
reference points
Quality-of-life
n/a
Strength
n/a
Endurance
n/a
IG : Intervention group; CG: Control Group; SD : Standard deviation; F: Frequency; I: Intensity; T: time; S : Setting; D: Duration (intervention period); RCT:
Randomized Controlled Trial; HHD: Hand Held Dynamometer; MMDT: Minnesota Manual Dexterity Test; AREA: Arm elevation assessment; NSAA: North Star
Ambulatory Assessment; A6MCT: Assisted 6 Minutes Cycling Test; PUL: Performance Of Upper Limb; MFM: Motor Function Measure; ROM : Range Of Motion;
HRQoL: Health Related Quality of Life; CCT : Clinical Controlled Trial; MVV: Maximal Voluntary Ventilation; FVC: Forced Vital Capasity; FEV1 : Forced Expiratory
Volume rst second; FEF: Forced Expiratory Flow; PEFR: Peak Expiratory Flow Rate; MRC: Medical Research Council (scale); PEDI: Pediatric Evaluation of Disability
Inventory; MEP: Maximal Expiratory Pressure; MIP and Pi Max : Maximal Inspiratory Pressure; Pe and Pi time: Expiratory or Inspiratory Pressure sustained over
time; Tlim: Time limit, maximal time a subject was able to sustain breathing against a predetermined inspiratory load without fatigue; VC: Vital Capacity; TLC:
Total Lung Capacity; Pesmax: Maximal Sniff assessed Esophageal; Pdi: Trans diaphragmatic Pressure; n/a: not available
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Study design
Six studies were randomized controlled trials (8, 24, 26,
30, 32, 34), 3 were randomized cross-over trials (28, 29,
31), and 3 were clinically controlled trials (27, 33, 35).
Participants
The total number of participants was 282, of whom
264 (94%) completed the studies. The sample size
range was 14–45 participants, mean age was 10.7
(range 5–24) years, 108 participants were wheelchair-
dependent, 86 were able to walk, and this information
was lacking for 88 participants. Withdrawals occurred
due to illness during the intervention period (29) or
motivational problems (26). Five participants died
(mean age 17.8 years) due to superimposed infection
and respiratory failure or respiratory failure alone; all
had severely restricted lung capacity (28, 31).
Interventions
Five studies used exercise training for limbs, and 7 applied
respiratory muscle training (RMT). For limb exercise,
2 studies used cycling (arms or arms and legs), 1 used
Fig. 2. Risk of bias of the included randomized controlled studies.
Fig. 3. Risk of bias by study level for the non-randomized studies.
Table II. Certainty of evidence
GRADE domain Judgement according to outcomes of interest Concerns about certainty domains
Methodological limitations of the
studies
Functioning: Three studies had some concerns regarding ROB (22, 24, 28), and 2 had
high risk of bias (7, 31), conservatively the trials were judged to have very serious
methodological limitations.
In the studies investigating lung function, 1 study was judged to have low ROB (30),
3 to have some concern (25, 27, 32), and 3 to have high risk of bias (26, 29, 33).
Conservatively the trials were judged to have very serious methodological limitations
Quality of life: Only 1 study reported this outcome (24). The study was judged to have
some concerns regarding ROB. The trial was judged to have serious methodological
limitations.
Very serious
Serious
Indirectness The patients, interventions and comparators in the studies all provided direct evidence
to the clinical question at hand.
Not serious
Imprecision Functioning: Five studies reported on function, with a total of 119 participants (very
low) (7, 22, 24, 28, 31). Two studies reported small improvements (7, 22), and 3 with
non-signicant results likely because of enrolling a small number of participants, and
presence of clinical heterogeneity (age, progression) (24, 28, 31). The evidence was
judged to have serious imprecision.
Seven studies reported in lung function parameters as outcome (25–27, 29, 30, 32,
33). One study reported improvements in lung function (32), while in 6 studies lung
function remained unchanged or declined with non-signicant changes (25–27, 29, 30,
33). The evidence was judged to have serious imprecision.
Quality of life: The only study including this outcome reported non-signicant
improvement in favour of intervention (24). The evidence was judged to have serious
or very serious imprecision.
Serious
Serious/very serious
Inconsistency Functioning: The direction and magnitude of effect varied across the different trials.
Overall the results showed either small or no change in functioning in favour exercise
training. The evidence was judged to have serious inconsistency.
In the studies who investigated change in lung function, the direction and magnitude
were similar across all except 1 of the studies with no change in lung function (32).
The evidence was judged to not serious inconsistency.
Serious
Not serious
Publication bias Functioning: Publication bias was not strongly suspected because both negative and
positive trials were published, and search for studies were comprehensive. Publication
bias was not strongly suspected with respect to lung function, except in 2 studies without
reported outcome data for the time-points and separate arms for the groups of intervention
(26, 29). In addition to this, publication bias was not strongly suspected, because both
negative and positive trials were published, and search for studies were comprehensive.
Quality of life: Publication bias was not strongly suspected, because a non-signicant
improvement in favour intervention was reported (24).
Not suspicious
Not suspicious
Grade evidence by ROB judgements was considered as; low to be no serious or serious, unclear to be equal to serious or very serious and high ROB to be very
serious. If GRADE domains were judged as serious, they were downgraded by 1 point, and very serious, certainty of evidence was downgraded by 2 points.
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videogames for arms, 1 used resistance training for legs,
and 1 used resistance training for arms and legs. For RMT,
inspiratory muscle training was used in 5, inspiratory and
expiratory muscle training in 1 and breathing exercises
in 2 studies. Exercise training was performed at home (7
studies), at school (4 studies) or in the hospital (1 study).
Half of the studies had a short-term training intervention
(range 36 days to 12 weeks), the other half had a long-term
training intervention (range 5–12 months).
Comparison
Eight studies used usual care for comparison (8, 26-
28, 31, 33–35), 2 used placebo (29, 32) and 2 used
alternative training (24, 30).
Outcomes
The studies did not report functioning outcomes uni-
formly (8, 24, 26, 33), and only one reported HRQoL
(26). Overall, studies with RMT as exercise training
intervention assessed respiratory muscle strength (28,
29, 31, 32, 34) or endurance (27, 28, 31, 32, 34), and/or
lung function parameters ((27–29, 31, 32, 34, 35). Limb
exercise training interventions assessed muscular strength
of the trained extremities (8, 24, 26, 30, 33), endurance
(8, 24, 26), and functioning measures (e.g. timed physical
tests or range of motion (ROM)) (8, 24, 26, 30, 33).
Risk of bias
ROB is summarized by outcome level of the RCT
studies in the meta-analysis (Fig. 2), and by the study
level for the non-randomized interventional studies
(Fig. 3). All but one of the included studies (32) pre-
sented unclear or high ROB factors.
Missing description of the allocation process (8, 24,
28, 30, 31, 34) led to “some concern” regarding risk of
bias. No intention-to-treat analysis (26) and no wash-
out time (29) led to “some concern” regarding risk of
bias. One study was judged “high risk” as participants
were moved between groups after randomization,
with no intention-to-treat analysis (8). Another study
was also considered to have high risk of bias due to
missing data from 7 participants (31). No intention-to-
treat analysis caused “some concern” (28), as did bias
Fig. 4. Forest plot of the effect on muscular strength of any exercise vs no exercise (1.1.1) and any exercise vs placebo (1.1.2) in persons with
Duchenne muscular dystrophy (DMD), with pooled effects of these 2 comparisons (Total). 95% CI: 95% condence interval; df: degrees of freedom;
I2: measure of heterogeneity; Tau2: measure of variance; SD: standard deviation.
Fig. 5. Forest plot of the effect on endurance after any exercise vs no exercise (2.1.1) and any exercise vs placebo (2.1.2) in persons with Duchenne
muscular dystrophy (DMD), with pooled effects of these 2 comparisons (Total). 95% CI: 95% condence interval; df: degrees of freedom; I2:
measure of heterogeneity; Tau2: measure of variance; SD: standard deviation.
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in outcome measurement without assessor blinding
(24), and biased results reporting was judged “high”
in 2 cross-over studies with lack of separate results for
specic time-points (28, 31) (Fig. 2).
Amongst non-randomized studies (Fig. 3), no in-
formation regarding confounders (e.g. age, training
supervision) (33, 35) led to serious ROB. Lack of infor-
mation regarding participant selection, retrospectively
assigned intervention classication, deviation from
intended intervention and missing data led to moderate
ROB in one study (33). Three studies had moderate
ROB in outcome measurement due to no information
regarding assessor blinding (27, 33, 35). As for the
reported results, ROB was considered moderate in 2
studies, which were judged to report “no information”
due to insufcient description (33, 35).
Synthesis of results
Due to the low number of studies included and the large
heterogeneity in outcome measures and comparisons,
it was not possible to perform a meta-analysis for the
primary outcomes, functioning and HRQoL. A meta-
analysis was performed for the secondary outcomes,
muscular strength and endurance following any exer-
cise intervention.
Narrative synthesis
Functioning. Two studies reported on multiple domains
of functioning at the ICF activity and participation
level, with no signicant differences evaluated by the
ABIL-Hand and PEDI-questionnaire (8, 26). When
measuring functioning using standardized functional
Fig. 6. Forest plot of the effect on muscular strength of the different types of exercise, exercise of limbs and postural muscle vs no exercise
(3.1.1), respiratory muscle training (RMT) and breathing exercises vs no exercise (3.1.2), and RMT vs placebo (3.1.3) in persons with Duchenne
muscular dystrophy (DMD). 95% CI: 95% condence interval; df: degrees of freedom; I2: measure of heterogeneity; Tau2: measure of variance;
SD: standard deviation.
Fig. 7. Forest plot of effects on endurance of the different types of exercise training, exercises of limb and postural muscle vs no exercise (4.1.1),
respiratory muscle training (RMT) and breathing exercises vs no exercise (4.1.2), and RMT vs placebo (4.1.3) in persons with DMD. 95% CI: 95%
condence interval; df: degrees of freedom; I2: measure of heterogeneity; Tau2: measure of variance; SD: standard deviation.
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S. Hammer et al.p. 10 of 13
assessments at ICF-activity level, the 2 studies using
arm-cycling revealed improved or maintained functio-
ning measured by arm elevation assessment and motor
function measure (8, 24). There were no improvements
in the other functioning outcome variables reported
(8, 26, 30, 33). RMT did not improve lung function
parameters (27–29, 32, 35), but breathing exercises
improved chest mobility (35).Vital capacity decreased
in all but one study (28) regardless of participants
underwent training or not (see Table II).
Health related quality-of-life. HRQoL was reported
in only one study (applying videogame exercise with
gravity compensation), no signicant improvements
were reported following the intervention (26) (see
Table II).
Meta-analysis
Muscular strength. The muscular strength outcomes of
studies that included any exercise training intervention
are shown in Fig. 4. Random effects meta-analysis
included 6 studies with 126 participants. Muscular
strength was improved by the interventions (SMD
0.92; 95% condence interval (95% CI) 0.21–1.63, I
2
70%) (Fig. 4). When comparing exercise vs placebo,
no effect on muscular strength was found (SMD 0.01;
95% CI –0.64 to 0.67, I 0%), but a large effect was
found for the comparison exercise vs no exercise (SMD
1.39; 95% CI 0.7–2.08, I
2
70%).
Endurance. The endurance outcomes from studies that
included any exercise training intervention are shown
in Fig. 5. Random effects meta-analysis included 5
studies with 89 participants. Endurance was improved
by the exercise training interventions (SMD 0.64; 95%
CI = 0.21–1.08, I
2
0%). When comparing exercise vs
placebo, the study found signicant differences in fa-
vour of exercise training vs placebo (SMD 1.29; 95%
CI 0.19–2.40) and exercise training vs no exercise
(SMD 0.52; 95% CI 0.05–1.00, I
2
0%)
Subgroup analysis
Due to study heterogeneity, subgroup analysis by type
and duration of exercise training intervention was
performed.
For muscular strength, effects were identied of
limb exercise training (SMD 1.23; 95% CI 0.42–2.05,
I
2
55%) and RMT (SMD 1.94; 95% CI 0.89–2.99, I
2
:
Table III. Summary of ndings
Outcomes Results from narrative synthesis
or meta-analyses with the
effect size Standardized mean
difference (95% condence
interval)
Number of participants (studies) Certainty of the evidence*
Functioning
Functional
assessments
Lung function
The studies showed small or no
effect in functioning
The studies showed no effect on lung
function
119 participants (4 randomized
controlled trials and 1 clinical
controlled trial)
163 participants (2 randomized
controlled trials, 3 cross-over trials
and 2 clinical controlled trials)
OOO
Very low
Due to very serious ROB, serious
inconsistency, serious imprecision (variance
in reported results and low numbers of
participants)
OOO
Very low
Due to very serious ROB, serious
inconsistency, serious imprecision.
Health-related
Quality of life
One study showed non-signicant
improvement,
the mean HRQoL improved 2.4 (SD
3.3) in intervention group and 1.4
(SD 2.4) in the control group by
Kidscreen 52.
19 participants
(1 randomized controlled trial)
OOO
Very low
Due to serious ROB, serious to very serious
inconsistency and imprecision (1 study, few
participants)
Muscular strength 0.92 (0.21, 1.63) 126 (5 randomized controlled trials
and 1 cross-over trial)
OOO
Very low
Due to very serious ROB, serious imprecision
(e.g. low number of participants), very
serious inconsistency (large CI).
Endurance 0.64 (0.21, 1.08) 89 participants (4 randomized
controlled trials, 1 clinical controlled
trial)
OOO
Very low
Due to very serious ROB, serious
inconsistency (broad CI), and serious
indirectness (low numbers of participants
and variance in reported results).
The primary outcomes were functioning and health-related quality of life for which a narrative synthesis of the evidence was provided. For the secondary outcomes
by muscular strength and endurance, a pooled effect estimate was possible.
*Commonly used symbols to describe certainty of evidence proles: high certainty , moderate certainty O, low certainty OO and very low certainty
OOO.
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not applicable) compared with no exercise. No effect
was seen of RMT compared with placebo (SMD 0.01;
95% CI –0.64 to 0.67, I
2
0%) (Fig. 6).
For endurance, no signicant effects were identied
for limb exercise training (SMD 0.46; 95% CI –0.26
to 1.18, I
2
12%) or RMT (SMD 0.57; 95% CI –0.10
to 1.25, I
2
0%) compared with no exercise, whereas
there was an effect for RMT vs placebo (SMD 1.29;
95% CI 0.19–2.40) (Fig. 7).
Safety of exercise training
Regarding the safety of exercise training intervention,
no studies systematically reported adverse events. In
2 studies, symptoms of fatigue or pain or blood se-
rum creatine kinase levels were monitored for safety
assessment (8, 34). Most studies provided careful
supervision.
Certainty of results
The certainty of results was assessed by the GRADE
approach. Due to high study heterogeneity, few parti-
cipants and imprecision by large condence intervals
for both muscular strength and endurance, the certainty
of evidence was downgraded 3 steps (Table III).
DISCUSSION
This systematic review included 12 studies with 282
participants with DMD. It was only possible to con-
duct a narrative synthesis for the primary outcomes of
functioning and HRQoL, and this indicated no clear
effect of exercise training interventions. Data from
126 participants were included in meta-analyses, with
ndings suggesting that any exercise training interven-
tion may improve muscular strength and endurance in
persons with DMD. Subgroup analyses to evaluate the
specic type of exercise intervention suggests that limb
exercise training improved limb muscular strength
and RMT improved respiratory muscular strength,
both compared with no training. For endurance, RMT
improved respiratory muscular endurance compared
with placebo. No study reported signs of overuse or
injuries during the intervention period; thus, long-term
effects and possible adverse effects of exercise training
intervention remain uncertain. Two studies reported the
death of 5 participants due to superimposed infections
and respiratory failure. The certainty of evidence was
very low, due to low quality studies and to large hete-
rogeneity between the included studies.
This systematic review identied few studies, with
small sample sizes and a wide range of interventions
and outcomes. This resulted in low evidence and high
risks of bias. Comparisons were challenging and did
not allow subgroup analyses by age or disease stage
(e.g. ambulatory or non-ambulatory). The majority of
study participants were children. As the severity of
impairment increases during the disease course, the re-
sults of this systematic review may not be generalizable
to all persons with DMD. In addition, exercise training
effects may be inuenced by the different phenotypes
of DMD (1), which are not covered in this review.
No previous reviews have examined the effects of
exercise training specic to persons with DMD. The
only other systematic review in DMD reported solely
on RMT intervention, indicating effects on muscular
strength and endurance (15); however, with similar
limitations.
The effect of exercise training in persons with DMD
has been controversial for a long time. DMD is characte-
rized by dystrophic muscle with enhanced fragility, and
exercise training was for years considered harmful, due
to the potential for increasing muscle damage and injury
(36, 37). In addition to a general recommendation for
submaximal exercise (1), there is a lack of guidelines re-
garding exercise training in DMD. As such, the included
studies evaluated a broad range of exercise interventions
in DMD. It was not possible to point out any specic
type of exercise training being more appropriate, but
exercise training might have potential benets, speci-
cally for the secondary outcomes muscular strength and
endurance. Subgroup analyses, although they should be
interpreted with caution due to the above-mentioned
limitations, indicated a larger effect size in favour of
RMT compared with limb exercise training. The RMT
studies generally reported signicant improvements in
inspiratory muscle endurance (28, 32, 34), while inspi-
ratory muscle strength improved only after a prolonged
training period (31, 34). Moreover, studies with exercise
for limbs aimed to prevent disuse of dystrophic muscles
and maintain or optimize the participants’ functioning.
The only study reporting HRQoL found non-signicant
improvements after the intervention compared with the
control group. Thus, no change after intervention may in
fact be benecial in a group of patients with a progres-
sive disease characterized by the gradual development
of muscle degeneration and weakness.
This systematic review included studies that com-
pared exercise training intervention with no training
or usual care, placebo exercise training or alternative
exercise training programmes. The term “usual care”
was not uniformly described in the individual studies,
and one cannot exclude the possibility that persons
in this group in fact participated in various forms of
exercise training. Placebo studies are impossible to
perform in traditional exercise training studies. In one
of the 2 RMT studies that used placebo treatment, the
only difference in exercise training intervention was
the intensity grading, while the other compared non-
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resistance expiration training by use of a peak ow
meter with inspiratory muscle resistance training,
which, in fact, might represent 2 different exercise
training interventions.
The results of this systematic review are very un-
certain and should be interpreted with caution. The
certainty of evidence was very low for key outcomes
for all comparisons. The study limitations indirect-
ness, imprecision or combinations of these were the
main reason for downgrading evidence. Five studies
were at high ROB in at least 1 domain, 4 were at
some concerns regarding ROB in at least 1 domain,
and only 1 had low ROB. The major limitation with
regard to validity of evidence was the small number
of studies, as well as the small sample sizes. None
of the RCTs described power analyses, intention-to-
treat analyses were not performed in 2, while 2 RCT
cross-overs had insufcient data. Overestimation of
treatment effect is more likely to occur with smaller
studies (38). The small samples may be explained by
the rarity of the disease. DMD causes early disability,
cognitive and behavioural problems, and comorbi-
dities such as cardiorespiratory limitation and joint
contractures represent important barriers for inter-
ventions. Blinding of participants is not possible in
exercise studies, but blinding of outcome assessors
is recommended (19).
By supplementing our systematic database search
with searches of reference lists, study registers and
grey literature, and by approaching authors by mail,
we probably identied most relevant studies. Given
the nearly complete consensus between the 2 review
authors responsible for study selection, the risks of
selection bias were probably low. However, none of
the study authors contacted responded to our request
for data; hence, these studies could not be included
in the meta-analysis. We encountered challenges in
performing and interpreting comparisons due to sub-
stantial differences between the studies, including de-
signs, population, exercise prescription, outcomes and
data presentation. In order to minimize heterogeneity
between studies, we performed 3 comparisons; hence
there were few studies for each comparison. This may
explain the high variance in reported results. We still
chose to perform a meta-analysis, acknowledging these
important obstacles to obtaining a valid result, as this
eld of medicine is in a developing phase, and more
research is needed to guide clinical decisions in this
vulnerable group of patients with a devastating disease.
Further research is needed. Ideally, studies should
include large groups of participants stratied by disease
severity. Due to the rarity and nature of DMD, it will
require international multicentre studies to include suf-
cient numbers. A more realistic approach would be to
plea for pragmatic trials as they better correspond to real
practice and the willingness to participate is greater. A
relevant aim for the study could be to increase the overall
physical activity level that can be measured objectively
by the use of accelerometers or smart watches, and with
self-reported participation in daily activities. Possible
inuence on functioning could be investigated by using
multivariate analyses due to disease stages. Qualitative
research may capture how participants experience ex-
ercise training, their potential wellbeing or enjoyment,
and evaluate changes in functioning and HRQoL. A se-
dentary or active lifestyle, based on the level of physical
activity at baseline, should be acknowledged, as it may
inuence outcomes, such that untrained persons may
respond with larger gains. In addition to a well-described
exercise training intervention, adherence should be
reported with respect to dose-response. Finally, safety
should be systematically addressed, in order to reveal
any negative effects in this vulnerable population.
CONCLUSION
This systematic review was performed to evaluate the
effects of exercise training interventions to improve
functioning and HRQoL in persons with DMD. It was
not possible to determine whether exercise training
improves functioning and HRQoL. However, the
meta-analysis indicated that exercise training impro-
ves muscular strength and endurance in persons with
DMD. Given that these secondary outcomes are im-
portant surrogate measures for functioning, this might
represent an effect of exercise intervention. It was also
not possible to conclude whether exercise training is
safe in persons with DMD. Due to the low number of
studies included and large heterogeneity, it was not
possible to identify the most effective exercise training
intervention in DMD. The certainty of evidence was
very low, and more research is needed.
ACKNOWLEDGEMENT
This project have been made possible by the funding received
from Dam Foundation
The authors have no conicts of interest to declare.
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