RESEARCH ARTICLE

Aerobic Training in Patients with Congenital

Myopathy
Gitte Hedermann*, Christoffer Rasmus Vissing, Karen Heje, Nicolai Preisler,
Nanna Witting, John Vissing
Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, University of Copenhagen,
Copenhagen, Denmark
* [email protected]

Abstract
Introduction
OPEN ACCESS
Citation: Hedermann G, Vissing CR, Heje K, Preisler
N, Witting N, Vissing J (2016) Aerobic Training in
Patients with Congenital Myopathy. PLoS ONE 11(1):
e0146036. doi:10.1371/journal.pone.0146036
Editor: Jonatan R Ruiz, University of Granada,
SPAIN

Congenital myopathies (CM) often affect contractile proteins of the sarcomere, which could
render patients susceptible to exercise-induced muscle damage. We investigated if exercise is safe and beneficial in patients with CM.

Methods
Patients exercised on a stationary bike for 30 minutes, three times weekly, for 10 weeks at
70% of their maximal oxygen uptake (VO2max). Creatine kinase (CK) was monitored as a
marker of muscle damage. VO2max, functional tests, and questionnaires evaluated efficacy.

Received: June 8, 2015

Accepted: December 11, 2015

Results

Published: January 11, 2016

Copyright: 2016 Hedermann et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are
credited.

Sixteen patients with CM were included in a controlled study. VO2max increased by 14% (range,
625%; 95% CI 720; p < 0.001) in the seven patients who completed training, and tended to
decrease in a non-intervention group (n = 7; change -3.5%; range, -113%, p = 0.083). CK levels were normal and remained stable during training. Baseline Fatigue Severity Scale scores
were high, 4.9 (SE 1.9), and tended to decrease (to 4.4 (SE 1.7); p = 0.08) with training. Nine
patients dropped out of the training program. Fatigue was the major single reason.

Data Availability Statement: All relevant data are

within the paper and its Supporting Information files.

Conclusions

Funding: Funding provided by Direktr Jacob

Madsen & Hustru Olga Madsen foundation. Grant no.
5289. No website. Received by GH. The funders had
no role in study design, data collection and analysis,
decision to publish, or preparation of the manuscript.
Competing Interests: NP reports received research
support, honoraria, and travel funding from Genzyme
Corporation. JV reports received research support,
honoraria, and travel funding from Genzyme
Corporation. There are no patents, products in
development or marketed products to declare. This

Ten weeks of endurance training is safe and improves fitness in patients with congenital
myopathies. The training did not cause sarcomeric injury, even though sarcomeric function
is affected by the genetic abnormalities in most patients with CM. Severe fatigue, which
characterizes patients with CM, is a limiting factor for initiating training in CM, but tends to
improve in those who train.

Trial Registration
The Regional Committee on Health Research Ethics of the Capital Region of Denmark H-22013-066 and ClinicalTrials.gov H2-2013-066

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Aerobic Training in Patients with CM

does not alter the authors' adherence to all the PLoS

ONE policies on sharing data and materials.
Abbreviations: CM, congenital myopathy; CK,
creatine kinase; FSS, Fatigue Severity Scale;
FRSTST, five repetition sit-to-stand test; MRC,
Medical Research Council; T14SST, timed 14-stepstair-test; VO2max, maximal oxygen uptake; 6MWT, 6minute walk test.

Introduction
Congenital myopathies (CM) are genetically and histologically heterogeneous disorders caused
by mutations in genes that often encode sarcomeric proteins. Traditionally, CM is divided into
three subtypes defined by histopathological findings on muscle biopsy: nemaline, central core
and centronuclear myopathy. Genetic studies have shown that this division cannot stand
alone. Thus, each subtype, defined by histological findings, can be caused by mutations in multiple genes, and mutation in a single gene can result in multiple phenotypic and histological
presentations. Despite the variations, these patients typically present with a non-progressive
early-onset muscle weakness. Some patients have involvement of extraocular and/or facial
musculature. Creatine kinase (CK) levels are in the normal range or slightly elevated [13].
Fatigue is a prominent symptom in patients with CM [4].
The majority of patients with neuromuscular disorders live a sedentary life [5]. It has
become evident from several studies, conducted in the last decade, that aerobic training is beneficial for several muscle diseases [610]. The effect of training has never been investigated in
patients with CM, and due to the involvement of contractile proteins of the sarcomere, it could
be hypothesized that training is deleterious in these conditions. The aim for this study was to
investigate the effect on maximal oxygen uptake (VO2max) of 10 weeks of aerobic training in a
cohort of patients with CM.

Materials and Methods

Subjects
To be eligible for inclusion in the study, patients had to be over the age of 18 and had to have
confirmed pathogenic mutation(s) in genes, which are known to cause CM (see Table 1).
Table 1. Characteristics of the sixteen patients included in the study. Patients 17 completed the training program. Patients 816 dropped out of the
training program. Patients 511 participated in the non-intervention group. Patients 2 and 11 had bilateral foot drop requiring braces. Patient 3 took Alendronat 70 mg weekly to prevent osteoporosis, and Patient 7 used BiPAP at night. Patient 8 took Budesonid inhalations for asthma.
Patient no./sex

Affected gene

Completed training
Age

BMI

Dropped out of
training program
Age

BMI

Non-intervention
Age

BMI

1/M

ACTA1

27

13

2/F

NEB

40

30

3/F

NEB

33

31

4/F

DNM2

24

17

5/F

DNM2

56

21

56

21

6/F

RYR1

40

19

40

19

7/M

TPM3

23

22

8/M

NEB

30

27

23

22

30

27

9/M

TPM3

31

13

31

13

10/M

DNM2

29

28

29

28

11/M

NEB

54

23

54

23

12/F

TPM2

43

18

13/F

RYR1

42

30

14/F

RYR1

32

18

15/M

DNM2

28

18

16/M

RYR1

36

21

36 9

22 6

38 13

22 5

Mean SD

35 12

22 7

doi:10.1371/journal.pone.0146036.t001

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Aerobic Training in Patients with CM

Additionally, patients had to be able to cycle for 30 minutes to be included in the study.
Patients with competing medical conditions such as contractures, arthritis, heart- and lung diseases that could interfere with interpretation of exercise testing in the eyes of the investigator,
and patients that performed more than one hour of aerobic training weekly were excluded.
Patients were recruited from a cohort of 33 genetically confirmed cases of CM older than 18
years. Eleven of the patients did not fulfil inclusion criteria, and 6 patients were not interested
in participating. The remaining 16 patients were included in the study (Fig 1A and Table 1)

Study design
The study setup dictated a non-blinded design, but was controlled by a parallel non-intervention
group that served as a control for the trained group (see Fig 1A, flowchart). On inclusion, all
patients accepted to conduct a 10-week training program. Patients were divided in two groups;
one started the training program and the other started a period of unchanged daily living (nonintervention group). After 10 weeks of unchanged daily living, the patients in the non-intervention group started their training program. The allocation to training first or later was not randomized, because of time constraints for a number of participants. All patients had to complete a
test day before and after the 10-week intervention or non-intervention periods. Based on effect (a
change of 18.6% or more) and variation (SD = 0.15) in VO2max responses to aerobic training for
1012 weeks in other muscle diseases [69], and assuming a chance of type 1 error of 0.05 and a
type 2 error of 0.19, the needed number in the training group to complete training is 7 persons.

Test days
Patients performed a peak exercise test on a cycle ergometer and three functional tests; a
6-minute walk test (6MWT), a five repetition sit-to-stand test (FRSTST), and a timed 14-stepstair-test (T14SST) (tests described in Table 2 and [10]). At inclusion, muscle strength was
evaluated by a modified 10-step Medical Research Council (MRC) scale. Muscle strength has
been measured by handheld dynamometry in previous studies on 1012 weeks of cycle training
in other muscle diseases [1112]. No significant outcome was seen with this type of exercise, so
muscle strength was not evaluated with a dynamometer in this study. Forced vital capacity
(FVC) was measured by spirometry in all patients.
Patients completed four questions from the SF-36 questionnaire concerning fatigue on all
test days.
Furthermore, they completed the Fatigue Severity Scale (FSS) at baseline and after the training. FSS rates fatigue perceived in the preceding week. FSS score  4 indicates abnormal
fatigue, and a score  5 indicates severe fatigue [4].
Plasma creatine kinase (CK) levels were measured on test days and after three weeks of
training as a marker of exercise-induced muscle damage.

Peak exercise testing

Testing was performed on an electronically braked Lode Excalibur Sport cycle ergometer. The
person who measured VO2max was not blinded, but the tests were carried out systematically
after standard guidelines in the laboratory. Prior to testing, patients were fitted with a heart
rate monitor, 3-lead ECG electrodes and a facial mask. Pulmonary gas exchange was measured
with breath-by-breath indirect calorimetry (Quark CPET, Cosmed Srl, Milan, Italy). Workload
was increased incrementally. The patients were verbally encouraged to keep exercising for as
long as possible. The test was terminated when the patients were unable to maintain their pedaling cadence (10% drop in rotation per minute (RPM) in 20 s). The VO2max was a mean of the
period of 20 seconds where they performed the highest VO2max.

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Aerobic Training in Patients with CM

Home-based, pulse-monitored training

The patients trained at home on a stationary bike three times weekly for ten weeks. The
patients were provided with stationary bikes and instructed in the set-up of the bike. It was not

Fig 1. Flowchart, maximal oxygen uptake, workload and plasma creatine kinase levels. (A) 16 patients with CM were included in the study. Four
patients from the 1st training group completed the training program. A non-intervention group of seven CM patients were tested twice, 10 weeks apart, before
they participated in the training program (2nd training group). Only 3 patients from the non-intervention group completed the subsequent training program. In
total, nine patients dropped out of the training program. (B) VO2max before and after 10 weeks of aerobic training in seven CM patients with an improvement
corresponding to 215 ml O2
min-1 (CI 121308 ml O2
min-1, * p = 0.001) (left bars). VO2max before and after 10 weeks of normal daily living in seven
patients with CM (right bars). Black bars represent values before, and gray bars represent values after. The change seen in the intervention group was
significant compared to the change in the non-intervention group (mixed Anova, p < 0.001). (C) Maximal workload before and after 10 weeks of aerobic
training in seven CM patients who improved Wmax by 18 W (CI 1124 W, ** p = < 0.001) (left bars). Wmax before and after 10 weeks of normal daily living in
seven CM patients (right bars). Black bars represent values before, and gray bars represent values after. The change seen in the intervention group was
significant compared to the change in the non-intervention group (mixed Anova, p < 0.001). (D) Dots represent plasma CK levels at week 0, 3 and 10 from the
seven CM patients who finished the training program. All values are within the normal range or slightly elevated when corrected for age and gender. VO2max:
maximal oxygen uptake; CM: congenital myopathy; Wmax: maximal workload; CK: creatine kinase.
doi:10.1371/journal.pone.0146036.g001

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Aerobic Training in Patients with CM

Table 2. Results of functional tests and questionnaires from the intervention and non-intervention groups. 6MWT: 6-minute walk test (m: distance in
meters). FRSTST: five times repetitive sit-to-stand test (s: seconds), the patient was asked to rise and sit from a chair five times as fast as possible.
T14SSTn: timed 14-step-stair-test (normal speed), the patient had to climb and decline 14 steps at their normal speed. T14SSTq: timed 14-step-stair-test
(quick), the patient had to climb and decline 14 steps as fast as possible. FSS: fatigue severity scale. ND: not determined. Values are mean standard deviation. P-values in the right column are calculated by a mixed Anova test, no significant difference was found between the improvements seen in the intervention group compared with the improvements in the non-intervention group.
Intervention group (n = 7)

Non-intervention group (n = 7)

Mixed ANOVA test

Before

After

% improvement

p-value

Before

After

% improvement

p-value

p-value

6MWT (m)

460 97

462 83

0.9

0.827

491 66

479 70

-2.7

0.061

0.118

FRSTST (s)

18.3 7.9

17.0 10.2

10.6

0.311

14.6 4.1

14.8 4.2

-1.4

0.866

0.326

T14SSTn (s)

26.6 12.1

29.4 19.3

-4.9

0.361

20.3 4.3

21.3 3.8

-6.4

0.339

0.553

T14SSTq (s)

23.3 13.3

27.1 21.6

-9.4

0.290

16.5 5.6

16.6 5.1

-2.2

0.776

0.290

SF36 Fatigue

51 19

54 23

7.0

0.570

58 19

59 16

2.5

0.846

0.820

FSS score

4.9 1.9

4.4 1.7

10.4

0.083

4.5 1.5

ND

doi:10.1371/journal.pone.0146036.t002

important that they trained on a specific type of stationary bike. They were instructed to have a
small flexion of 515 degrees in their knee when they sat on the bike with the leg stretched.
They were advised to cycle with the same cadence as used at the peak exercise test, between 60
80 RPM. The intensity was controlled by a pulse interval corresponding to 70% of their
VO2max as determined from the peak exercise test. The duration of the training sessions
increased from 20 minutes during the first two weeks to 30 minutes the last eight weeks. The
training was always initiated by a 5-10-minute warm-up to allow the patients to reach their
pulse interval gradually before starting the training session.
Compliance was monitored by downloading data from pulse watches. The patients also
kept a diary of their training sessions and recorded adverse effects. Patients were phoned
weekly to facilitate compliance.

Primary outcome measures

Primary efficacy was change in VO2max and fatigue (FSS questionnaire). VO2max is an indicator
of cardiovascular fitness and aerobic endurance, and a change reflects the physiological response
to training. Patients were not told prior to testing that training might improve their fatigue.

Secondary outcome measures

Secondary efficacy was assessed by changes in 6MWT, FRSTST, and T14SST.

Ethics and statistics

The Regional Committee on Health Research Ethics of the Capital Region of Denmark approved
the study (H-2-2013-066), and written informed consent was obtained from all patients.
Values are mean standard error, unless otherwise stated. Changes were assessed by a
paired Student t-test, and a p-value < 0.05 (two tailed testing) was considered significant.
Some results, when indicated, were assessed by a mixed Anova test.

Results
Demographic data of the patients
The included patients represent patients with CM, who have mutations in a broad range of
genes (Table 1). The mean BMI for the patients was normal (Table 1). Two patients had a BMI
of 13, which is not an uncommon finding in patients with CM [2].

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Aerobic Training in Patients with CM

Compliance and dropouts

Due to a high dropout rate, only seven of sixteen patients finished the training program (Fig
1A). Compliance was high in those who finished the training program. They completed 2632
training sessions of 30 target sessions during the 10 weeks.
Nine patients dropped out of the training program, and fatigue was a major reason for dropping out for six of the patients. One patient dropped out due to personal matters, and two
patients were lost to follow-up. None of the dropouts exercised for longer than half of the training period before exclusion and were therefore not evaluated for efficacy according to the
protocol.

Peak oxidative capacity, workload and plasma CK levels

Training caused a significant increase in VO2max from 28 3 to 31 4 ml O2
kg-1
min-1
(range of increase, 1.97.1 ml O2
kg-1
min-1) (Fig 1B). Parallel changes were seen in peak
workload (Fig 1C). Mean peak heart rate was 184 4 before and 183 2 after 10 weeks of
training in the intervention group. No change was seen in the non-intervention group with an
average VO2max of 31 3 at baseline vs. 30 3 ml O2
kg-1
min-1 at 10 weeks (Fig 1B).
All patients had stable CK levels during training (before, 92 34; after, 80 25 U/l;
p = 0.334) (Fig 1D).

Functional tests, muscle strength, FVC and questionnaires

No changes were seen in any of the functional tests or SF36 questionnaire in either group (see
Table 2). Baseline MRC scores are shown in Fig 2. FVC (n = 15) as percentage of predicted values were lower than seen in age-, sex- and height-matched healthy subjects (69 5% of normal). Baseline FSS scores (n = 14) showed severe fatigue (5.1 0.4), which is concordant to
observations found in other CM patients [4]. FSS scores from the intervention group tended to
decrease following training from 4.9 1.9 to 4.4 1.7 (p = 0.08).

Discussion
This study indicates that 10 weeks of moderate-intensity, endurance training on a cycle ergometer is safe and an efficient way to improve fitness. But it is difficult to apply this therapy to all
patients with CM due to fatigue. If trained, fatigue can potentially be reduced in patients with
CM. Training improved VO2max significantly by 14% in the seven patients who completed the
training program. No change was seen in mean peak heart rate indicating that the change was
independent of will of the patient trying to push harder or encouragements by the un-blinded
investigator. Improving fitness in patients with CM probably has other beneficial effects, as it is
known that higher levels of physical fitness delay all-cause mortality, including lower rates of
cardiovascular disease and cancer [13]. This is important, since patients with neuromuscular
diseases are at higher risk of developing cardiovascular risk factors as a part of metabolic syndrome [5].
Although most patients carry mutations in genes encoding sarcomeric proteins or other
contraction-excitation coupling related mechanisms, exercise does not appear to cause sarcomeric injury, since CK values were stable during the intervention and patients reported no
myalgia. The improvement corresponds to improvements seen in similar training programs
for patients with different types of muscular dystrophies [610].
Training of patients with other muscle diseases has shown unchanged or reduced fatigue
following training. In our study, fatigue tended to decrease with training, which is of particular
interest in this group, as fatigue is a disabling symptom in the every day life of patients with

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Aerobic Training in Patients with CM

Fig 2. Baseline muscle strength evaluated by MRC score in the seven patients who finished the training program (black bars) and in the nine
patients who dropped out of the training program (gray bars). A significant difference was found between the two groups in three muscle groups; ankle
plantar flexion, * p < 0.001; ankle dorsal flexion, ** p = 0.032; hip abduction, *** p = 0.014. Error bars indicate standard error of the mean.
doi:10.1371/journal.pone.0146036.g002

CM [4]. Fatigue was also the main single cause for dropping out. Nine patients dropped out of
the training program, six of them due to fatigue. Fatigue therefore poses a limitation for initiating training in patients with CM, which is unlike the experience in other muscle diseases. However, fatigue is a major contributing factor for the lack of training effects in patients with motor
neuron diseases [12, 14]. Unfortunately, fatigue was not assessed over time in the non-intervention group for comparison. However, fatigue is not likely to change in such a short period
of time without interventions, as CMs are largely non-progressive. Pulmonary function tests
showed a rather mild impairment, and only one patient used nocturnal respiratory assistance
(Table 1). No correlation was seen between the FVC and FSS scores. It is therefore unlikely that
increased fatigue in our patients with CM was caused by respiratory failure. Despite weekly
phone contact between the investigator and the patient, patients were not compliant.
Since CM subtypes are very rare, it was necessary to include patients with different genetic
backgrounds. Training responses could differ among CM genotypes and gender. However,
training had the same consistent positive effect across all patients studied, which indicates that
training is beneficial and safe in most types of CM.
The three functional tests were included, which improved with a similar training program
in patients with LGMD2L (anoctamin 5 deficiency) [10]. However, no significant

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Aerobic Training in Patients with CM

improvements were seen in patients with CM (see Table 2). This could relate to the short duration of the trial. Likely the improvements in endurance could translate into functional
improvements if the training period had been prolonged, but future studies must investigate
this.
Overall, the present study shows that for those CM patients who were able to complete the
training, there was a significant improvement in VO2max, but it also illustrates how difficult it is
to maintain CM patients on a training schedule, possibly due the high basal level of fatigue in
this patient group. Alternative methods of training such as strength training or shorter training
sessions at higher work intensities should be explored in CM.

Supporting Information
S1 Text. Consort checklist.
(DOC)
S2 Text. Trial study protocol in Danish.
(DOCX)
S3 Text. Trial study protocol in English.
(DOCX)

Author Contributions
Conceived and designed the experiments: GH NW JV. Performed the experiments: GH CRV
KH. Analyzed the data: GH NP JV. Contributed reagents/materials/analysis tools: GH NP JV.
Wrote the paper: GH JV. Critical revision of manuscript: KH CRV NP NW JV.

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