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Effect of High-Dose Creatine Therapy on Symptoms of Exercise Intolerance in McArdle Disease
Double-blind, Placebo-Controlled Crossover Study
Matthias Vorgerd, MD;
Jochen Zange, PhD;
Rudolf Kley;
T. Grehl, MD;
Anika Hüsing;
Matthias Jäger, PhD;
Klaus Müller, MD;
Rolf Schröder, MD;
Wilhelm Mortier, MD;
Klaus Fabian, PhD;
Jean-Pierre Malin, MD;
Alwin Luttmann, PhD
Arch Neurol. 2002;59:97-101.
ABSTRACT
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Background In a recent study, we showed that administration of low-dose creatine
(Cr) (60 mg/kg daily) improved work capacity in patients with McArdle disease.
Objective To assess the efficacy of high-dose Cr therapy in McArdle disease.
Design Randomized, double-blind, placebo-controlled crossover study.
Patients Nineteen patients with McArdle disease.
Intervention Treatment with Cr, 150 mg/kg daily. Each treatment phase with Cr or
placebo lasted 5 weeks.
Main Outcome Measures The patient's daily rating of symptoms of exercise intolerance. At the
end of each treatment phase, serum creatine and serum creatine kinase levels,
phosphorus 31 magnetic resonance spectroscopy, and surface electromyograms
were assessed.
Results Clinical end points revealed increases in the intensity of exercise-induced
pain in working muscles (mean treatment-induced difference [d], 0.30 in log(score);
95% confidence interval [CI], 0.05-0.55; P = .02), the limitation
of daily activities (d, 0.59; 95% CI, 0.22-0.97;P
= .005), and body mass index (d, 0.33 kg/m2, 95% CI, 0.10-0.56
kg/m2; P = .008) with Cr use. Surface
electromyograms revealed a smaller increase in the electromyographic amplitude
over time during muscle contraction with Cr use (d, -13.52%/min; 95%
CI, -23.71%/min to -3.34%/min; P = .01).
There were no significant changes in phosphorus 31 magnetic resonance spectroscopy
variables.
Conclusions Administration of high-dose Cr worsened the main clinical symptoms of
exercise intolerance in McArdle disease. These neurologic adverse effects
represent a major dose-limiting factor in Cr therapy for McArdle disease.
Taken together with results of a previous study, the indication for symptomatic
therapy with Cr needs to be clarified. An effective Cr dosage without adverse
effects may be between 60 and 150 mg/kg daily.
INTRODUCTION
MCARDLE DISEASE (glycogenosis type V) is one of the most common metabolic
myopathies and is caused by genetic defects of the muscle-specific isozyme
of glycogen phosphorylase, which block adenosine triphosphate (ATP) formation
from glycogen in skeletal muscle. Typically, patients with McArdle disease
have exercise intolerance, with premature muscle fatigue, exercise-induced
muscle pain in working muscles, and recurrent myoglobinuria. Treatment of
McArdle disease has been unsatisfactory to date and therefore remains an important
clinical challenge.
In a recent study, we1 showed the beneficial
effects of short-term low-dose oral creatine (Cr) monohydrate (60 mg/kg daily)
therapy in McArdle disease based on a trend toward subjective improvement,
increased exercise capacity associated with greater depletion of phosphocreatine
(PCr), and a greater slope of decline of the median frequency in surface electromyograms
(S-EMGs). It was concluded that Cr may have a role in symptomatic therapy
of McArdle disease, but further studies were required to find the optimal
dosage.
In this follow-up study, we investigated whether use of a higher dose
of Cr (150 mg/kg per day) is effective in relieving exercise intolerance.
We performed a double-blind, placebo-controlled trial encompassing a quantitative
approach to evaluate symptoms of exercise intolerance, phosphorus 31 magnetic
resonance spectroscopy (31P-MRS), S-EMG, and laboratory studies
to search for an effect of high-dose Cr therapy in McArdle disease.
PATIENTS AND METHODS
PATIENTS AND STUDY DESIGN
Nineteen patients with genetically confirmed McArdle disease entered
the trial (8 women and 11 men; mean [SD] age, 33.8 [11.8] years [range, 11-59
years]; mean [SD] disease duration, 27.7 [12.1] years [range, 3-53 years]).
All patients had symptoms of exercise intolerance, such as exercise-induced
pain in working muscles and early fatigue. They all led normal lives but were
limited in daily activities, such as walking uphill and climbing stairs, and
they could not carry out vigorous activities.
A double-blind, placebo-controlled crossover trial with Cr (150 mg/kg
daily) was performed (Figure 1).
Capsules used for administration of placebo and Cr were identical in appearance.
Each study phase lasted 5 weeks, with a washout of 4 weeks between study periods.
This study was approved by the local ethics committee of the Ruhr-University
Bochum, Bochum, Germany. Each patient gave written informed consent before
starting the trial.
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Figure 1. Trial profile. S-EMG indicates
surface electromyogram; 31P-MRS, phosphorus 31 magnetic resonance
spectroscopy.
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CLINICAL OUTCOME MEASURES AND LABORATORY STUDIES
During both phases, patients used a diary to quantify the main symptoms
of exercise intolerance and to record any adverse events. All patients were
asked to note the daily frequency (bouts) of muscle pain. Duration of each
bout of muscle pain was quantified in 5 grades: 1 is less than 1 minute; 2,
1 to 5 minutes; 3, greater than 5 to 10 minutes; 4, greater than 10 to 60
minutes; and 5, greater than 60 minutes. Severity of each bout of muscle pain
was rated on a scale from 1 (no pain) to 10 (most severe pain), and its intensity
was calculated as a product of duration and severity. Average daily early
fatigability and limitation in daily activities were also rated on a scale
from 1 (no complaints) to 10 (most disabling). At the beginning and end of
each treatment phase, the patient's height and weight were measured and body
mass index (calculated as weight in kilograms divided by the square of height
in meters) was calculated. Blood samples were obtained from the antecubital
vein at the end of each treatment phase. Serum creatine and serum creatine
kinase levels were determined.
31P-MRS AND S-EMG
On the final day of each treatment period, the effects of treatment
on muscle bioenergetics and on myoelectrical changes were measured by 31P-MRS and S-EMG using a standardized calf muscle ergometric test according
to a valid protocol that has been shown to be sensitive in McArdle disease.1 In our first study,1
the target test force of 30% maximum voluntary contraction (MVC) was related
to the MVC value during each session. In this follow-up study, 30% MVC was
related to the patient's initial MVC value. Therefore, the target force and
absolute force-time integral were the same for each patient in all test periods.
This design allows interpretation of changes in S-EMG characteristics and
energy metabolism independently from changes in MVC development.
STATISTICS
The sums of patient scores in both phases were compared to determine
carryover effects. The differences between treatment and placebo phases in
both groups were used to test for period effects. Treatment effects were analyzed
using the differences between the second and first phase in each group. All
comparisons were made using t tests. The scores for
severity and intensity of daily muscle contractures, the time constants for
oxidative PCr recovery after contractions, and the levels of serum creatine
and serum creatine kinase were log-transformed for this analysis. Statistical
significance was set at P<.05.
RESULTS
EFFECTS OF TREATMENT
Two patients in group 2 were excluded because of protocol violation
(both patients limited the daily doses without occurrence of adverse events).
Seventeen patients qualified for clinical outcome measures and laboratory
studies. Surface EMG and 31P-MRS were evaluated in 14 patients
(Figure 1). Statistical analysis
showed no evidence of carryover or period effects in the selected variables
(data not shown). Primary clinical end points revealed significant increases
in the mean severity (Table 1)
and the average daily intensity (Figure 2) of muscle pain and in the limitation of daily activities with
Cr use (Figure 2). There were no
significant changes in the daily frequency of muscle pain or in early fatigability
(Table 1).
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Effects of Creatine and Placebo Use on Clinical Outcome Measures, 31P-MRS, S-EMG, and Laboratory Studies*
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Figure 2. Treatment-induced differences
in the average daily intensity of exercise-induced muscle pain (A) and in
the limitation of daily activities (B), calculated as differences in phase
2 minus phase 1.
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A significant elevation in body mass index with Cr therapy was found,
most likely because of an increase in body fat–free mass and increased
muscle water content, as demonstrated in Cr supplementation for gyrate atrophy
and in athletes using Cr long term.2-3
The plasma level of creatine increased with Cr use and serum creatine kinase
values remained unaltered (Table 1).
FINDINGS FROM 31P-MRS AND S-EMG
Results of 31P-MRS indicated no significant increase in the
PCr/ATP ratio at rest with Cr use (Table
1). The bioenergetic efficiency of muscle contraction, measured
as initial rates of [PCr] + [ATP] decrease per force-time integral during
both forms of exercise, did not change significantly with Cr therapy (data
not shown). There were no significant differences in the PCr and ATP consumptions
during aerobic and ischemic exercise. The time constants for oxidative PCr
recoveries after both contractions remained unaltered. There was no significant
change in the MVC or in the force-time integrals during aerobic and ischemic
exercise (Table 1).
Results of S-EMG revealed a significantly smaller increase in the EMG
amplitude during muscle contraction with Cr use (Table 1 and Figure 3),
which is accompanied by a nonsignificant reduction in the time-related decrease
of the median frequency (Table 1).
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Figure 3. Treatment-induced differences
in the increase in the surface electromyographic amplitude over time (indicated
by the slope of the root mean square [RMS] of the gastrocnemius muscle), calculated
as differences in phase 2 minus phase 1.
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COMMENT
Oral Cr monohydrate is a commercially available dietary supplement and
is used in a range of neuromuscular disorders.4-7
It has also become popular in augmentation of athletic performance in professional
and amateur sports.8-9 Among the
many effects of Cr, the mechanisms of ergogenic enhancement may include increased
intramuscular PCr, improvement of intracellular Ca2+handling, enhanced
energy shuttling, cell protection, and protein synthesis stimulation.10-11 The safety of oral Cr intake has
so far been questioned in only 2 patients with renal dysfunction linked to
its use.12-13
We1 recently demonstrated the beneficial
effects of low-dose Cr supplementation (60 mg/kg daily) in McArdle disease.
In this follow-up study, we found that higher dosages of Cr (150 mg/kg daily)
worsened the main clinical features of exercise intolerance in McArdle disease.
Taken together, both studies provide evidence for a dose-related effect of
Cr on clinical outcome measures, S-EMG, and 31P-MRS. These findings
have implications for appropriate symptomatic therapy not only for McArdle
disease but also for other neuromuscular disorders for which Cr therapy is
recommended. If Cr is used as symptomatic monotherapy in McArdle disease,
it should be administered in a dosage well below 150 mg/kg daily to avoid
adverse effects and of at least 60 mg/kg daily to enhance working capacity.
Further studies are warranted to clarify the indication for Cr supplementation
and to establish an optimal Cr dosage regimen.
In the present study, the absence of significant changes in the 31P-MRS variables might be explained by the failure of even high-dose
Cr administration to increase the level of intramuscular Cr and thereby PCr
concentration. This is in contrast to several studies mainly in trained healthy
individuals that showed an improvement in muscle performance even with short-term
low-dose Cr supplementation (3 g/d) associated with a higher PCr concentration
and accelerated rate of PCr resynthesis as measured by 31P-MRS.14-20
Human muscle cells take up Cr from blood through specific Cr transporters
that are regulated by plasma Cr levels, insulin, vitamin E, high-carbohydrate
loading, and exercise.16, 21-22
Exercise intolerance due to blocked muscle glycogen breakdown in McArdle disease
encourages a sedentary lifestyle. The absence of training-related stimuli
may reduce the capacity of muscle cells to uptake Cr and thus the ability
to increase muscle PCr with Cr supplementation (J. Zange, PhD, unpublished
data, 2001). Individualized, force-velocity training in combination with Cr
supplementation might improve exercise intolerance and increase intramuscular
PCr in patients with McArdle disease, but this needs to be explored in a controlled
clinical trial.
Surface EMG reveals an increase in electrical activity generated during
fatiguing contractions in healthy individuals and in patients with McArdle
disease because the increasing number of fatiguing muscle fibers requires
additional recruitment of motor units to compensate for fatigue. Low-dose
Cr therapy may lead to a shorter twitch time of muscle fibers and thereby
cause a decrease in the force-time integral produced per action potential.
Consequently, a greater number of action potentials is needed to hold a given
force. This hypothesis is compatible with our previous findings1
of a steeper increase in the EMG amplitude with low-dose Cr use. In contrast,
high-dose Cr therapy revealed an opposite effect and caused a smoother increase
in the EMG amplitude, which indicates a lower level of motor unit recruitment
during isometric muscle contraction. This suggests an enhanced force production
per action potential, possibly because of an improvement in reduced muscle
fiber membrane excitability. In patients with McArdle disease, such an impaired
sarcolemmal function has been assumed because a decline in the compound muscle
action potential with repetitive stimulation and reduced levels of skeletal
muscle sodium/potassium-ATPases were found, which may cause a decline in muscle
force generation.23-25
It may be speculated that an insufficient adaption to this improved electromechanical
efficacy leads to overuse of the muscle contractility in exercise and thus
worsening of clinical symptoms in McArdle disease.
In conclusion, our data demonstrate that high-dose Cr administration
worsens clinical symptoms of exercise intolerance in McArdle disease despite
positive neurophysiological findings. We believe that administration of high-dose
Cr as a symptomatic therapy for patients with McArdle disease should be approached
with caution.
AUTHOR INFORMATION
Accepted for publication August 28, 2001.
Author Contributions: Conception and
design (Drs Vorgerd, Zange, and Luttmann); acquisition of data (Drs Vorgerd, Zange, Grehl, Jäger, Müller, Fabian, and Luttmann
and Mr Kley); analysis and interpretation of data (Drs Vorgerd,
Zange, Grehl, Jäger, Müller, and Luttmann; Mr Kley; and Ms Hüsing); drafting of the manuscript (Drs Vorgerd, Grehl, Jäger, Schröder,
Fabian, and Luttmann and Mr Kley); critical revision of the manuscript
for important intellectual content (Drs Vorgerd, Zange, Grehl, Jäger,
Müller, Mortier, Malin, and Luttmann and Ms Hüsing); statistical
expertise (Dr Vorgerd and Ms Hüsing); obtaining funding (Dr Vorgerd); administrative, technical, or material support (Drs Vorgerd, Zange, Grehl, Jäger, Müller, Schröder,
Mortier, Fabian, Malin, and Luttmann and Mr Kley); supervision
(Drs Vorgerd, Zange, and Luttmann).
This work was supported in part by a grant from the Werner Richard–Dr.
Carl Dörken Stiftung (Herdecke, Germany) (Dr Vorgerd).
Corresponding author and reprints: Matthias Vorgerd, MD, Department
of Neurology, Ruhr-University Bochum, Kliniken Bergmannsheil, Bürkle-de-la-Camp-Platz
1, 44789 Bochum, Germany (e-mail: matthias.vorgerd{at}ruhr-uni-bochum.de).
From the Departments of Neurology (Drs Vorgerd, Grehl, and Malin and
Mr Kley), Medical Informatics, Biometrics, and Epidemiology (Ms Hüsing),
and Pediatrics (Dr Mortier), Ruhr-University Bochum, Bochum; the German Aerospace
Center, Cologne (Drs Zange and Müller); the Institute of Occupational
Physiology, University of Dortmund, Dortmund (Drs Jäger and Luttmann);
the Department of Neurology, University of Bonn, Bonn (Dr Schröder);
and the Institute of Sports Medicine, University of Dresden, Dresden (Dr Fabian),
Germany.
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