Effect of High-Dose Creatine Therapy on Symptoms of Exercise Intolerance in McArdle Disease: Title and subTitle BreakDouble-blind, Placebo-Controlled Crossover Study FREE

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.

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.

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.

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.

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.

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).

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).

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).

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.

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@ruhr-uni-bochum.de).