Effectiveness of creatine monohydrate in mitochondrial encephalomyopathies

Introduction 

The mitochondrial encephalomyopathies are a heterogeneous group of genetic disorders resulting in a deficient oxidative metabolism, which disrupts the balance between energy supply and demand [8]. Extensive studies during the past 15 years accumulated an enormous knowledge about etiology and pathogenesis, and a multitude of mutations in mitochondrial and nuclear genes have been described in mitochondrial disorders. In contrast, the therapeutic possibilities are limited. No treatment has been established so far. Since the first description by Przyrembel in 1987, treatment of mitochondrial disorders by cofactor supplementation has been widely used. However, because of the controversial results of case reports and several studies the effectiveness of cofactor supplementation remains questionable [10].

Alterations of the respiratory chain in patients with mitochondrial encephalomyopathies cause disturbed [ADP]/[ATP]and[NAD+]/[NADH] ratios of the cellular redox state. For compensation, capacities of the glycloytic and the creatine/phosphocreatine shuttle is enhanced [13]. The latter encompasses the transfer of energy-rich phosphate from unstable adenosine triphosphatase generated by the respiratory chain to creatine to from phosphocreatine via the mitochondrial creatine kinase. This stable product is then transported to the cytosol to be a source of phosphate groups to form adenosine triphosphatase by the cytosolic creatine kinase. In patients with respiratory chain diseases, intramuscular concentration of phosphocreatine and adenosine triphosphatase are decreased [12] with a concomitant reduction of the creatine transporter protein content and elevation of mitochondrial creatine kinase [13]. In addition, decrease in the phosphocreatine/creatine ratio effectively increases the sensitivity of mitochondrial respiration to ADP [17]. Thus supplementation of creatine may enhance adenosine triphosphatase synthesis in the cytosol by increasing levels of phosphocreatine and in addition may serve as activator of glycogenolysis and glycolysis in affected tissues.

These data strongly support the potential of creatine supplementation as therapeutic intervention.

Creatine supplement in therapy has successfully been used in diseases like gyrate atrophy, guanidinoacetate methyltransferase deficiency, and chronic heart failure [5], [9], [15]. In a report of mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS), Hagenfeldt et al. demonstrated an increase in cycle ergometry performance [6]. In 1997, Tarnopolsky et al. [14] published a randomized controlled short-term study of creatine in adults with mitochondrial cytopathies, which suggested an increase in muscle strength in high-intensity anaerobic and aerobic activities. We made similar observations in children with mitochondrial encephalomyopathies [1]. These findings in four patients and one additional patient with MELAS are described herein in more detail, using a set of different tools for disease monitoring including bicycle ergometry.

Patients and methods 

We studied one male and four females with mitochondrial encephalomyopathies and mitochondrial DNA (mtDNA) mutation (Table 1). Their ages ranged from 7 to 19 years. Two patients suffered from Kearns-Sayre syndrome with mitochondrial DNA (mtDNA) single large-scale deletions, one patient exhibited neuronal muscle weakness, ataxia, and retinitis pigmentosa (NARP) syndrome with the T8993C mtDNA mutation, and two patients suffered from MELAS with the common A3243G mtDNA mutation.

Table 1. Patient data

	Patient No.	1	2	3	4	5
	Diagnosis	KSS	KSS	NARP	MELAS	MELAS
	Sex	F	M	F	F	F
	Family history	–	–	NARP:mother & younger brother	MELAS:mother	–
	Development	normal	normal	moderate MR	normal	normal
	Age of onset	13 yr	10 yr	2 yr 2 mo	8 yr	11 yr
	Initial symptom	Ptosis	Ptosis	unable to walk for 6 wks after high fever	hearing loss headache	headache
	Cardiomyopathy	↖ cardiac pacemaker ↗		–	since 11 years	–
	Mit DNA analysis	deletion 7048 7877-14924	deletion 69277495-14421	point mutation nt-8993 T → G	point mutation ↖ nt-3243 A → G ↗
	Muscle biopsy
	RRF	+		−	+	+
	COX-negative	50%	50%	0%	n.d.	10%
	EM path.		+	+	n.d.	+
	Biochemistry complex	I II III IV ↓	IV ↓	normal	n.d.	I IV ↓
	C-MRI		normal	normal	infarction: occipital (bil.)	infarction occipital basal ganglia calcification
	MRS	LA ↑	LA(borderline)	LA ↑	LA ↑	LA ↑
		NAA ↓	NAA →	NAA →	NAA ↓	NAA ↓
	EEG
	Basic activity	normal	Slow(θ) irregular	normal	Slow(θ) Diffuse	normal
	Paroxysmal discharges	-	high δ-waves with occasional preceding sharp waves	–	irregular spike waves	spike waves,polyspike waves
	Age at creatine therapy	13 yr 5 mo	13 yr 1 mo	7 yr 7 mo	11 yr	19 yr 9 mo

Abbreviations C-MRI  Central magnetic resonance imaging   COX  Cytochrome c oxidase   DNA  Deoxyribonucleic acid   EEG  Electroencephalogram   EMM  Electron microscopy   F  Female   KSS  Kearns-Sayre syndrome   LA  Lactate   M  Male   MELAS  Mitochondrial myopathy encephalopathy, lactic acidosis, and stroke-like episodes   Mit.  Mitochondria   MR  Mental retardation   MRS  Magnetic resonance spectroscopy   NAA  N-acetylaspartate   NARP  Neuronal muscle weakness, ataxia, and retinitis pigmentosa syndrome   nt  Nucleotide   RRF  Ragged-red fibers

All patients complained of exercise intolerance and gait disturbance including ataxia, mainly during or after long periods of exercise.

Both patients (Patients 1 and 2) with Kearns-Sayre syndrome demonstrated ptosis, external ophthalmoplegia, and only mild generalized weakness. Later they developed heart block and a cardiac pacemaker was implanted to prevent sudden heart arrest.

One patient (Patient 3) with NARP syndrome was mentally mildly retarded and demonstrated severe motor impairment.

Patient 4, who had MELAS, developed signs of a mild cardiomyopathy. After normal development, she complained of severe headache at approximately 8 years of age. The parents noticed also early fatigability. At 10 years of age, she suffered a first seizure, which was diagnosed as migraine. However, seizures reoccurred and took the form of epilepsia partialis continue. She had several strokelike episodes and became gradually blind.

The symptomatology in Patient 5 (with MELAS) began with attacks of migraine at 11 years, 6 months of age and she later had a first focal seizure. Over the years, recurrent status epilepticus occurred accompanied by varying neurologic symptoms such as hemiparesis, dysarthria, and cranial nerve dysfunction. Magnetic resonance imaging revealed characteristic signal abnormalities in different vascular areas. Finally she developed cortical atrophy accompanied by mild dementia.

Both patients with MELAS died at 12 and 21 years of age, respectively.

Results 

Self rating (Table 2) 

Using a questionnaire, most of the patients and parents reported an improvement of muscular functions and coordination, whereas cognitive functions (school performance) remained unchanged.

Table 2. Patient/parent self-rating during creatine supplementation

	n = 5	Improvement	Unchanged	Deterioration
	Weakness	4	1	0
	Ataxia	2	3	0
	Walking	3	2	0
	Running	4	1	0
	Climbing steps	4	1	0
	School performance	1	3	1

Discussion 

The supplementation of creatine has the potential to increase creatine phosphate and thus adenosine triphosphate resynthesis in the cytosol, as well concerning activate glycogenolysis and glycolysis in tissues [4], [16].

Five children with genetically proven mitochondrial disorders were orally treated with pure creatine monohydrate. To evaluate the effectiveness, maximum of muscle performance, functional muscle speed, and vital capacity of the lung were measured according to standardized protocol prior and during the treatment.

All patients reported herein demonstrated an improvement of maximal muscle performance with an increase of 4-30% (mean, 12.1%). In one patient an “on/off” study was performed, which demonstrated a decrease of maximal performance to the baseline during the “off” phase. In this patient the second “on” phase was performed with a threefold dose of creatine, which resulted in a twofold increase in performance. This dose dependancy was also demonstrated in the second patient. Studies from athletes have demonstrated that there is an increase of muscle strength with rising creatine dosages [18]. Although the bicycle ergometry reflects the long-holding muscle power, the functional muscle tests were designed to test the short-acting muscle strength.

Our data reveal that creatine supplementation augment long-acting muscles even more than the short-acting muscles. This observation is in line with the results of studies on athletes [18]. An explanation might be that type 1 muscle fibers contain many mitochondria contributing to continual physical exercise by aerobic respiration. On the other hand, type 2 fibers contain few mitochondria contributing to the instantaneous physical exercise mainly by anaerobic glycolysis. Our results indicate that the continuous physical exercise is more affected than the instantaneous physical exercise, because administration of creatine improves predominantly the aerobic function in mitochondria.

Determination of the lactate levels before and at the end of bicycle ergometry with and without creatine supplementation did not reveal any significant results. As reported by others [14], lactate levels rose from the baseline to high concentrations to the same extent as in control subjects irrespective of creatine treatment.

In conclusion, we present further evidence that supplementation of creatine monohydrate has the potential to enhance muscle performance in patients with mitochondrial disorders. The extent of improvement may vary in the individual patient according to his biochemical and genetic properties of single muscle fibers. In general, however, there is an increase of muscle performance and power, which is more pronounced in long-acting exercises.

Side effects of creatine supplementation in doses used in our study were negligible. Creatine supplementation should therefore be considered particularly in patients with mitochondrial disorders showing a predominant muscular involvement.

Before a general recommendation for the supplementation of creatine in mitochondrial disorders can be given, a randomized trial over an extended period is necessary.