A placebo-controlled crossover trial of creatine in mitochondrial diseases

Klopstock, Thomas; Querner, V.; Schmidt, Frank-Peter; Gekeler, Florian; Mc, Walter; Hartard, Manfred; Dipl-Stat, M. Hennig; Gasser, Thomas; Pongratz, D.; Straube, A; Dieterich, M.; Müller‐Felber, Wolfgang

doi:10.1212/wnl.55.11.1748

Cited by 80 publications

(36 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…If our results are corroborated in future independent cohorts, measurement of plasma Cr could improve the accuracy of minimally invasive diagnosis of RCD and, importantly, provide a means for monitoring disease progression. Oral Cr supplementation often is prescribed to individuals with RCD and myopathy with the goal of improving muscle function (26,27); baseline plasma Cr measurement may be informative for predicting whether Cr supplementation is likely to be effective.…”

Section: Discussionmentioning

confidence: 99%

A plasma signature of human mitochondrial disease revealed through metabolic profiling of spent media from cultured muscle cells

Shaham

Slate

Goldberger

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

130

123

View full text Add to dashboard Cite

Mutations in either the mitochondrial or nuclear genomes can give rise to respiratory chain disease (RCD), a large class of devastating metabolic disorders. Their clinical management is challenging, in part because we lack facile and accurate biomarkers to aid in diagnosis and in the monitoring of disease progression. Here we introduce a sequential strategy that combines biochemical analysis of spent media from cell culture with analysis of patient plasma to identify disease biomarkers. First, we applied global metabolic profiling to spotlight 32 metabolites whose uptake or secretion kinetics were altered by chemical inhibition of the respiratory chain in cultured muscle . These metabolites span a wide range of pathways and include lactate and alanine, which are used clinically as biomarkers of RCD. We next measured the cell culture-defined metabolites in human plasma to discover that creatine is reproducibly elevated in two independent cohorts of RCD patients, exceeding lactate and alanine in magnitude of elevation and statistical significance. In cell culture extracellular creatine was inversely related to the intracellular phosphocreatine:creatine ratio suggesting that the elevation of plasma creatine in RCD patients signals a low energetic state of tissues using the phosphocreatine shuttle. Our study identifies plasma creatine as a potential biomarker of human mitochondrial dysfunction that could be clinically useful. More generally, we illustrate how spent media from cellular models of disease may provide a window into the biochemical derangements in human plasma, an approach that could, in principle, be extended to a range of complex diseases.biochemical genetics | biomarker | metabolomics | mitochondria T he respiratory chain (RC) of mammalian cells comprises a series of five enzymatic complexes embedded in the inner mitochondrial membrane and serves as the machinery for oxidative phosphorylation. Changes in RC activity influence key parameters such as the cellular energy charge and the NADH/ NAD + ratio and can impact the numerous metabolic pathways coupled to the RC directly or indirectly. In humans, inherited defects in mitochondrial (mt) or nuclear genes that encode RC proteins or factors necessary for its maturation and assembly lead to respiratory chain disease (RCD) (1). It is estimated that RCD affects at least 18.4 in 100,000 people (2) and represents the most common group of inborn errors of metabolism (3).The clinical presentation of RCD is highly variable in severity, age of onset, and the combination of organ systems involved, and the factors contributing to this variability are poorly understood (1). Consequently, the diagnosis can be challenging, and there are very limited means of objectively monitoring disease progression. A number of diagnostic algorithms have been proposed (4-6) that integrate clinical, biochemical, histological, and molecular findings. Abnormal concentrations of several metabolites in biological fluids, including the elevation of lactate, alanine, pyruvate, and the lac...

show abstract

Section: Discussionmentioning

confidence: 99%

A plasma signature of human mitochondrial disease revealed through metabolic profiling of spent media from cultured muscle cells

Shaham

Slate

Goldberger

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

130

123

View full text Add to dashboard Cite

show abstract

“…The second trial, conducted at Ludwig-Maximilians University was also a double blind, placebo-controlled, crossover trial [46]. Patients were randomized to receive creatine, 20 g/d (a higher dose), or placebo for 4 weeks, then, after a 4-week washout interval, received the other alternative for another 4 weeks ( Table 1).…”

Section: Creatine (Alone or In Combination With Antioxidants)mentioning

confidence: 99%

Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

Kerr

2013

Neurotherapeutics

View full text Add to dashboard Cite

Over the last 15 years, some 16 open and controlled clinical trials for potential treatments of mitochondrial diseases have been reported or are in progress, and are summarized and reviewed herein. These include trials of administering dichloroacetate (an activator of pyruvate dehydrogenase complex), arginine or citrulline (precursors of nitric oxide), coenzyme Q 10 (CoQ 10 ; part of the electron transport chain and an antioxidant), idebenone (a synthetic analogue of CoQ 10 ), EPI-743 (a novel oral potent 2-electron redox cycling agent), creatine (a precursor of phosphocreatine), combined administration (of creatine, α-lipoate, and CoQ 10 ), and exercise training (to increase muscle mitochondria). These trials have included patients with various mitochondrial disorders, a selected subcategory of mitochondrial disorders, or specific mitochondrial disorders (Leber hereditary optic neuropathy or mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). The trial designs have varied from open-label/uncontrolled, openlabel/controlled, or double-blind/placebo-controlled/crossover. Primary outcomes have ranged from single, clinicallyrelevant scores to multiple measures. Eight of these trials have been well-controlled, completed trials. Of these only 1 (treatment with creatine) showed a significant change in primary outcomes, but this was not reproduced in 2 subsequent trials with creatine with different patients. One trial (idebenone treatment of Leber hereditary optic neuropathy) did not show significant improvement in the primary outcome, but there was significant improvement in a subgroup of patients. Despite the paucity of benefits found so far, well-controlled clinical trials are essential building blocks in the continuing search for more effective treatment of mitochondrial disease, and current trials based on information gained from these prior experiences are in progress. Because of difficulties in recruiting sufficient mitochondrial disease patients and the relatively large expense of conducting such trials, advantageous strategies include crossover designs (where possible), multicenter collaboration, and the selection of very few, clinically relevant, primary outcomes.

show abstract

“…52 Creatine monohydrate (CrM) has been tried in six patients with MELAS and one with undefined mitochondrial disease in a randomized controlled study; there was improvement of high-intensity activities but not of lower intensity aerobic exercise. 53 In a subsequent randomized placebocontrolled crossover trial, Klopstock et al 54 studied the effects of CrM (20 g daily for 4 weeks) in 13 participants with progressive external ophthalmoplegia and three with mitochondrial myopathy. No significant effects of treatment were noted.…”

Section: Creatinementioning

confidence: 99%

“…No significant effects of treatment were noted. 54 Inborn errors of energy metabolism have been identified in three of the main steps in creatine metabolism. Oral CrM has been shown to improve the clinical symptoms in some of these cases.…”

Section: Creatinementioning

confidence: 99%

Electron transfer mediators and other metabolites and cofactors in the treatment of mitochondrial dysfunction

Orsucci

Filosto²,

Siciliano

et al. 2009

Nutrition Reviews

View full text Add to dashboard Cite

Mitochondrial disorders (MDs) are caused by impairment of the mitochondrial electron transport chain (ETC). The ETC is needed for oxidative phosphorylation, which provides the cell with the most efficient energy outcome in terms of ATP production. One of the pathogenic mechanisms of MDs is the accumulation of reactive oxygen species. Mitochondrial dysfunction and oxidative stress appear to also have a strong impact on the pathogenesis of neurodegenerative diseases and cancer. The treatment of MDs is still inadequate. Therapies that have been attempted include ETC cofactors, other metabolites secondarily decreased in MDs, antioxidants, and agents acting on lactic acidosis. However, the role of these dietary supplements in the treatment of the majority of MDs remains unclear. This article reviews the rationale for their use and their role in clinical practice in the context of MDs and other disorders involving mitochondrial dysfunction.

show abstract

A placebo-controlled crossover trial of creatine in mitochondrial diseases

Cited by 80 publications

References 9 publications

A plasma signature of human mitochondrial disease revealed through metabolic profiling of spent media from cultured muscle cells

A plasma signature of human mitochondrial disease revealed through metabolic profiling of spent media from cultured muscle cells

Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

Electron transfer mediators and other metabolites and cofactors in the treatment of mitochondrial dysfunction

Contact Info

Product

Resources

About