Creatine in Clinical Trials : Muscular Dystrophy

Clinical Scenarios Where Creatine is Being Tested

1. Muscular Dystrophy

2. Neurodegenerative Disorders

3. Ischemia and hypoxia


Creatine Supplementation Helps Alleviate Symptoms of Muscular Dystrophy

Clinical Trials Examining the Effects of Creatine Supplementation on Muscular Dystrophy

Clinical trials examining the potential use of creatine supplementation for mitigating some of the symptoms associated with certain forms of Muscular Dystrophy are yielding some very promising results.

Any situation that compromises a cell’s energy supply will jeopardize its survival. Moreover, if such the condition spreads to encompass more than just a few thousand cells, then the well being of the entire organism will also be undermined. It is thus not surprising that a reduction in cellular phosphocreatine levels is a hallmark feature of many known neuromuscular disorders. Consequently, dynamic cellular ATP levels are also compromised (1). In these cases, the resulting energy deficit results in weakness, chronic fatigue, and eventual muscle wasting (atrophy). Therefore, creatine supplementation, although not necessarily representing a cure per se, might nevertheless, serve to partially alleviate the symptom associated with such disorders.

Cells expend much of their precious energy resources in maintaining cellular equilibrium, a process known as homeostasis. One particularly large drain of cellular energy is the round-the-clock maintenance of ionic concentrations within strictly specified limits. Deterioration in this process can have disastrous consequences for the cell. Indeed, Duchenne and Becker muscular dystrophies are characterized by an abnormal accumulation of calcium within muscle cells. The question was thus asked: “Could the inability of dystrophic muscle cells to successfully regulate internal calcium levels be a downstream effect of reduced PCr?” In response, one pioneering study examined the effect of creatine on mice exhibiting a form of Duchenne muscular dystrophy (2). This study elegantly demonstrated that the ability of diseased muscle cells to successfully maintain internal calcium levels within safe limits could be restored by the administration of creatine. Most importantly, this effect of creatine translated into enhanced survival for dystrophic muscle cells. Obviously, PCr-dependent energy production is essential for maintaining ionic harmony within the cell.

Clinical studies conducted on humans have also produced promising results. One study showed that individuals with muscular dystrophy improved in strength while being administered creatine (3). This was in sharp contrast to nonsupplemented patients that tended to decline in strength during the time course of the study. And, with the exception of one reported incident of muscle cramping (4), creatine administration was well tolerated by all subjects. In fact, most subjects self-assessed that their condition had improved because of creatine use. Most promisingly, children with Duchenne muscular dystrophy appeared to respond the most favorably to the creatine treatment (6). Finally, one case study examined the effects of creatine treatment on a 9-year-old boy with Duchenne muscular dystrophy (5). After 155 days of creatine administration, the youngster exhibited an improved sense of balance and was able to increase his walking distance from 50 meters on a flat surface to over 450 meters on an inclined slope! These results are very promising.

Selected Scientific Reference

How Creatine Supplementation Might Help Alleviate the Symptoms of Muscular Dystrophy

1. Wyss, M. et al. (1998) The therapeutic potential of oral creatine supplementation in muscle disease. Medical Hypotheses, Volume 51, pages 333-336.

2. Pulido, S. M. et al. (1998) Creatine supplementation improves intracellular calcium handling and survival in mdx skeletal muscle cells. Federation of European Biochemical Societies Letters, Volume 439, pages 357-362.

3. Walter, M. C. et al. (2000) Creatine monohydrate in muscular dystrophies: A double-blind, placebo-controlled clinical study. Neurology, Volume 54, pages1848-1850.

4. Tarnopolsky, M. & Martin, J. (1999) Creatine monohydrate increases strength in patients with neuromuscular disease. Neurology, Volume 52, pages 854-857.

5. Felber S. et al. (2000) Oral creatine supplementation in Duchenne muscular dystrophy: A clinical and 31P magnetic resonance spectroscopy study. Neurological Research, Volume 22, pages 145-150.

The Calcium Hypothesis of Muscular Dystrophy

Again, a key pathological feature of X-linked (Duchenne and Becker) muscular dystrophies is the exaggerated loading of muscle fibers with calcium. Abnormally high levels of intracellular calcium, in turn, activate ezymes (proteases) that digest muscle proteins as well as initiate the cell death program, or apoptosis. The removal of calcium from the intracellular compartment requires energy (in the form of phospho-creatine) and is hence, an especially energetically taxing process in dystrophic muscle fibers. Consequently, the creatine stores of dystrophic muscle fibers are characteristically depleted and in dire need of replenishment. In this capacity, creatine supplementation may help alleviate the muscular symptoms of those inflicted with Duchenne and Becker muscular dystrophies. Therefore, creatine supplementation, although not necessarily representing a cure per se, might nevertheless, serve to improve the quality of life of individuals inflicted with X-linked muscular dystrophies.

One hypothesis accounting for the loading of dystrophic muscle cells with calcium is that the aberrant gating of calcium-permeable ion channels expressed on the muscle surface provide the entry pathway for calcium into dystrophic muscle. Normally, such calcium channels open only transiently in response to physiologically relevant cues (mechanical and gravitational forces, the presence of trophic factors, etc.), thereby providing the muscle with safe and appropriate amounts of calcium to perform essential cellular duties. However, when such channels are open almost continuously, as might be the case for certain forms of muscular dystrophy, the muscle loads with calcium and starts to exhibit signs of deterioration i.e., muscular dystrophy is manifested. In this hypothetical scenario therefore, the principal mutation in muscular dystrophy would act to deregulate the activity of calcium channels, which would then lead to muscle degeneration (necrosis). In truth, it was my early graduate studies examining such calcium regulatory mechanisms in dystrophic muscle that first got me interested in the theme of creatine. One of my (Franco-Obregón) original published articles on the topic is given below.

Selected Scientific Reference

Increased Calcium Channel Activity in Dystrophic Skeletal Muscle

A study examining the role of calcium-permeable ion channels on the surface of dystrophic muscle cells.

Franco-Obregón, A. and Lansman, J.B. (2002) Changes in mechanosensitive channel opening and gating following mechanical stimulation in skeletal muscle myotubes from the mdx mouse Journal of Physiology, Volume 539 (2), pages 391-407.

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