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Creatine Use in Clinical Trials
Creatine is currently being tested in clinical trials for potential therapeutic use during the treatment of several neurological and neuromuscular disorders. Nonetheless, despite the recent boom in creatine research, our current knowledge of just how creatine supplementation benefits tissues other than skeletal muscle is far from complete. One obvious global benefit, however, is creatine's ubiquitous ability to buffer cellular energy levels – a clear advantage for any cell type in possible danger of energy exhaustion. Another source of broad-reaching benefits has to do with creatine's positive effect over cellular methylation status. These biochemical mechanisms must be understood in order to take full advantage of creatine supplementation for general health and well-being.
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.
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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 un-supplemented 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.
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Selected Scientific References:
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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Creatine Combats Many Neurodegenertive Disorders
By far, creatine is best known for its ergogenic (muscle-enhancing) benefits. Ironically, creatine supplementation may provide an even greater service to society as a whole on the neurological level. In fact, the neurological deficits associated with inborn errors in creatine production and storage are typically more pronounced than the corresponding muscular symptoms, reflecting the importance of creatine to the proper functioning of the nervous system.
Unfortunately, dietary creatine intake only increases brain creatine levels one third as much as it does our muscular reserves. The reason for this discrepancy appears to be the blood brain barrier, which typically serves to protect the brain from foreign blood born toxins and pathogens. Henceforth, other strategies need to be to more developedeffectively deliver creatine to the central nervous system of humans inflicted with those neurodegenerative disorders associated with creatine deficiencies.
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Despite this apparent limitation, the latest scientific research is clearly showing that creatine is an extremely important neuroprotectant, an agent that increases the survival of nerve cells (neurons) to environmental insults. Many neurodegenerative disorders are associated with compromises in energy metabolism and the production of Reactive Oxygen Species (ROS). In both these capacities creatine may help brain cells survival metabolic and physical trauma. In this respect, creatine supplementation is currently being tested (quite successfully) in clinical and animal studies for amyotrophic lateral sclerosis (ALS), Huntington's disease and Parkinson's disease. Furthermore, recent animal studies have demonstrated creatine to be effective treatment in greatly reducing the size of brain lesions in response to ischemia (a localized reduction in blood flow). In the future creatine may be used as a method to preserve brain function following acute stroke.
Genetic conditions giving rise to a decrease in creatine synthesis or transport into brain cells (neurons) results in severe mental retardation. In this respect, it is not surprising that creatine supplementation has been recently shown to aid in the performance of exhausting mental tasks as well as in the recollection of a complicated series of digits (see here). Creatine supplementation is becoming a smart practice!
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Selected Scientific Reference
Review: Creatine's Possible Therapeutic Value for Several Neurological, Vascular & Muscular Disorders
Below is the reference to a beautifully written commentary on the subject (creatine's neurological benefits) co-authored by an admired colleague and friend, Markus Wyss of Switzerland.
Wyss, M. and Schulze, A. (2002) Health implications of creatine: Can oral creatine supplementation protect against neurological and atherosclerotic disease? Neuroscience, Volume 112 (2), pages 243-260.
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The Muscular Dystrophy Association (MDA) is currently planning a multi-center trial to test the effectiveness of creatine in humans with amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease). Please give to the MDA and help support research investigating the neuroprotective consequences of creatine supplementation.
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Creatine is a Neuroprotectant!
Creatine's energy allotment is proving to have far reaching ramifications for overall health, resistance to disease and protection from cellular trauma. Below are two studies from distinct parts of the world (United States and Switzerland) showing that creatine protects brain cells from dying following reduced blood flow (ischemia) that could starve brain cells for oxygen (hypoxia) and essential nutrients.
Swiss Study
The loss of oxygen to brain regions leads to energy failure, cell death and possibly chronic neurological symptoms. Low oxygen levels (hypoxia) as a result of blood flow restriction (ischemia) are especially devastating to the nervous systems of newborn infants (neonates) and can result in life-long neurological disorders such as cerebral palsy. This study examined the ability of creatine supplementation to reduce the extent of brain damage in neonateal rats after exposure to ischemia-hypoxia.
Swiss Study Design: Six day old rat pups were injected with 3 grams of creatine per kilogram of body weight for three days. Injection was necessary to assure that all specimens received a standard dose of creatine monohydrate. On the fourth day the pups were exposed to hypoxia after blocking blood flow (via the carotid artery) to the brain (I'll spare you the bloody details of how ischemia-hypoxia was created). However, via this technique one hemisphere of the brain (ipsilateral-opposite side) is preferentially subjected to reduced blood flow. The pups were then allowed to recover for an hour before being exposed to hypoxia for 100 minutes (approximately one and a half hour). On the fifth day the brains of these pups were examined using Magnetic Resonance Imaging (MRI) and the size of the edemic brain lesions noted.
Results and Conclusions: The brain lesions observed in rats that had been previously supplemented with creatine were 25% smaller than those present in non-supplemented rats. That is, creatine supplementation protected against the loss of brain cells in response to ischemia-hypoxia.
Quoting the authors of this study: "It is our belief that supplementation with exogenous creatine during and after HI (hypoxia-ischemia), by preserving brain energy levels, with its positive consequences on calcium homeostasis and mitochondrial function, could limit, if not prevent, damage caused by HI (hypoxia-ischemia) by ameliorating SEF (secondary energy failure)."
The authors of the study proposed that the combination of several effects contributed to the life sparring effect of creatine supplementation: 1) an increase in anaerobic energy stores (ATP and PCr); 2) the prevention of energy deficiency-induced calcium overloading; 3) the prevention of mitochondrial transition pore opening (mitochondrial death); 4) and the direct antioxidant properties of creatine . Therefore, creatine administration may prove to be a course of action in human neonates exposed to hypoxia.
Scientific Reference: Adcock K. H. et al. (2002) Neuroprotection of creatine supplementation in neonateal rats with transient cerebral hypoxia-ischemia. Developmental Neuroscience, Volume 24, pages 382-388.
USA Study
The previously discussed Swiss study showed that creatine supplementation protects brain cells from dying following oxygen deprivation (hypoxia). In this instance, hypoxia was produced by blocking blood flow to the brain, a physiological condition known as ischemia. This study also focussed on the neonateal brain and found that creatine supplementation reduced areas of brain damage following regional hypoxia. Stroke is an example of hypoxic brain damage that might occur in adults. The mechanism of neuronal death in these instances, however, is not specific for hypoxia, but rather, involves the induction of a general death program known as apoptosis (also known as programmed cell death). In essence, environmental insult provokes neurons to literally commit suicide. It is thus not surprising that creatine supplementation protects against several forms of brain insult including Amyotrophic Lateral Sclerosis (ALS), Huntington’s disease, Parkinson’s disease, and traumatic brain injury.
USA Study Design: Briefly, this study followed the expression of two biochemical markers for apoptosis, caspase-3 activation and cytochrome c release from the mitochondria, in response to restricted blood flow to the brain. One group of mice were fed a creatine supplemented diet (2%) for one month while another group was given a normal (control) diet. Blood flow to the brain was interrupted for two hours (again, I'll spare you the gruesome details), following which they were allowed to recovery for 24 hours before histological examination and biochemical analysis.
Results and Conclusions: In contrast to the previous study where brain damage was reduced by 25% in rats administered creatine, this study demonstrated an astounding 56% (!) reduction in area of brain damage in response to creatine treatment. Caspase-3 activity and cytochrome c release were also attenuated in the creatine treated mice, indicating that the degree of apoptosis was similarly attenuated. Once again, this study unequivocally demonstrated that creatine supplementation enhances brain survival following ischemia.
Interestingly, one week of supplementation appeared to have no effect, indicating that this effect requires more than merely increasing neuronal creatine reserves. That is, longer-term biochemical changes in brain metabolism are likely to be necessary for this effect to be fully manifested. Creatine-induced enhancement in methylation capacity is the most likely candidate for a biochemical pathway giving rise to this effect.
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Therefore, two independent reports have given outstanding proof that creatine protects the brain from damage after ischemic insult. Although this data was generated from rats and mice, I am willing to venture a guess that the neuroprotective effects of creatine supplementation will extend to the human species as well.
Quoting the authors of this study: "Given that creatine is a relatively safe compound, people at high risk of cerebral ischemic injury might be good candidates to receive creatine supplementation."
Furthermore, combining creatine supplementation with targeted B-vitamin supplementation will bouble the neurooprotective and anabolic capabilities of either separately.
Scientific Reference: Zhu S. et al. (2004) Prophylactic creatine administration mediates neuroprotection in cerebral ischemia in mice. Journal of Neuroscience, Volume 24 (26), pages 5909-5912.
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Click here for more discussion about the effects of creatine and essential B-vitamins on brain health.
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