CommentaryHealth implications of creatine: can oral creatine supplementation protect against neurological and atherosclerotic disease?
Section snippets
The first 150 years of creatine research
Creatine (from the Greek kreas, flesh) was first isolated from meat extract by Chevreul (1835) (Table 1). It took almost another hundred years until Fiske and Subbarow (1927) and Eggleton and Eggleton (1927) discovered PCr which, because of its labile nature, was also called ‘phosphagen’. Lundsgaard (1930) showed that muscle contraction is accompanied by PCr breakdown rather than lactate production, and therefore proposed that PCr plays a central role in energy supply for muscle contraction.
Insights from CK knockout mice: the problem of redundancy
Stimulated by the findings on sea urchin spermatozoa (see above), many researchers in the field expected CK knockout mice to confirm the critical importance of the CK/PCr/Cr system for high-energy phosphate metabolism and transport. Surprisingly, however, most CK knockout mice displayed rather mild phenotypes (for a review, see Wyss and Kaddurah-Daouk, 2000).
In higher vertebrates, four CK isoenzymes are present. The muscle cytosolic isoform of CK (M-CK) and sarcomeric Mi-CK (Mib-CK) are found
Inborn errors of creatine metabolism
In order to more fully comprehend the clinical manifestations associated with Cr biosynthesis disorders, it seems important to provide a short introduction into the basics of Cr metabolism in humans (for a review see Wyss and Kaddurah-Daouk, 2000). Cr is either taken up from the food by intestinal absorption, and/or is synthesized endogenously, primarily in kidney, pancreas, and liver. Arginine:glycine amidinotransferase (AGAT) catalyzes the reversible transamidination of the guanidino group
Health—beneficial effects of creatine and its analogues: oral creatine supplementation as a multi-purpose prevention strategy?
A considerable list of health benefits have been reported or proposed for oral supplementation with Cr and/or its analogues (Table 2; for a review, see Wyss and Kaddurah-Daouk, 2000). Based on this list, one might be inclined to consider Cr and its analogues promising pharmaceutical drugs. The following thoughts and arguments, however, are intended to help put the current knowledge on the potential benefits and limitations of oral Cr supplementation into context.
- 1.
Since disruption of the
Neuroprotective effects of creatine
Despite the fact that neurological disorders are caused by many different primary defects, they often converge to display similar impairments in cellular energy metabolism in the brain. In these instances, intracellular concentration of ATP is decreased, resulting in cytosolic accumulation of Ca2+ and stimulation of formation of reactive oxygen species (ROS). Ca2+ and ROS, in turn, trigger apoptotic or necrotic cell death (see Fig. 1). For many of these disorders, impairments of brain Cr
Potential of creatine supplementation in lowering plasma homocysteine concentration
Homocysteine has been suggested to be an independent, graded risk factor for atherosclerotic disease affecting coronary, cerebral and/or peripheral vessels (for reviews, see Boers, 1998, Welch and Loscalzo, 1998, Selhub, 1999, Hankey and Eikelboom, 1999). For instance, a 5-μM increment in total homocysteine plasma level was found to be associated with an increased risk for developing coronary heart disease of 60% for men and 80% for women. Additional studies have demonstrated associations
Safety of oral creatine supplementation
Little in the area of Cr metabolism has been discussed so controversially over the last several months and years as the safety of oral Cr supplementation. Rather than to further polarize the discussion, this section tries to provide a comprehensive overview of the perceived and potential risks of oral Cr supplementation. As such, this section may serve as a rational basis for educated decisions on when and how broadly to allow and/or advocate oral Cr supplementation for ergogenic or preventive
Conclusions
Although Cr was discovered 170 years ago, and despite its astounding success as an ergogenic aid since the 1990s, much is still unknown about its biological functions. This is particularly true for its potential in disease prevention. Recent progress in different areas of research has consistently shown that there may be a tight correlation between the capacity of the CK system and brain function. Inborn errors of Cr metabolism in humans and knockout mice lacking CK activity in the brain are
Note added in Proof
In the context of the present article, three notable articles have recently been published. Watanabe et al. (2002) present evidence that Cr supplementation reduces mental fatigue when subjects repeatedly perform simple mathematical calculations. According to Jacobs et al. (2002), creatine supplementation enhances upper extremity work capacity in subjects with complete cervical-level spinal cord injury. And finally, Lawler et al. (2002) demonstrate direct antioxidant effects of creatine.
Acknowledgments
The participants of the 6th International Conference on Guanidíno Compounds in Biology and Medicine (Cincinnati, OH, USA, 31 August–3 September 2001) and, in particular, Joseph F. Clark, are gratefully acknowledged for stimulating discussions.
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