Creatine and Creatinine Metabolism - Physiological Reviews
Creatine and Creatinine Metabolism - Physiological Reviews
Creatine and Creatinine Metabolism - Physiological Reviews
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1182 MARKUS WYSS AND RIMA KADDURAH-DAOUK Volume 80<br />
have to be studied in detail in humans. It will be particularly<br />
relevant to investigate the kinetics of downregulation<br />
<strong>and</strong> reexpression of the Cr transporter during <strong>and</strong><br />
after Cr supplementation. According to current knowledge,<br />
a “loading phase” of 5–10 days should be sufficient<br />
to obtain maximal benefit. Thereafter, the ration should<br />
be reduced considerably or even completely to allow<br />
reexpression of the Cr transporter <strong>and</strong>, thereby, to prepare<br />
the muscle for a next Cr loading phase.<br />
To conclude, Cr supplementation may improve muscle<br />
performance in three different ways: by increasing the<br />
muscle stores of PCr which is the most important energy<br />
source for immediate regeneration of ATP in the first few<br />
seconds of intense exercise; by accelerating PCr resynthesis<br />
during recovery periods; <strong>and</strong> by depressing the<br />
degradation of adenine nucleotides <strong>and</strong> possibly also the<br />
accumulation of lactate during exercise. The results published<br />
so far provide both a rational explanation <strong>and</strong><br />
promising results for an ergogenic action of Cr in intermittent,<br />
supramaximal exercise. On the other h<strong>and</strong>, there<br />
is hardly any indication so far that Cr supplementation<br />
might also increase endurance performance (see also<br />
Refs. 46, 225, 674, 1038, 1106). In addition to its application<br />
in humans, Cr supplementation may also be useful as<br />
an ergogenic aid for racing horses, racing camels, greyhounds,<br />
or huskies (e.g., Ref. 577).<br />
Even though Cr supplementation is commonly regarded<br />
as safe, no proper clinical study has been conducted<br />
yet to evaluate the compound’s safety profile in<br />
humans. Side effects of Cr supplementation have occasionally<br />
been described (for a review, see Ref. 442): mild<br />
asthmatic symptoms <strong>and</strong> gastrointestinal distress (208,<br />
1038), muscle cramps <strong>and</strong> muscle strains (128, 985), <strong>and</strong><br />
heat intolerance. Muscle cramps <strong>and</strong> heat intolerance<br />
may be related to the increased water retention in muscle<br />
during the initial days of Cr supplementation. During this<br />
period, therefore, subjects should take care to be properly<br />
hydrated <strong>and</strong> to avoid strenuous exercise (128, 442). This<br />
is especially true for subjects attempting to rapidly reduce<br />
body mass, e.g., in sports like wrestling, judo, karate, or<br />
weight-lifting where athletes often compete in a weight<br />
class below their usual body mass. As a matter of fact, Cr<br />
supplementation during the period of weight loss proved<br />
to even have an adverse effect on muscle performance<br />
(733). Anecdotal reports of adverse events to the Food<br />
<strong>and</strong> Drug Administration included rash, dyspnea, vomiting,<br />
diarrhea, nervousness, anxiety, fatigue, migraine, myopathy,<br />
polymyositis, seizures, <strong>and</strong> atrial fibrillation<br />
(Food <strong>and</strong> Drug Administration Special Nutritionals Adverse<br />
Event Monitoring System Web Report October 20,<br />
1998; http://vm.dfsan.fda.gov/cgi-bin/aems.cgi?QUERY�<br />
creatine&STYPE�EXACT).<br />
As already suggested in section IXA, subjects with<br />
impaired renal function <strong>and</strong> those at risk should avoid Cr<br />
supplementation. While in normal subjects Cr supplemen-<br />
tation only slightly increases serum [Crn], a considerably<br />
more pronounced increase may be seen in patients with<br />
renal dysfunction that is potentially associated with an<br />
increase in Crn-derived uremic toxins (see sect. IXH).<br />
Accordingly, Cr supplementation had no effect on serum<br />
markers of hepatic <strong>and</strong> renal function as well as on routine<br />
clinical chemistry in healthy volunteers (208, 776),<br />
whereas Koshy et al. (507) reported on a 20-yr-old man<br />
developing interstitial nephritis while on Cr supplementation,<br />
<strong>and</strong> Pritchard <strong>and</strong> Kalra (786) described the case<br />
of a 25-yr-old man with focal segmental glomerulosclerosis<br />
where rapid deterioration of renal function was linked<br />
to Cr supplementation. Upon discontinuation of Cr supplementation,<br />
renal function parameters recovered.<br />
Clearly, both short- <strong>and</strong> long-term side effects of Cr supplementation<br />
must be studied more carefully in the future.<br />
Despite the current popularity of Cr supplementation,<br />
it must be kept in mind that it is virtually impossible<br />
by natural means to ingest 20–30 g Cr/day. Therefore, <strong>and</strong><br />
also based on the lack of proper investigations on the<br />
potential side effects of this compound <strong>and</strong> on its mechanism<br />
of action, discussions should continue on whether<br />
Cr supplementation is a legal ergogenic aid or whether it<br />
should be regarded as a doping strategy (605, 1106).<br />
XIII. CONCLUSIONS AND PERSPECTIVES<br />
As outlined in this review, research on Cr <strong>and</strong> Crn<br />
metabolism has received a fresh impetus in recent years.<br />
For example, the DNA sequencing <strong>and</strong> three-dimensional<br />
structure determination of enzymes involved in Cr metabolism—in<br />
particular the identification <strong>and</strong> characterization<br />
of the Cr transporter—the potential link of the CK/<br />
PCr/Cr system to a variety of diseases, together with the<br />
emerging potential therapeutic value of Cr analogs, the<br />
widespread use of Cr as an ergogenic dietary supplement,<br />
or the identification of cooked food mutagens derived<br />
from Cr <strong>and</strong> Crn have stimulated activities in many different<br />
areas of research. It seemed therefore timely to<br />
summarize the current knowledge to point out the many<br />
complex relationships between the different areas of Cr<br />
research, <strong>and</strong> thereby to provide a starting point for future<br />
multidisciplinary efforts to unravel the still existing<br />
mysteries associated with Cr <strong>and</strong> Crn.<br />
Although, at the molecular level, many details are<br />
currently known, the integration <strong>and</strong> regulation of Cr<br />
metabolism in mammals is still only incompletely understood.<br />
It seems that the Cr transporter, a saturable uptake<br />
mechanism for Cr found in the plasma membrane of<br />
tissues unable to synthesize Cr, plays a central role in<br />
regulating intracellular Cr <strong>and</strong> PCr concentrations (sect.<br />
IV). Because this protein was discovered only in 1993<br />
(319), research on its relevance for Cr metabolism is still