Creatine and Creatinine Metabolism - Physiological Reviews

July 2000 CREATINE AND CREATININE METABOLISM 1183
in its infancy. An interesting question to be addressed is
the potential downregulation of the Cr transporter by
extracellular Cr in both health and disease. Preliminary
data suggest that such regulation could indeed exist (317,
571).
Despite being investigated for many years already,
CK has just recently evoked renewed interest. The availability
of CK knockout mice, the first description of a
three-dimensional structure of a CK isoenzyme, as well as
the potential regulation and inactivation of CK by AMPactivated
protein kinase, NO and ROS represent major
steps forward to more clearly understand the physiological
functions of the CK/PCr/Cr system in health and disease
(see sect. VIID). In addition, it has been realized that
the CK and adenylate kinase systems can, to some extent,
mutually replace each other in mediating intracellular
transport of high-energy phosphates, which may explain
why targeted disruption of CK genes in transgenic animals
and other strategies directed at compromising the functional
capacity of the CK/PCr/Cr system often have relatively
mild effects.
The ergogenic effects of Cr have prompted its widespread
use among athletes. Short periods of supplementation
with high doses of Cr (20–30 g/day over 5–7 days)
significantly improved work performance in a variety of
short-term, intermittent, supramaximal exercise tests
(see sect. XI). On the other hand, an improvement in
endurance performance with Cr supplementation seems
at present unlikely. Two questions in this area await
clarification: 1) Is the increased short-term performance
due to improved power indexes of the existing muscle
mass, or simply to a stimulation of muscle growth? The
latter possibility must be favored at present on the basis
of the increase in body weight normally associated with
Cr supplementation. 2) Should Cr supplementation be
considered a natural ergogenic aid or an illegal doping
strategy by the legal sports authorities? Although high
amounts of Cr are tolerated by athletes, conclusions
about the safety of Cr supplementation are still premature
and await further studies. The rare and often anecdotal
reports on potentially adverse side effects of Cr supplementation
need to be studied carefully. Crn, which
slightly increases in concentration upon Cr supplementation,
is the precursor of a uremic toxin, methylguanidine
(see sect. IXH). Cr and Crn, when present in food and
cooked at high temperatures, seem to be precursors of
food mutagens that are carcinogenic in different tissues of
rodents and monkeys (see sect. IXF). Even though the
relevance of these pathways may be called in question,
definite conclusions cannot be drawn until sound studies
on the long-term complications of Cr supplementation
become available.
Potential relationships between disturbances in Cr
metabolism and diseases of skeletal muscle, heart, brain,
and kidney were presented in sections IXA-IXC, IXG, and
IXH. Although some of the relationships may be accidental,
it is nevertheless striking in how many cases a close
correlation between the functional capacity of the CK/
PCr/Cr system, tissue integrity, and metabolic capacity
was observed. If these correlations are corroborated in
the future, Cr supplementation may become a versatile
therapeutic tool for treating such diseases. In addition, Cr
analogs may develop into an interesting new class of
therapeutic agents possibly having novel mechanisms of
action that are not yet fully clarified.
Cr supplementation was shown to be of benefit to
patients suffering from gyrate atrophy of the choroid and
retina, mitochondrial cytopathies and other neuromuscular
diseases (see sect. IXA), and GAMT deficiency (see
sect. IXG). Clearly, these results are preliminary and need
to be confirmed.
cCr displays significant antitumor activity when used
alone and synergistic effects when used in combination
with currently used anticancer drugs (see sect. IXD). Because
cCr has a mode of action different from those of
other anticancer agents, it is a particularly promising
candidate for combination therapies. Cr analogs also displayed
antiviral effects (sect. IXE) and had an impact on
blood glucose levels (sect. VIIIB). Both long-term and
short-term treatment of experimental animals with cCr
yielded considerable protection against ischemic damage
of skeletal muscle, heart, and brain. Therefore, Cr analogs
like cCr may be instrumental for increasing the survival
time of organs during (cold) preservation, an issue that is
particularly relevant at present for heart transplantation.
Finally, Cr and cCr had potent protective effects in several
animal models of neurodegenerative disease, e.g., in
the MPTP model of Parkinson’s disease, in a transgenic
mouse model of amyotrophic lateral sclerosis, or in malonate-
and 3-nitropropionic acid-induced models of Huntington’s
disease (see sect. IXG).
The recent discovery of a number of new aspects of
Cr metabolism has created new interest in the physiological
and pathological relevance of the CK/PCr/Cr system,
as well as in novel ergogenic and therapeutic applications
that may be derived from these findings. In addition,
despite more than 150 years of research since the discovery
of Cr (121), Cr and its metabolism as a whole are
likely to provide us with many new, unexpected surprises
also in the future.
M. F. Beal, D. J. T. Porter, J. F. van Pilsum, T. Roenneberg,
J. Siedel, S. Soboll, and T. Suzuki are gratefully acknowledged
for providing unpublished results and valuable comments; H. M.
Eppenberger and R. Margreiter for support; T. Wallimann for
discussion in the initial stages of this project; and M. O’Keefe for
invaluable help.
This work was supported by Swiss National Science Foundation
Fellowship 823A-037106 and Austrian Science Foundation
Lise Meitner Fellowship M00198-MED (both to M. Wyss).
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