Creatine and Creatinine Metabolism - Physiological Reviews

July 2000 CREATINE AND CREATININE METABOLISM 1145
mal region (728). Therefore, it might be interesting to test
the hypothesis that ragged-red fibers are exposed to oxidative
stress, that Mi-CK (which is sensitive to oxidative
inactivation; see sect. VIID) is inactivated by NO or peroxynitrite,
and that the modified Mi-CK displays an increased
tendency to form crystalline aggregates in subsarcolemmal
mitochondria. This interpretation would be
in line with a similar conclusion by O’Gorman et al. (720).
In patients with muscle hypotonotrophy of the thigh
due to knee osteoarticular lesions, intravenous injection
of 1 g PCr daily during the rehabilitation phase significantly
accelerated recovery of muscle strength and power
peak torque (847). After 30 days of treatment, the difference
between PCr-treated and nontreated patients was
13% in muscle flexion and 18% in extension. Intramuscular
injection of PCr in the rat before 4hofischemia followed
by 30 min of reperfusion prevented the increase in membrane
ion conductance and the loss of excitability of the
muscle fibers upon reperfusion (1016).
Finally, recent gene localization studies revealed interesting
relationships. The gene for the Cr transporter is
localized on human chromosome Xq28, a locus to which
several (neuro)muscular disorders have been mapped, for
example, Emery-Dreifuss muscular dystrophy, Barth syndrome,
or myotubular myopathy (see Refs. 309, 317, 691).
Similarly, the gene for M-CK on human chromosome
19q13.2–19q13.3 is one of the most tightly linked markers
of myotonic dystrophy (101, 506). The genes for ubiquitous
Mi-CK and AGAT on human chromosome 15q15.3
and for sarcomeric Mi-CK on human chromosome 5q13.3
are in close proximity to the genes for limb-girdle muscular
dystrophy type 2A (LGMD2A) and for proximal
spinal muscular atrophy, respectively (260, 805, 940). So
far, however, evidence is lacking that mutations in the Cr
transporter, CK, or AGAT genes may be the cause of the
respective muscle diseases (see, e.g., Ref. 42).
To conclude, a wealth of experimental evidence suggests
that muscle diseases and disturbances of Cr metabolism
are related. However, little is known so far about
the causal links, either direct or indirect, between the
disturbances of Cr metabolism on one hand and the primary
defects or the clinical expression of the disease on
the other hand. Future studies should not only provide the
missing links but may also hint at alternative therapeutic
approaches for muscle diseases. Possibly, oral Cr supplementation
may turn out to be a simple and practicable
way for alleviating at least some of the clinical symptoms
in a broad range of muscle diseases. Just very recently,
Tarnopolsky and Martin (985) provided experimental support
for this hypothesis, in that Cr supplementation in fact
increased handgrip, dorsiflexion, and knee extensor
strength in more than 80 patients with neuromuscular
disease (mitochondrial cytopathies, neuropathic disorders,
dystrophies/congenital myopathies, inflammatory
myopathies, and miscellaneous conditions), with no obvious
differences between subgroups.
B. CK, Phosphorylcreatine, and Cardiac Disease
The question whether the capacity of the CK/PCr/Cr
system critically determines cardiac function is still a
matter of debate. Some authors believe that the CK system
simply serves a backup role by buffering [ATP] and
[ADP] intracellularly, with no major impact of changes in
PCr and Cr contents or CK activity on cardiac performance.
Others, however, have accumulated evidence in
favor of a close correlation between the functional capacity
of the CK/PCr/Cr system and cardiac mechanical performance.
If these latter correlations in fact turn out to be
valid, disturbances in Cr metabolism may be one of the
underlying causes of cardiac disease.
There are numerous arguments supporting a correlation
between cardiac performance and CK function. 1) In
rat heart, flux through the CK reaction was shown by
31 P-NMR saturation transfer measurements to increase in
parallel with the workload imposed, thus suggesting a
close coupling between the rate of ATP synthesis and/or
utilization on one hand and flux through the CK reaction
on the other hand (see Refs. 401, 402, 516, 518, 611, 620,
1155). 2) Exposure of isolated perfused rat hearts to
iodoacetamide causes rather selective inhibition of CK
and, concomitantly, contractile dysfunction. After iodoacetamide
exposure, [ATP] and [PCr], end-diastolic pressure,
left ventricular developed pressure, rates of tension
development and relaxation, coronary flow rate, and
heart rate were maintained in the control range at low
levels of developed pressure. In contrast, large changes in
these parameters relative to controls were observed at
increased workloads (259, 329, 402, 611, 1005; see also
Ref. 1006). Matsumoto et al. (611) observed a linear correlation
between CK flux and rate-pressure product in
these iodoacetamide-treated rat hearts. 3) Similarly, perfusion
of rabbit hearts with the CK inhibitor DNFB
strongly depressed left ventricular output at a time when
[ATP] and [PCr] were decreased by only 16 and 20%,
respectively (282). Furthermore, in frog hearts subjected
to metabolic inhibition by cyanide, the decrease in developed
tension did correlate neither with electrical activity
(Ca 2� metabolism, action potential amplitude or duration)
nor with metabolic acidosis but with [PCr] (1061). 4)
Very recently, Gross et al. (315) presented an interesting
hypothesis in that NO may exert its physiological effects
on cardiac contractile performance by reversibly inhibiting
myocardial CK activity. In control rat hearts, a high
Ca 2� challenge (3.5 mM) transiently increased the ratepressure
product by 74% and decreased [PCr], while
[ATP] was maintained. In hearts perfused with the NO
donor S-nitrosoacetylcysteine, on the other hand, the