Creatine and Creatinine Metabolism - Physiological Reviews
Creatine and Creatinine Metabolism - Physiological Reviews
Creatine and Creatinine Metabolism - Physiological Reviews
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July 2000 CREATINE AND CREATININE METABOLISM 1137<br />
ent lantern muscles contain both PArg/ArgK <strong>and</strong> PCr/CK<br />
in varying proportions (220, 1092). CK <strong>and</strong> ArgK in these<br />
lantern muscles were suggested to be associated more<br />
with tonic <strong>and</strong> phasic contractions, respectively (1092).<br />
Clearly, if PCr simply represented a functional improvement<br />
over PArg, it would be inconceivable why PArg in<br />
these invertebrates was replaced by PCr only in some<br />
tissues, but not in others. The following excursus shall<br />
provide an alternative explanation (see also Ref. 221).<br />
To test the effects of Cr analogs on energy metabolism<br />
during ischemia, Walker <strong>and</strong> co-workers (reviewed<br />
in Ref. 1076) fed chickens either with a control diet or<br />
with the same diet supplemented with cyclocreatine (cCr;<br />
1-carboxymethyl-2-iminoimidazolidine; see Fig. 10), homocyclocreatine<br />
(hcCr; 1-carboxyethyl-2-iminoimidazolidine),<br />
or Cr. cCr <strong>and</strong> hcCr compete with Cr for uptake<br />
into the tissues, are accumulated instead of Cr inside the<br />
cells, <strong>and</strong> are finally phosphorylated by intracellular CK.<br />
PhcCr is �200,000-fold less potent than PCr <strong>and</strong> 1,500fold<br />
less potent than PcCr in acting as a substrate for CK,<br />
<strong>and</strong> both PhcCr <strong>and</strong> PcCr display a �G°� of hydrolysis<br />
�7.3–8.4 kJ/mol less negative than that of PCr (37°C; see<br />
Table 1) (810, 1076).<br />
Hearts of chickens fed cCr for at least 6 days accumulate<br />
15 �mol � (g wet wt) �1 of cCr plus PcCr. This<br />
accumulation is paralleled by a triplication of the glycogen<br />
levels <strong>and</strong> by a decrease in the Cr � PCr levels from<br />
FIG. 10. Chemical formulas of synthetic creatine analogs. Phosphinic<br />
creatine, N-methyl-N-amidino-aminomethylphosphinic acid;<br />
phosphinic cyclocreatine, 2-iminoimidazolidine-1-methylphosphinic<br />
acid; ethyl creatine, N-ethyl-N-amidinoglycine.<br />
the normal 6 �mol/g to 1.8 �mol/g (1028). During total<br />
ischemia in vitro, these hearts utilize PcCr for the regeneration<br />
of ATP, display greatly prolonged glycolysis, <strong>and</strong><br />
exhibit a two- to fivefold delay in ATP depletion relative to<br />
controls. Accumulation by chicken hearts of a comparable<br />
amount of PhcCr is also paralleled by a triplication of<br />
the glycogen levels, but by a decrease in Cr � PCr levels<br />
to only 4.2 �mol/g. During ischemia, these hearts exhibit<br />
prolonged glycolysis but do not utilize PhcCr <strong>and</strong> manifest<br />
no delay in ATP depletion relative to controls. Therefore,<br />
the cCr effects on energy metabolism during ischemia<br />
are most probably not due to the increased glycogen<br />
levels. Similar to hcCr, no delay in ATP depletion was<br />
observed during ischemia in hearts of Cr-fed chickens<br />
having accumulated 14.8 �mol/g of Cr plus PCr.<br />
In further investigations, long-term feeding of cCr<br />
was found 1) to increase the total high-energy phosphate<br />
levels in mouse brain <strong>and</strong> skeletal muscle (24, 1119); 2)to<br />
delay ATP depletion during ischemia in mouse brain,<br />
mouse skeletal muscle, rat heart, rat skin, <strong>and</strong> chicken<br />
breast muscle (24, 147, 419, 808, 1027, 1119); 3) to delay<br />
onset of rigor contraction in ischemic rat heart <strong>and</strong> mouse<br />
skeletal muscle (24, 419, 808); <strong>and</strong> 4) to enhance survival<br />
of experimental skin flaps in the rat (147). On the basis of<br />
these results, it may be hypothesized that at the lower<br />
phosphorylation potentials <strong>and</strong> at the more acidic pH<br />
values characteristic of later stages of ischemia, substantial<br />
levels of a kinetically competent <strong>and</strong> thermodynamically<br />
rather stable phosphagen are advantagous to assist<br />
glycolysis in buffering decreases <strong>and</strong> oscillations in the<br />
ATP/ADP <strong>and</strong> ATP/(ADP � P i) ratios (1028). In contrast,<br />
PCr <strong>and</strong> PhcCr are not suited for this purpose for thermodynamic<br />
reasons <strong>and</strong> because of kinetic limitations,<br />
respectively. Very similar to the synthetic phosphagen<br />
PcCr, the phosphagens characteristic of invertebrates<br />
(i.e., PArg, PGc, PTc, PL) display �G°� values of hydrolysis<br />
that are 2.9–5.2 kJ/mol less negative than that of PCr<br />
(221). Provided that the corresponding guanidino kinases<br />
are also present, these phosphagens may thus be advantagous<br />
in invertebrate phyla under conditions of hypoxia<br />
or intracellular acidosis (221, 1124).<br />
In vertebrates, which almost perfectly maintain intracellular<br />
homeostasis <strong>and</strong> where pronounced acidification<br />
is only observed in extreme situations, PCr may in fact<br />
represent a functional improvement over PArg, since it<br />
can efficiently buffer the cytosolic phosphorylation potential<br />
at a higher value. In many invertebrates, on the other<br />
h<strong>and</strong>, changes in the extracellular environment may cause<br />
pronounced fluctuations in intracellular composition<br />
(e.g., pH, temperature, oxygen <strong>and</strong> substrate concentrations).<br />
Intracellular acidosis, for example, is a common<br />
occurrence, especially in mollusks (see Ref. 221). Under<br />
these conditions, PCr may be quite susceptible to hydrolysis,<br />
resulting in net energy dissipation. PArg <strong>and</strong> the<br />
other invertebrate phosphagens, on the other h<strong>and</strong>, are