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 1181<br />
may be relevant for muscle performance during highintensity,<br />
intermittent exercise <strong>and</strong> might allow harder<br />
training units, mostly in explosive sports disciplines, but<br />
possibly also in endurance sports. Hespel <strong>and</strong> co-workers<br />
(1051, 1041), however, reported that in their studies, Cr<br />
supplementation (20–25 g/day for 2–5 days) had no effect<br />
on PCr resynthesis rate but accelerated muscle relaxation<br />
during intermittent brief isometric muscle contractions,<br />
which also may contribute to the ergogenic action of Cr.<br />
More research is required to solve this controversy.<br />
To further study the metabolic effects of Cr supplementation,<br />
plasma ammonia <strong>and</strong> hypoxanthine concentrations<br />
were evaluated as measures of adenine nucleotide<br />
degradation, <strong>and</strong> plasma as well as muscle lactate<br />
concentrations as measures of anaerobic glycolysis. In<br />
short-duration, high-intensity, anaerobic exercise lasting<br />
�30 s, Cr supplementation sometimes decreased plasma<br />
accumulation of ammonia <strong>and</strong> hypoxanthine as well as<br />
the loss of muscular ATP during <strong>and</strong> after exercise, despite<br />
no change or even an increase in total work performed<br />
(see Refs. 113, 308, 441). In these exercise tests,<br />
blood lactate levels <strong>and</strong> accumulation of lactate in muscle<br />
were either decreased (see Refs. 47, 441) or not affected<br />
by Cr supplementation (see Refs. 1, 51, 308, 441, 765). On<br />
the other h<strong>and</strong>, Cr supplementation increased blood lactate<br />
accumulation in maximal kayak ergometer tests of<br />
150- <strong>and</strong> 300-s duration where it was associated with a<br />
higher work performance (627), <strong>and</strong> in a treadmill run of<br />
3–6 min until exhaustion, with this latter finding not being<br />
readily explainable (45). In a series of supramaximal<br />
1-min cycling bouts, no changes were caused by Cr supplementation<br />
in the intramuscular concentrations of ATP,<br />
ADP, AMP, IMP, ammonia, glycogen, <strong>and</strong> lactate as well<br />
as in blood pH, lactate, <strong>and</strong> ammonia concentrations before<br />
<strong>and</strong> after exercise (232). During more prolonged,<br />
submaximal exercise, performed by continuous running<br />
at 10 km/h on a treadmill at predetermined workloads of<br />
50, 60, 65, 70, 75, 80, <strong>and</strong> 90% of maximal oxygen uptake<br />
for 6 min each, as well as during subsequent recovery, Cr<br />
supplementation (20 g/day for 5 days) had no effect on<br />
respiratory gas exchange (oxygen consumption, respiratory<br />
exchange ratio, carbon dioxide production, or expired<br />
gas volume), blood lactate concentration, or heart<br />
rate (954).<br />
In mildly hypertriglyceridemic <strong>and</strong> hypercholesterolemic<br />
subjects, Cr supplementation (20 g/day for 5 days,<br />
followed by 10 g/day for 51 days) reduced the plasma<br />
concentrations of total cholesterol, triacylglycerols, <strong>and</strong><br />
very-low-density lipoprotein-C by 5–26% while having no<br />
effect on the concentrations of low-density lipoprotein-C,<br />
high-density lipoprotein-C, <strong>and</strong> Crn (208). In addition, Cr<br />
supplementation slightly but significantly increased<br />
plasma urea nitrogen <strong>and</strong> urinary uric acid excretion in<br />
women <strong>and</strong> showed a trend to decrease the blood glucose<br />
level in men (208, 1040).<br />
In a study on the effect of intravenous injection of<br />
PCr (0.3 g at 24 h <strong>and</strong> 30 min before exercise) on the cycle<br />
ergometer performance of untrained volunteers, total<br />
work <strong>and</strong> anaerobic threshold were increased by 5.8–<br />
6.8% in a protocol involving a stepwise increase in physical<br />
exercise until exhaustion (1069). On the other h<strong>and</strong>,<br />
accumulation of lactate <strong>and</strong> lactate dehydrogenase in the<br />
blood was decreased. PCr administration also improved<br />
exercise tolerance during prolonged submaximal exercise<br />
at 70% of the individual’s maximal oxygen uptake. Favorable<br />
effects of PCr administration on muscle performance<br />
were also observed in other investigations on trained<br />
cyclists, other athletes, or patients during recovery from<br />
leg immobilization (see Ref. 128). Whether intravenous<br />
injection of PCr <strong>and</strong> oral Cr supplementation share the<br />
same mechanism of action is at present unclear.<br />
The studies on humans have recently been complemented<br />
by analogous experiments on rats. Cr supplementation<br />
for 10 days at a rate of 3.3 g � (kg diet) �1 significantly<br />
increased the concentrations of Cr, PCr, <strong>and</strong> total<br />
Cr in both plantaris <strong>and</strong> soleus muscle, with no further<br />
increase when supplementation was continued for another<br />
18 days (92). While having no effect on CK activity<br />
<strong>and</strong> myosin heavy chain distribution, Cr supplementation<br />
increased citrate synthase activity in soleus muscle of<br />
sedentary rats <strong>and</strong>, in combination with high-intensity run<br />
training, caused a modest hypertrophy as well as a 30%<br />
increase in citrate synthase activity in plantaris muscle. In<br />
both run duration (60 m/min, 15% inclination) <strong>and</strong> repetitive<br />
interval treadmill performance tests (30-s intervals of<br />
high-intensity running separated by 30-s recovery periods),<br />
Cr supplementation alone had a modest ergogenic<br />
effect. However, the combination of run training <strong>and</strong> Cr<br />
supplementation resulted in a marked enhancement of<br />
performance that may be due to an increase in both<br />
anaerobic (PCr stores) <strong>and</strong> aerobic capacity (citrate synthase<br />
activity). On the other h<strong>and</strong>, Cr supplementation<br />
(0.2 g daily for �10 wk) decreased mitochondrial �-hydroxyacyl-CoA<br />
dehydrogenase activity in rat soleus muscle<br />
by 47% (983), <strong>and</strong> endurance performance was unchanged<br />
or tended to be compromised in Cr-fed rats (983,<br />
1073, 1074). Cr supplementation (400 mg � kg �1 � day �1<br />
subcutaneously for 7 days) increased the blood plasma<br />
concentration of urea, particularly in endurance-trained<br />
rats, but did not significantly affect glycogen levels in rat<br />
liver <strong>and</strong> skeletal muscle before or 24 h after exhaustive<br />
swimming (734; see also Ref. 983). In a preliminary study,<br />
excessive Cr supplementation (4% in the diet plus 50 mM<br />
in the drinking water) over an unrealistically long period<br />
of 3–6 mo seemed to decrease the expression of the Cr<br />
transporter in rat quadriceps muscle, whereas GPA administration<br />
(2.5% in the diet plus 1% in the drinking<br />
water) may have a slight opposite effect (317). Both an<br />
increased plasma urea level <strong>and</strong> decreased Cr transporter<br />
expression would be undesirable so that these aspects