Creatine and Creatinine Metabolism - Physiological Reviews

July 2000 CREATINE AND CREATININE METABOLISM 1181
may be relevant for muscle performance during highintensity,
intermittent exercise and might allow harder
training units, mostly in explosive sports disciplines, but
possibly also in endurance sports. Hespel and co-workers
(1051, 1041), however, reported that in their studies, Cr
supplementation (20–25 g/day for 2–5 days) had no effect
on PCr resynthesis rate but accelerated muscle relaxation
during intermittent brief isometric muscle contractions,
which also may contribute to the ergogenic action of Cr.
More research is required to solve this controversy.
To further study the metabolic effects of Cr supplementation,
plasma ammonia and hypoxanthine concentrations
were evaluated as measures of adenine nucleotide
degradation, and plasma as well as muscle lactate
concentrations as measures of anaerobic glycolysis. In
short-duration, high-intensity, anaerobic exercise lasting
�30 s, Cr supplementation sometimes decreased plasma
accumulation of ammonia and hypoxanthine as well as
the loss of muscular ATP during and after exercise, despite
no change or even an increase in total work performed
(see Refs. 113, 308, 441). In these exercise tests,
blood lactate levels and accumulation of lactate in muscle
were either decreased (see Refs. 47, 441) or not affected
by Cr supplementation (see Refs. 1, 51, 308, 441, 765). On
the other hand, Cr supplementation increased blood lactate
accumulation in maximal kayak ergometer tests of
150- and 300-s duration where it was associated with a
higher work performance (627), and in a treadmill run of
3–6 min until exhaustion, with this latter finding not being
readily explainable (45). In a series of supramaximal
1-min cycling bouts, no changes were caused by Cr supplementation
in the intramuscular concentrations of ATP,
ADP, AMP, IMP, ammonia, glycogen, and lactate as well
as in blood pH, lactate, and ammonia concentrations before
and after exercise (232). During more prolonged,
submaximal exercise, performed by continuous running
at 10 km/h on a treadmill at predetermined workloads of
50, 60, 65, 70, 75, 80, and 90% of maximal oxygen uptake
for 6 min each, as well as during subsequent recovery, Cr
supplementation (20 g/day for 5 days) had no effect on
respiratory gas exchange (oxygen consumption, respiratory
exchange ratio, carbon dioxide production, or expired
gas volume), blood lactate concentration, or heart
rate (954).
In mildly hypertriglyceridemic and hypercholesterolemic
subjects, Cr supplementation (20 g/day for 5 days,
followed by 10 g/day for 51 days) reduced the plasma
concentrations of total cholesterol, triacylglycerols, and
very-low-density lipoprotein-C by 5–26% while having no
effect on the concentrations of low-density lipoprotein-C,
high-density lipoprotein-C, and Crn (208). In addition, Cr
supplementation slightly but significantly increased
plasma urea nitrogen and urinary uric acid excretion in
women and showed a trend to decrease the blood glucose
level in men (208, 1040).
In a study on the effect of intravenous injection of
PCr (0.3 g at 24 h and 30 min before exercise) on the cycle
ergometer performance of untrained volunteers, total
work and anaerobic threshold were increased by 5.8–
6.8% in a protocol involving a stepwise increase in physical
exercise until exhaustion (1069). On the other hand,
accumulation of lactate and lactate dehydrogenase in the
blood was decreased. PCr administration also improved
exercise tolerance during prolonged submaximal exercise
at 70% of the individual’s maximal oxygen uptake. Favorable
effects of PCr administration on muscle performance
were also observed in other investigations on trained
cyclists, other athletes, or patients during recovery from
leg immobilization (see Ref. 128). Whether intravenous
injection of PCr and oral Cr supplementation share the
same mechanism of action is at present unclear.
The studies on humans have recently been complemented
by analogous experiments on rats. Cr supplementation
for 10 days at a rate of 3.3 g � (kg diet) �1 significantly
increased the concentrations of Cr, PCr, and total
Cr in both plantaris and soleus muscle, with no further
increase when supplementation was continued for another
18 days (92). While having no effect on CK activity
and myosin heavy chain distribution, Cr supplementation
increased citrate synthase activity in soleus muscle of
sedentary rats and, in combination with high-intensity run
training, caused a modest hypertrophy as well as a 30%
increase in citrate synthase activity in plantaris muscle. In
both run duration (60 m/min, 15% inclination) and repetitive
interval treadmill performance tests (30-s intervals of
high-intensity running separated by 30-s recovery periods),
Cr supplementation alone had a modest ergogenic
effect. However, the combination of run training and Cr
supplementation resulted in a marked enhancement of
performance that may be due to an increase in both
anaerobic (PCr stores) and aerobic capacity (citrate synthase
activity). On the other hand, Cr supplementation
(0.2 g daily for �10 wk) decreased mitochondrial �-hydroxyacyl-CoA
dehydrogenase activity in rat soleus muscle
by 47% (983), and endurance performance was unchanged
or tended to be compromised in Cr-fed rats (983,
1073, 1074). Cr supplementation (400 mg � kg �1 � day �1
subcutaneously for 7 days) increased the blood plasma
concentration of urea, particularly in endurance-trained
rats, but did not significantly affect glycogen levels in rat
liver and skeletal muscle before or 24 h after exhaustive
swimming (734; see also Ref. 983). In a preliminary study,
excessive Cr supplementation (4% in the diet plus 50 mM
in the drinking water) over an unrealistically long period
of 3–6 mo seemed to decrease the expression of the Cr
transporter in rat quadriceps muscle, whereas GPA administration
(2.5% in the diet plus 1% in the drinking
water) may have a slight opposite effect (317). Both an
increased plasma urea level and decreased Cr transporter
expression would be undesirable so that these aspects