Creatine and Creatinine Metabolism - Physiological Reviews

1178 MARKUS WYSS AND RIMA KADDURAH-DAOUK Volume 80
Cr supplementation was recognized to increase the total
Cr concentration in muscle (for references, see Refs. 144,
305, 368). Nowadays, Cr supplementation most commonly
involves a “loading phase” of 5–7 days, where 20–30 g of
Cr monohydrate are consumed per day, and a “maintenance
phase” with 2–5 g Cr/day. These values must be
compared with a daily Cr requirement of only 2 g (provided
through the diet or by de novo biosynthesis) and
with a Cr content of raw meat of �4–5 g/kg. Because, in
addition, Cr is partially converted to Crn during cooking,
it goes without saying that it is virtually impossible by
natural means to ingest 20 g Cr/day.
Cr loading with 20–30 g/day was shown to significantly
increase the muscle concentrations of Cr, PCr, and
total Cr while having no effect on ATP concentration (for
reviews, see Refs. 674, 1106; see also Refs. 918, 1040,
1041). Large interindividual differences were noted, both
as far as initial Cr concentration and responsiveness to Cr
supplementation are concerned. Some subjects, particularly
those with a high initial muscle concentration of Cr,
did not respond to Cr supplementation. On the other
hand, the greatest increase in total Cr content, e.g., from
114 to 156 mmol � (kg dry mass) �1 , was observed in subjects
with a low initial Cr content (307, 338). Muscle
concentrations of total Cr remain elevated for at least 30
days or 10 wk when supplementation is continued at a
rate of 2 or 5 g/day, respectively (387, 1040). A similar
increase in total muscle Cr concentration was achieved by
Cr supplementation over 28 days at a rate of 3 g/day,
suggesting favorable effects also in the near-physiological
range (46, 387). Upon discontinuation of Cr supplementation,
a 28-day washout period was sufficient to return
the Cr and PCr concentrations to baseline values (232,
387, 1040).
Resting PCr concentration in the quadriceps muscle
was found to be lower in middle-aged (58 � 4 yr) compared
with young subjects [30 � 5 yr; 35.0 vs. 39.5
mmol � (kg wet wt) �1 ], and middle-aged subjects also
showed a lower PCr resynthesis rate between exercise
bouts (913). Cr supplementation (0.3 g � kg �1 � day �1 for 5
days) increased both resting PCr concentration and PCr
resynthesis rate more in the middle-aged than in the
young group, so that the values became identical. In addition,
Cr supplementation significantly increased time to
exhaustion in both groups combined from 118 to 154 s.
These results suggest that the ergogenic potential of Cr
supplementation even increases with age.
Cr supplementation increased the urinary excretion
of Crn, which is in line with elevated muscle concentrations
of Cr and PCr (145, 225, 387, 823, 1040, 1041). Upon
discontinuation of Cr ingestion, urinary Crn excretion
slowly returned to the presupplementation value.
A few studies addressed the question of whether Cr
accumulation can be influenced by dietary or other factors.
In fact, exercise further stimulates Cr uptake into
muscle. When subjects performed 1hofstrenuous exercise
per day with only one leg, Cr supplementation increased
the mean muscle Cr content from 118 to 149
mmol � (kg dry mass) �1 in the control leg, but to 162
mmol � (kg dry mass) �1 in the exercised leg (338; see also
Ref. 522). Supplementation and exercise resulted in a
total Cr content in one subject of as much as 183
mmol � (kg dry mass) �1 , suggesting that the upper limit of
total muscle Cr concentration of 155–160 mmol � (kg dry
mass) �1 proposed by some authors (see Refs. 46, 305, 441,
674, 1106) can be surpassed at least under certain conditions.
Simultaneous ingestion of relatively large amounts
of carbohydrates (glucose and simple sugars) also augments
Cr retention in muscle (302, 303). This effect seems
to be mediated indirectly by insulin, which increased in
plasma almost 20-fold within 20 min of carbohydrate ingestion
(see also Ref. 943). In vitro and in vivo work on rat
skeletal muscle, mouse myoblasts, and humans suggests
that insulin may stimulate Cr uptake (see sect. IVB). That
the composition of the supplement may in fact be critical
for the ergogenic effect of Cr has been demonstrated in a
study showing no significant (or considerably smaller)
improvements in exercise performance with Cr supplementation
alone; however, addition of glucose, taurine,
and electrolytes to the Cr supplement promoted significant
increases in both one repetition maximum bench
press and vertical jump performance, as well as a decrease
in 100-yard sprint times (952). It should be noted
that the ergogenic action of Cr seems to be counteracted
by high-dose ingestion of Cr during exercise that also
resulted in postexercise distress and even syncope (1038).
Not all of the ingested Cr can be retained in the body.
While a high proportion of Cr is usually retained in the
initial days of Cr supplementation, urinary Cr excretion
progressively increases with continued ingestion of Cr
(62, 116, 338, 583, 823, 1040). Urinary excretion of Cr can,
however, be reduced significantly by simultaneous ingestion
of carbohydrates (302, 303). Because guanidinoacetate
and Cr compete for the same reabsorption mechanism
in the kidney, Cr supplementation also stimulates
urinary excretion of guanidinoacetate (368). Finally, as
discussed in sections IVA and IXA, an increase in the
plasma concentration of Cr, from a normal level of �25–
100 �M to up to 1.8 mM 1 h after Cr supplementation (303,
338, 776, 1035), will downregulate endogenous Cr biosynthesis
by repressing AGAT expression. This downregulation
is fully reversible (see Ref. 1077).
In most studies, Cr supplementation was accompanied
by a significant increase in body weight. Although in
most cases this weight gain was in the range of 1–2 kg,
higher values of 3–5 kg have occasionally been reported
(for reviews, see Refs. 442, 674, 1106; see also Refs. 116,
302, 303, 387, 418, 583, 627). The underlying basis for this
weight gain is still unclear. It may be due to stimulation of
muscle protein synthesis (255, 406, 1153) or to increased