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