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The effects of creatine pyruvate and creatine citrate on performance during high intensity exercise

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A double-blind, placebo-controlled, randomized study was performed to evaluate the effect of oral creatine pyruvate (Cr-Pyr) and creatine citrate (Cr-Cit) supplementation on exercise performance in healthy young athletes. Performance during intermittent handgrip exercise of maximal intensity was evaluated before (pretest) and after (posttest) 28 days of Cr-Pyr (5 g/d, n = 16), Cr-Cit (5 g/d, n = 16) or placebo (pla, 5 g/d, n = 17) intake. Subjects performed ten 15-sec exercise intervals, each followed by 45 sec rest periods. Cr-Pyr (p < 0.001) and Cr-Cit (p < 0.01) significantly increased mean power over all intervals. Cr-Cit increased force during the first and second interval (p < 0.01) compared to placebo. The effect of Cr-Cit on force decreased over time and the improvement was not significant at the sixth and ninth interval, whereas Cr-Pyr significantly increased force during all intervals (p < 0.001). Cr-Pyr (p < 0.001) and Cr-Cit (p < 0.01) resulted in an increase in contraction velocity, whereas only Cr-Pyr intake significantly (p < 0.01) increased relaxation velocity. Oxygen consumption measured during rest periods significantly increased with Cr-Pyr (p < 0.05), whereas Cr-Cit and placebo intake did not result in significant improvements. It is concluded that four weeks of Cr-Pyr and Cr-Cit intake significantly improves performance during intermittent handgrip exercise of maximal intensity and that Cr-Pyr might benefit endurance, due to enhanced activity of the aerobic metabolism.
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BioMed Central
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Journal of the International Society
of Sports Nutrition
Open Access
Research article
The effects of creatine pyruvate and creatine citrate on
performance during high intensity exercise
Ralf Jäger*
1
, Jan Metzger
2
, Karin Lautmann
2
, Vladimir Shushakov
2
,
Martin Purpura
1
, Kurt-Reiner Geiss
3
and Norbert Maassen
2
Address:
1
Increnovo LLC, 2138 E Lafayette Pl, Milwaukee, WI 53202, USA,
2
Department of Sports Physiology, Hannover Medical School, Carl-
Neuberg-Str. 1, D-30625 Hannover, Germany and
3
ISME, Weingartenstr. 2, D-64546 Mörfelden-Walldorf, Germany
Email: Ralf Jäger* - ralf.jaeger@increnovo.com; Jan Metzger - Metzger.Jan@mh-hannover.de; Karin Lautmann - Lautmann.Karin@mh-
hannover.de; Vladimir Shushakov - Shushakov.Vladimir@mh-hannover.de; Martin Purpura - martin.purpura@increnovo.com; Kurt-
Reiner Geiss - isme.gmbh@t-online.de; Norbert Maassen - Maassen.Norbert@mh-hannover.de
* Corresponding author
Abstract
Background: A double-blind, placebo-controlled, randomized study was performed to evaluate
the effect of oral creatine pyruvate (Cr-Pyr) and creatine citrate (Cr-Cit) supplementation on
exercise performance in healthy young athletes.
Methods: Performance during intermittent handgrip exercise of maximal intensity was evaluated
before (pretest) and after (posttest) 28 days of Cr-Pyr (5 g/d, n = 16), Cr-Cit (5 g/d, n = 16) or
placebo (pla, 5 g/d, n = 17) intake. Subjects performed ten 15-sec exercise intervals, each followed
by 45 sec rest periods.
Results: Cr-Pyr (p < 0.001) and Cr-Cit (p < 0.01) significantly increased mean power over all
intervals. Cr-Cit increased force during the first and second interval (p < 0.01) compared to
placebo. The effect of Cr-Cit on force decreased over time and the improvement was not
significant at the sixth and ninth interval, whereas Cr-Pyr significantly increased force during all
intervals (p < 0.001). Cr-Pyr (p < 0.001) and Cr-Cit (p < 0.01) resulted in an increase in contraction
velocity, whereas only Cr-Pyr intake significantly (p < 0.01) increased relaxation velocity. Oxygen
consumption measured during rest periods significantly increased with Cr-Pyr (p < 0.05), whereas
Cr-Cit and placebo intake did not result in significant improvements.
Conclusion: It is concluded that four weeks of Cr-Pyr and Cr-Cit intake significantly improves
performance during intermittent handgrip exercise of maximal intensity and that Cr-Pyr might
benefit endurance, due to enhanced activity of the aerobic metabolism.
Background
Creatine monohydrate supplementation has been found
to enhance high intensity intermittent athletic perform-
ance [1]. Long-term creatine supplementation increases
the effects of resistance training on muscle volume,
strength and power [2,3]. Short-term creatine supplemen-
tation results in an increase of muscle force and power
output during intermittent exercise, even in the absence of
Published: 13 February 2008
Journal of the International Society of Sports Nutrition 2008, 5:4 doi:10.1186/1550-2783-5-
4
Received: 21 June 2007
Accepted: 13 February 2008
This article is available from: http://www.jissn.com/content/5/1/4
© 2008 Jäger et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0
),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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resistance training [4,5]. Facilitated muscle phosphocreat-
ine resynthesis [6] and more rapid and efficient recovery
periods [5,7] have been stated as proposed mechanisms
for this ergogenic effect. However, a majority of studies
suggest that creatine supplementation does not improve
endurance exercise capacity [8,9]. The effect of creatine
supplementation can be highly variable amongst individ-
uals [10] and low initial muscle creatine content has been
found to be a prerequisite for maximum ergogenic effects
[6,11]. Total muscle creatine concentration can be
increased by approximate 20% using a loading dose of 20
g/d for 6 days followed by a maintenance dose of 2 g/d
[12]. A more gradual increase can be achieved by 28-days
of low dose (3 g/d) supplementation [12], however, stud-
ies examining the effect of slowly loading the muscle with
creatine (3 g/d for six weeks [13], 1 g/d or 5 g/d for 10
weeks [14]) on exercise performance showed no signifi-
cant effect over placebo.
Combining creatine, a weak base which is usually
ingested in the form of creatine monohydrate, with an
acid intended to boosting endurance exercise capacity
such as pyruvic acid, could ultimately benefit athletes
involved in sports combining endurance and high inten-
sity exercise. High-dose pyruvate intake in combination
with dihydroxyacetone can positively influence endur-
ance exercise capacity [15]. Low-dose, short-term supple-
mentation of an inorganic pyruvate salt failed to increase
endurance capability measured by the critical power test
(8.1 g/d) [16], failed to increase endurance performance,
and had no significant effect on energy metabolism dur-
ing exercise in well-trained cyclists (7 g Ca-pyruvate per
day for 7 days) [17], questioning the efficacy of short-
term, low-dose pyruvate administration. The delivery of
orally ingested pyruvate to the skeletal muscle is probably
small due to partial decarboxylation in the stomach and
small intestine, and rapid clearance by the liver to be used
as a gluconeogenic precursor [17]. However, long-term
pyruvate (6 g pyruvate per day for 28 days) intake has
been found to increase plasma pyruvate concentration by
60% (n = 3) [18]. Citric acid might be another suitable
candidate since citrate supplementation has been found
to increase performance in intense exercise lasting
between 2 and 50 min, a duration in which the aerobic
metabolism becomes more important [19,20]; however,
no conclusive evidence exists that citrate supplementation
is able to increase endurance exercise capacity.
A recent bioavailability study on one-time creatine pyru-
vate (Cr-Pyr) and tri-creatine citrate (Cr-Cit) supplemen-
tation showed a significant increase in creatine plasma
levels with Cr-Pyr in comparison to creatine monohydrate
[21]. Two studies investigating endurance exercise capac-
ity of short-term Cr-Pyr supplementation showed mixed
results. 7 days of 7 g per day Cr-Pyr supplementation did
not beneficially impact endurance capacity or intermittent
sprint performance in well-trained cyclists [22], whereas 5
days of 7.5 g per day Cr-Pyr intake increased paddling
speed and resulted in decreased lactate concentrations in
Olympic canoeists suggesting an increase in aerobic
metabolism [23]. A combination of creatine monohy-
drate and calcium pyruvate was not more effective than
creatine monohydrate supplementation to enhancing
maximum strength and power during 5-weeks of in-sea-
son college football training [24]. High-dose, short-term
Cr-Cit supplementation (4 × 5 g Cr-Cit per day for 5 days)
has been found to increase anaerobic working capacity
(AWC) in healthy physically active women [25] and is
able to delay the onset of neuromuscular fatigue during
cycle ergometry [26].
This study investigates the effects of 28-days of Cr-Pyr, Cr-
Cit or placebo supplementation on endurance capacity
and intermittent handgrip power in healthy young ath-
letes using a daily dose intended to slowly load the muscle
with creatine (5 g/d of Cr-Pyr or Cr-Cit, equaling approx-
imate 3 g/d of creatine). Intermittent handgrip exercise of
maximal intensity is an exercise that combines endurance
as well as high intensity elements. This kind of exercise
allows investigating the effects of Cr-Pyr and Cr-Cit sup-
plementation to boosting power and endurance exercise
capacity.
Methods
Subjects
Forty-nine healthy male subjects participated in this
study. All subjects in this investigation participated in a
familiarization session. During the familiarization ses-
sion, subjects were informed as to the experimental proce-
dures, completed a personal/medical history form,
creatine supplementation history form and signed
informed consent statements in adherence with the
human subject's guidelines of the American College of
Sports Medicine. The study was approved by the Ethical
Review Committee of the University of Paderborn. Sub-
ject characteristics are presented in Table 1. No subject in
this trial was a vegetarian with all subjects reportedly con-
suming meat in their daily diet. Exclusion criteria on
admission were creatine supplementation within a period
of 3 months prior to the experiments or the intake of any
other nutritional supplement or medication at the time of
the study. The subjects were instructed to avoid changes in
their diet and training habits during the study.
Study Protocol
A double-blind, placebo-controlled study was performed
over a period of 5 weeks. The subjects performed 3 exer-
cise tests at the same time of the day (day 1: incremental
test, day 8: pre-test, day 35: post-test).
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Choice of muscle group and type of exercise
Handgrip exercise is a simple movement with low
dependence on coordination. The exercise targets a spe-
cific muscle group while the use of auxiliary muscles is
excluded. During exercise of this muscle group, blood
samples from the working muscles can easily be taken
from a cubital vein [27]. The tone of the sympathetic
nerve system [28] and the composition of the arterial
blood remain almost unchanged. Any change of a param-
eter of cubital venous blood can almost exclusively be
attributed to the working muscles. Thus, differences
between the trials can be interpreted as consequences of
the different supplementations on muscle metabolism.
Incremental test
Handgrip exercise was performed with the arm stretched
in a horizontal position. The hand was lying on the hand-
grip and the arm was supported under the elbow. All sub-
jects had to use the right hand in this exercise. The
handgrip was connected to a basket that could be loaded
with variable weights. Displacement of the weights -at
maximum 3 cm- was recorded through an inductive
device connected to the basket (see Figure 1). The seat and
the arm support were adjusted for each subject to main-
tain a constant angle at the shoulder between subjects.
Maximum forearm performance was measured starting at
a weight of 7.5 kg. The weight was increased by 2.5 kg
every 3 minutes until subjective fatigue of the muscle
group. The contraction frequency was 24 times per
minute. A metronome was placed in sight of the subject to
facilitate sustaining the correct contraction frequency.
Pre and post-test
After an overnight fast the subjects reported to the lab and
their anthropometrical data was taken (age, height, body
weight, body fat (measured by bioelectrical impedance
analysis) and forearm circumference). Afterwards, blood
was sampled from a cubital vein to determine kidney
function (creatinine, urea), fat metabolism (free fatty
acids, Cholesterol (total, HDL, LDL)) and liver function
(gamma GT, OT, PT). Exercise started 45 min after blood
sampling and after having a standardized light breakfast
consisting of two rolls and jam (see Figure 2).
To test the effects of Cr-Pyr and Cr-Cit the subjects per-
formed intermittent, dynamic handgrip exercise of high
intensity. The weight of the basket was 80% of the maxi-
mum weight reached in the incremental test. The subjects
were instructed to squeeze the handgrip as many times as
possible during a 15 sec exercise period. Ten intervals were
carried out separated by breaks of 45 sec. A fan was placed
above the forearm to reduce skin blood flow by cooling.
Blood samples were taken before and after the 1
st
, 2
nd
, 6
th
,
9
th
and 10
th
interval from a cubital vein. Blood hemo-
globin ([Hb]) and oxy-hemoglobin concentrations
([HbO
2
], OSM III, Radiometer, Copenhagen) as well as
hematocrit (Hct, microcentrifugation at 19500 g, Biofuge,
Schematic presentation of the experimental set upFigure 1
Schematic presentation of the experimental set up.
The working arm was in a horizontal position supported
under the elbow. The handgrip had to be squeezed with the
highest contraction frequency possible. The maximum dis-
placement was 3 cm. The fan was used to reduce skin blood
flow by cooling.
elbow support
fan
adjustable seat
handgrip
weights
inductive device
computer
Table 1: Anthropometrical data and blood values after overnight fast
Cr-Pyr P Value (pre/post) Cr-Cit P Value (pre/post) Pla P Value (pre/post)
Age (years) 26.8 ± 3.6 26.7 ± 4.4 26.3 ± 4.5
Height (cm) 184.4 ± 4.9 182.7 ± 6.2 180.2 ± 5.4
Bodyweight (kg) pre 81.7 ± 10.9 < 0.001 78.1 ± 9.0 < 0.001 77.6 ± 7.3 n.s.
post 83.2 ± 10.7 79.5 ± 9.2 77.7 ± 7.3
Body Fat (%) pre 16.7 ± 4.6 n.s. 15.0 ± 4.3 n.s. 15.0 ± 5.2 n.s.
post 16.6 ± 4.8 14.7 ± 3.9 14.8 ± 7.3
Forearm circumference
(cm)
pre 29.0 ± 2.2 < 0.05 28.1 ± 1.5 < 0.001 28.3 ± 1.2 n.s.
post 29.7 ± 2.2 28.6 ± 1.5 28.6 ± 1.2
Creatine (µmol/l) pre 94.7 ± 5.5 < 0.001 98.8 ± 8.4 < 0.05 93.1 ± 9.0 n.s.
post 105.1 ± 6.7 108.3 ± 14.1 93.5 ± 8.5
Means ± SD, n.s. = not significant.
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Hereaus) were measured. Arterio-venous difference in
oxygen (a-vDO
2
) was calculated assuming an oxygen sat-
uration of 95% in the arterial blood. Lactate concentra-
tion ([Lac]) was measured polarimetrically in cubital
venous blood (Biosen 5030, EKF Barleben, Germany).
Ammonia concentration [NH
3
] was determined in
plasma (test no. 1877984, Roche, Mannheim, Germany).
In order to calculate NH
3
-release it was assumed that arte-
rial [NH
3
] remained constant during the present exercise
protocol. The fraction of NH
3
entering the red cells was
neglected. Blood flow was measured by venous occlusion
plethysmography during the recovery periods between
intervals 6 and 7.
Calculation of mechanical data
The first 3 contractions of each interval were discarded
because some of the subjects adjusted the position of their
hand. Work per contraction (J) was calculated from the
displacement and the lifted weight. Total work was calcu-
lated from the sum of work of each contraction performed
in the first, second, sixth and ninth interval. Mean power
was calculated as total work divided by the time evalu-
ated. Contraction velocity was calculated from displace-
ment and contraction time. In the same way, relaxation
velocity was calculated. Force was calculated from the
contraction velocity and the lifted weight. The 10
th
inter-
val was excluded from the evaluation as subjects often
used additional muscles (movements of upper body) dur-
ing the last interval.
Experimental conditions
The subjects were assigned in random order to either the
Cr-Pyr (n = 16), the Cr-Cit (n = 16) or the placebo (pla, n
= 17) group. It was attempted to match groups for body
mass/height ratio and the maximum weight achieved in
the incremental test. Athletes with a high degree of hand-
grip utilization (martial arts, wrestling, etc) could possibly
benefit to a greater degree due to training effect, as
opposed to sports that neglect the upper extremity/hand
grip (track, soccer, etc). To avoid potential differences
between groups, athletes with a high degree of handgrip
utilization have been equally distributed between groups.
The 28-day supplementation period was started immedi-
ately after the pre-test and was continued until the day
before the post-test. Subjects either received Cr-Pyr
(Creapure™ Pyruvate, Degussa, Germany, containing 60%
creatine and 40% pyruvate) or Cr-Cit (Creapure™ Citrate,
Degussa, Germany, containing 65% creatine and 35% cit-
rate) in form of lemon flavored effervescent tablets at a
dose of 5 g per day, while the others received correspond-
ing placebo supplements. Cr-Pyr and Cr-Cit contained
<100 ppm creatinine, whilst dicyandiamide and dihyrdo-
triazine levels and polymeric pyruvates in CrPyr were not
detectable by HPLC. The subjects were instructed to take
the effervescent tablets (2 in the morning, 1 at noon and
2 in the evening) after the main meals accompanied by a
carbohydrate rich drink. Intake of coffee and soft drinks
containing caffeine was restricted to two cups a day.
Forearm exercise started 45 min after the first blood sample had been takenFigure 2
Forearm exercise started 45 min after the first blood sample had been taken. Exercise consisted of 10 maximal
bouts of 15 sec separated by a 45 sec rest period. Timing of blood samples are indicated by small arrows (open arrow: pre
exercise sample; filled arrow: post exercise sample).
anthro
pometrical
data
45minutes 10
exercise
light
breakfast
2 43 5 6 7 8 91 10
forearm exercise
-
pometrical
data
45minutes
blood sampling
after over night fast
rest
light
breakfast
2 43 5 6 7 8 91 10
10 minutes
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Statistics
Group data were expressed as mean ± SD and statistical
significance was set at the p < 0.05 level. Subjects' charac-
teristics before the investigation were compared using
ANOVA. Pre and Post differences of anthropometric data
and total means were analyzed by two-way ANOVA for
repeated measures with post-hoc t-test considering the
multi-comparison problem (Holm-Sidak). Force and
relaxation velocity was analyzed by three-way ANOVA. In
case of significant main effects for the treatment the effects
within the groups were separately analyzed by a two-way
ANOVA with repeated measurement in both factors.
Results
Anthropometric data and blood parameters
Body weight increased in both creatine groups by a similar
amount (p < 0.001, Table 1), whereas the weight in the
placebo-group remained unchanged. Circumference of
the forearm increased significantly in both creatine groups
(p < 0.01, Table 1). Cr-Pyr and Cr-Cit were well tolerated.
Creatinine levels increased significantly in both creatine
groups but remained within the normal range. Data for all
other measured blood parameters were in the normal
range and no difference between groups could be deter-
mined.
Performance data
The pre-test performance data was not statistically differ-
ent among all groups. Supplementation with Cr-Pyr (p <
0.001) and Cr-Cit (p < 0.02) resulted in a significant
increase in mean power (see Figure 3), while the placebo
group showed no increase in power. A-vDiff in O
2
increased insignificantly (p > 0.05) in both creatine
groups. The oxygen uptake to mean power ratio was
slightly reduced with Cr-Cit and Cr-Pyr, however, the
changes were not statistically significant (p > 0.05, Figure
3). Blood flow was enhanced with Cr-Pyr but decreased
slightly with Cr-Cit, however, both were not statistically
significant (p > 0.05). A-vDiff in O
2
and blood flow meas-
ured during the recovery periods significantly increased (p
< 0.05) in the Cr-Pyr group concordantly with muscular
oxygen consumption compared to the pre-tests. Venous
blood lactate levels remained unchanged with either treat-
ment. Mean muscular NH
3
release was significantly
reduced in the Cr-Cit group (p < 0.05). The NH
3
release
per unit of power decreased after Cr-Pyr and Cr-Cit treat-
ments, conversely, only Cr-Cit group resulted in signifi-
cant changes (p < 0.015, Figure 3).
The contraction velocity increased 24% with Cr-Pyr (p <
0.01) and 20% with Cr-Cit (p < 0.01, Table 2). This
increase is accompanied by a significant increase in force
(p < 0.001) and relaxation velocity (p < 0.01) in the Cr-
Pyr group. The Cr-Cit group showed a significant increase
in force (p < 0.01), however, the change in relaxation
velocity was not significant. In addition, Cr-Cit signifi-
cantly increased force only during the first two intervals,
when compared to placebo. The effect of Cr-Cit on force
decreased over time and the improvement was not signif-
icant at interval 6 and 9. The increase in contraction fre-
quency is the major reason for the increase in mean
power.
Discussion
Main findings
The results of this study suggest that 4 weeks of low dose
Cr-Pyr and Cr-Cit intake significantly increased mean
power in comparison to placebo. Cr-Pyr improved con-
traction velocity and reduces fatigability during intermit-
tent exercise of high intensity. Cr-Pyr showed significant
improvements in force during all intervals, whereas the
effects of Cr-Cit decreased and improvements were not
significant during the later intervals. The effect of Cr-Pyr
resulted from an increased contraction and relaxation
speed and is accompanied by enhanced oxygen consump-
tion and blood flow.
Effects on body weight
Daily creatine intake ranged from 0.027 to 0.047 g/kg bw
(mean 0.037) in the Cr-Pyr group and from 0.036 to
0.052 g/kg bw (mean 0.044) in the Cr-Cit group. Despite
a 19% difference in mean creatine dosage per body weight
there was a similar increase in body weight in both creat-
ine groups without significant changes in body fat. Weight
increased in 15 of 16 subjects (94%) with Cr-Pyr and in
14 of 16 subjects (88%) with Cr-Cit. The weight gain is
similar to previously reported weight gains of short-term,
high-dose [6,29] or long-term, low-dose creatine supple-
mentation [12].
Performance enhancement during the first interval
The efficacy of creatine during the first exercise interval is
dependent on the type, the intensity and the duration of
exercise. The exercise must be of high intensity and of a
certain duration allowing PCr stores to drop significantly.
Additionally, the efficacy of creatine supplementation
seems to be dependent on the speed of movement. Dur-
ing isometric exercise, creatine supplementation was
found to have no or small effects on isometric torque pro-
duction [30,31]. An increase in power of about 20% was
measured in fast movements using Wingate tests [32] and
isokinetic tests resulted in moderate improvements of
mean and peak power (6% and 8%, respectively) [33]. Cr-
Cit and Cr-Pyr supplementation increase performance
during the first intervals (see Table 2) in contrast to previ-
ously published data [5,34]. The increase of Cr-Pyr group
was larger compared to the Cr-Cit group; however, the dif-
ference was not significant. The type of exercise used in
this study consisted of a large amount of negative work. If
only the active work is considered (contraction velocity, as
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the reduction of the displacement can be neglected in the
first interval), the improvement is 18 and 15%, respec-
tively, an increase comparable to studies using Wingate
tests.
The increase in performance in both creatine groups at the
beginning of the intermittent exercise is related to an
increased contraction speed. Contraction speed during
fatiguing exercise seems to be reduced when free ADP
increases [35]. Creatine has been reported to increase ATP
re-synthesis and thus reduce the increase in free ADP [36].
This is confirmed by smaller muscular NH
3
release during
exercise which suggests a lower adenosine (AMP) to inos-
ine (IMP) conversion rate (ATP dependent), and thus
lower inorganic phosphate concentration. A reduced NH
3
release or concentration in blood was shown in previous
creatine supplementation studies [33,37]. Creatine sup-
plementation results in reduced hypoxanthine concentra-
tions [37] which might be the explanation for the
observed improvement in the first interval with Cr-Cit
and Cr-Pyr. Relaxation speed increased in both Creatine
groups after the first exercise interval comparable to previ-
ous observations [31]. But the increase was only signifi-
cant with Cr-Pyr.
Performance during repeated intervals
The effect of creatine supplementation on performance in
repeated intervals varies with the diversity of tests and the
beneficial effect decrease at later intervals of the exercise.
Short-term, high-dose creatine supplementation did show
the greatest improvement in performance between inter-
vals 4 and 7 during 10 intervals of 6 sec maximum cycling
exercise [34]. Subsequent intervals showed a decrease in
improvement [34]. Thirty sec exercises intervals resulted
in a decrease of improvement in performance from the
second interval [36], showed no improvement in the third
interval [33], or no difference in the fourth and fifth inter-
val [5]. The beneficial effect of creatine intake on interval
exercise was related to an increased rate of PCr re-synthe-
sis during breaks [6,38] but the existing literature is incon-
clusive. PCr re-synthesis was found not to be enhanced
[38] or even reduced [39] and the rate of synthesis defined
as dPCr*s
-1
after dynamic [38] and isometric work [31]
was not influenced by creatine supplementation. Cycling
with maximal intensity for 30 sec resulted in decreased
PCr levels of 49 mmol kg
-1
dry weight without and 57
mmol kg
-1
dry weight with creatine ingestion [36]. How-
ever, the difference in re-synthesis after exercise was only
2 mmol after 4 min [36] indicating an enhanced accumu-
lation of inorganic phosphate (Pi) during repeated inter-
vals, especially if the breaks are short. Increased Pi might
cause fatigue [40] which might be compensated by an
increased PCr pool during early intervals. PCr decreases
during later intervals [33] and is not able to compensate
the effects of increased Pi. The decrease in performance
relative to the initial performance might be greater after
creatine supplementation [5,31,33,36]. Cr-Cit intake
showed such a performance pattern (see Table 2) indicat-
ing that fatigue occurred in parallel to PCr-breakdown
[41]. If PCr re-synthesis would have been increased after
creatine ingestion, Pi concentration should not increase.
As a result, ATP production must be enhanced resulting in
an increased oxygen uptake during the breaks. Compara-
ble to previous research did Cr-Cit supplementation not
Top: Mean power over all evaluated intervals was signifi-cantly improved with Cr-Pyr and Cr-Cit; middle: ratio of mean oxygen to mean power; bottom: Cr-Cit significantly improves ratio mean ammonia release to mean power (Left: pre supplementation, right: post supplementation, *** P < 0.001; * <0.02)Figure 3
Top: Mean power over all evaluated intervals was sig-
nificantly improved with Cr-Pyr and Cr-Cit; middle:
ratio of mean oxygen to mean power; bottom: Cr-
Cit significantly improves ratio mean ammonia
release to mean power (Left: pre supplementation,
right: post supplementation, *** P < 0.001; * <0.02).
0
2
4
6
8
10
12
14
16
18
0
2
4
6
8
10
12
14
16
Ɣ Ɣ
0
1
2
3
4
5
6
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change oxygen uptake. Therefore the ratio VO
2
to mean
power decreased slightly (see Figure 3), indicating that the
additional energy was derived from anaerobic sources and
that PCr re-synthesis was not enhanced.
The increase in performance with Cr-Pyr during the first
intervals is slightly larger than with Cr-Cit. Moreover, Cr-
Pyr reduces fatigability during all following intervals. The
improvement results from an increase in contraction
velocity during all intervals and an increase in relaxation
velocity [31]. This suggests ADP or Pi levels are reduced
and ATP re-synthesis is increased during exercise, which
should lead to an increased VO
2
. In fact, the improvement
in performance is accompanied by an increase in muscu-
lar VO
2
measured during the breaks. As blood flow
decreases during the 15 sec of exercise due to the high
forces occurring [42], muscular oxygen uptake during
exercise cannot be very high. Therefore, measurements
during the breaks are representative for the oxygen con-
sumption during the exercise period. The ratio VO
2
to
mean power drops similar to Cr-Cit indicating that most
of the improvement is due to the increased VO
2
, however
a small amount of energy is still derived from anaerobic
sources. The energy must be derived from phosphate
stores since lactate levels did not change. The amount is
comparable to that observed after the Cr-Cit supplemen-
tation. The additional amount of aerobic work after Cr-
Pyr supplementation compensates the creatine effect on
ammonia release as the ratio ammonia release to mean
power is not significantly different between pre and post-
tests. Thus the improvement by Cr-Pyr seems to be caused
by a different mechanism perhaps resulting in increased
ADP concentration compared to Cr-Cit.
Possible reasons for the increased aerobic metabolism
A potential creatine effect on the time course of VO
2
is
related to Phosphocreatine breakdown (Bessman cycle or
Phospho-Creatine shuttle) [43]. Cr-Cit and Cr-Pyr supple-
mentation should result in a similar increase in muscle
creatine content; hence varieties in VO
2
cannot be
explained by differences in the Bessman cycle. Addition-
ally, there are some studies showing that VO
2
during exer-
cise is unaffected [9], or the VO
2
-kinetics is even slowed
down after creatine supplementation [44] and oxygen
consumption after exercise of high intensity or during
breaks is unchanged [45].
The observed results suggest additional pyruvate benefits
in the Cr-Pyr group. The role of pyruvate supplementation
might be to decrease the relative inhibition on aerobic gly-
colysis due to elevated creatine phosphate and ATP levels.
It may also be reflective of a more rapid regeneration of
ATP and reduction in the inorganic phosphate increase,
allowing for higher intracellular calcium ion concentra-
tion, permitting the higher frequency contraction and
relaxation. To achieve an additional effect of pyruvate an
increase in plasma pyruvate concentration should occur.
A recent study showed that one-time administration of 5
g Cr-Pyr does not increase plasma pyruvate concentra-
tions [21]. However, previous research found a cumula-
tive effect of pyruvate administration increasing the
plasma pyruvate concentration by about 60% after 4
Table 2: Force and relaxation velocity.
Interval 1 Interval 2 Interval 6 Interval 9
Cr-Pyr
Force (N) pre 209 ± 47 202 ± 47 202 ± 50 204 ± 52
post 218 ± 48** 212 ± 49** 212 ± 52** 213 ± 49**
Relaxation Velocity (m/s) pre 0.151 ± 0.033 0.141 ± 0.032 0.143 ± 0.046 0.150 ± 0.040
post 0.164 ± 0.019* 0.158 ± 0.025* 0.163 ± 0.034* 0.166 ± 0.032*
Cr-Cit
Force (N) pre 191 ± 53 184 ± 51 184 ± 54 184 ± 55
post 198 ± 54* 193 ± 54* 188 ± 54
188 ± 55
Relaxation Velocity (m/s) pre 0.154 ± 0.020 0.135 ± 0.033 0.135 ± 0.033 0.137 ± 0.035
post 0.169 ± 0.034
0.142 ± 0.023
0.135 ± 0.026
0.140 ± 0.027
Placebo
Force (N) pre 180 ± 45 173 ± 43 171 ± 44 171 ± 39
post 182 ± 42
176 ± 41
173 ± 38
174 ± 39
Relaxation Velocity (m/s) pre 0.155 ± 0.031 0.139 ± 0.036 0.131 ± 0.048 0.146 ± 0.062
post 0.160 ± 0.032
0.142 ± 0.037
0.146 ± 0.047
0.152 ± 0.049
Means ± SD, ** p < 0.001, * p < 0.01,
= not significant.
Journal of the International Society of Sports Nutrition 2008, 5:4 http://www.jissn.com/content/5/1/4
Page 8 of 9
(page number not for citation purposes)
weeks [18]. In the intestine and the liver, pyruvate can eas-
ily be converted to ketone compounds [46] or different
amino acids [47]. If parts of these substances or of the
pyruvate absorbed were distributed to the muscle the pool
of substances for anaplerotic reactions would increase.
This enables the muscle to replenish the pool of tri-car-
bon-cycle intermediates rapidly at the beginning of exer-
cise. This replenishment might favor the flux through the
TCA cycle and thus increase the delivery of protons to the
respiratory chain. The increased concentration of interme-
diates might also act as a pyruvate buffer, with the func-
tion to deliver carbon skeletons to the TCAC. Both
mechanisms could be beneficial during the transition
from rest to high intensity exercise to increase oxygen
uptake [48]. Given the transient presence of anaplerotic
substrates, the effect might be short-lived and not subject
to long-term accumulation over time. The results of more
acute administration or different organic salts of pyruvate
would be of interest.
Conclusion
Cr-Cit and Cr-Pyr supplementation significantly increases
mean power in high intensity exercise. Cr-Pyr intake sig-
nificantly increases force and decreases fatigability during
all intervals due to an enhanced contraction and relaxa-
tion velocity. The performance with Cr-Cit decreases with
time and improvements were not significant during the
later intervals. Further research is required to exam the
mechanism of decreasing fatigue during intermittent exer-
cise of high intensity observed with Cr-Pyr intake.
Competing interests
The author(s) declare that they have no competing inter-
ests.
Authors' contributions
NM, KRG, RJ and MP participated in the design of the
study. NM, JM, KL and VS organized the blood collection
and assayed the samples. NM analyzed the results statisti-
cally, and RJ and NM drafted the manuscript. All authors
have read and approved the final manuscript.
Acknowledgements
The authors would like to thank Prof. Jeff Stout, University of Oklahoma,
and Liz Frinzi for a critical reading of the manuscript and Degussa AG, Fre-
ising, Germany, and FSI Nutrition, Omaha, NE, USA, for funding this
research.
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... A number of creatine salts have been marketed as sources of creatine for dietary supplements including creatine citrate (including di-and tri-forms) [172][173][174]; creatine maleate, creatine fumarate, creatine tartrate [31]; creatine pyruvate [32,[174][175][176]; creatine ascorbate [33]; and creatine orotate [30,176,177], among others. Some creatine salts are less stable when compared to CrM. ...
... A number of creatine salts have been marketed as sources of creatine for dietary supplements including creatine citrate (including di-and tri-forms) [172][173][174]; creatine maleate, creatine fumarate, creatine tartrate [31]; creatine pyruvate [32,[174][175][176]; creatine ascorbate [33]; and creatine orotate [30,176,177], among others. Some creatine salts are less stable when compared to CrM. ...
... For example, Smith and colleagues [180] found ingesting 20 g/day of di-creatine citrate for 5 days delayed neuromuscular fatigue in women. Jäger et al. [174] reported that ingestion of 5 g/day of CC (providing 3.25 g/day of creatine) for 28 days significantly increased intermittent maximal effort handgrip force compared to placebo. Graef and coworkers [181] reported that 10 g/day of CC supplementation for 30 days during high-intensity interval training significantly increased the ventilatory threshold, but did not enhance maximal aerobic capacity. ...
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In 2011, we published a paper providing an overview about the bioavailability, efficacy, and regulatory status of creatine monohydrate (CrM), as well as other “novel forms” of creatine that were being marketed at the time. This paper concluded that no other purported form of creatine had been shown to be a more effective source of creatine than CrM, and that CrM was recognized by international regulatory authorities as safe for use in dietary supplements. Moreover, that most purported “forms” of creatine that were being marketed at the time were either less bioavailable, less effective, more expensive, and/or not sufficiently studied in terms of safety and/or efficacy. We also provided examples of several “forms” of creatine that were being marketed that were not bioavailable sources of creatine or less effective than CrM in comparative effectiveness trials. We had hoped that this paper would encourage supplement manufacturers to use CrM in dietary supplements given the overwhelming efficacy and safety profile. Alternatively, encourage them to conduct research to show their purported “form” of creatine was a bioavailable, effective, and safe source of creatine before making unsubstantiated claims of greater efficacy and/or safety than CrM. Unfortunately, unsupported misrepresentations about the effectiveness and safety of various “forms” of creatine have continued. The purpose of this critical review is to: (1) provide an overview of the physiochemical properties, bioavailability, and safety of CrM; (2) describe the data needed to substantiate claims that a “novel form” of creatine is a bioavailable, effective, and safe source of creatine; (3) examine whether other marketed sources of creatine are more effective sources of creatine than CrM; (4) provide an update about the regulatory status of CrM and other purported sources of creatine sold as dietary supplements; and (5) provide guidance regarding the type of research needed to validate that a purported “new form” of creatine is a bioavailable, effective and safe source of creatine for dietary supplements. Based on this analysis, we categorized forms of creatine that are being sold as dietary supplements as either having strong, some, or no evidence of bioavailability and safety. As will be seen, CrM continues to be the only source of creatine that has substantial evidence to support bioavailability, efficacy, and safety. Additionally, CrM is the source of creatine recommended explicitly by professional societies and organizations and approved for use in global markets as a dietary ingredient or food additive.
... Other studies examining Cr nitrate supplementation highlight nitrate's ability to improve aerobic exercise performance and suggest a potential synergist effect (13). Similarly, the proposed ergogenic effects of pyruvic acid and citric acid supplementation have been used to support Cr pyruvate and Cr citrate supplementation despite the lack of convincing evidence that either increases exercise capacity (24,42). Multiple alternative forms of creatine claim superior solubility, bioavailability, and digestion compared to CrM, eliminating gastrointestinal side effects and the need for creatine loading (36,42). ...
... The effect of Cr citrate supplementation on exercise performance and body composition was assessed in 9 studies (9,10,12,14,24,33,34,37,45). Results were inconsistent. ...
... Results were inconsistent. Three of these studies examined the effect of Cr citrate on aerobic performance measures and reported no significant effect between treatment and placebo groups on peak oxygen consumption, maximal oxygen consumption (V̇O 2 max), time to exhaustion, critical velocity, or oxygen consumption to mean power ratio (14,24,33). A study on recreationally active men reported that Cr citrate supplementation at 5 g per day for 30 days significantly improved ventilatory threshold (16 vs. 10% improvement in placebo) during a graded exercise test (GXT) on a cycle ergometer (14). ...
... An increase in body weight of around 1.5 kg was also observed in the creatine group. Further information about the incidence of adverse effects was not reported [64]. Another study did not include any information about adverse effects after intake of 7 g creatine pyruvate per day for 7 days in men [65]. ...
... An increase in body weight of 1.5 kg was observed in the creatine group. Further information about the incidence of adverse effects was not reported [64]. In other short-term studies with exception of an increased body weight (0.4-1 kg) [73,74], information about adverse effects after intake of 20 g (di)creatine citrate per day divided into 4 doses for 5 days was not included [73][74][75][76]. ...
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... For humans and nonruminants, several studies have shown that CrPyr can enhance body energy metabolism. Jäger et al. [8] reported that CrPyr could promote aerobic metabolism in athletes to enhance endurance performance. Chen [9] found that CrPyr supplementation increased the creatine kinase activity and phosphocreatine concentration in the muscle of broilers and increased glycogen reserve in muscle by reducing the decomposition of glycogen by decreasing phosphorylaseb activity. ...
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... These include, but are not limited to supplementary glucose, various amino acids [6][7][8] (i.e., L-arginine [9], beta-alanine [10,11], citrulline (in the form of citrulline-malate [12,13] or citrulline alone [12,14,15], glutamine [3,16], taurine [17] among other amino acids [18] and/ or a combination of branched-chain amino acids, particularly including L-Leucine [19]. Additional ergogenic and anaplerotic agents have been investigated, including [20][21][22], pyruvate [23][24][25], citrate [26][27][28], or malate [29] alone, creatine [22,30,31] (often in the form of pyruvate-creatine or creatine citrate [32,33], carnitine [34,35], various vitamins [36,37], co-factors [38], and antioxidants [39,40], among many others, particularly plant derived extracts or natural products (for example green tea [41], Cordyceps sinensis and yohimbine [42]) or complex derivatives thereof concocted into fortified beverages with supplementary carbohydrates [28,43] or protein isolates [44]. Additional investigations have explored the augmentation of athletic performance by specifically boosting nitric oxide levels via supplementation with L-arginine [20,45], or indirectly by using an arginine precursor such as citrulline [17] which has been shown to extend time to exhaustion [46]. ...
... A Cr loading phase followed by a maintenance phase might improve HIIT more than the low-dose supplementation used in the current study. However, Jager et al. found improvements in interval exercise performance using a similar dose of creatine citrate (5 g/day for 28 days) [56]. Due to the possibility that any benefits of low-dose creatine supplementation were masked by the effectiveness of HIIT alone, a longer training period may be implemented in future studies to determine whether low-dose Cr supplementation will induce further improvements when results from training begin to plateau. ...
... Creatine supplementation has also be shown to have an ergogenic effect on the forearm flexors, which are specifically important in bouldering, with studies reporting an 18% increase in "Nutritional Considerations for Bouldering" by Smith EJ, Storey R, Ranchordas MK International Journal of Sport Nutrition and Exercise Metabolism © 2017 Human Kinetics, Inc. handgrip time-to-fatigue and a 15% increase in sustained maximal grip power (Urbanski et al., 1999, Kurosawa et al., 2003. Further beneficial mechanisms of creatine supplementation include a 38% increase in forearm blood flow and an up to 14% improvement in relaxation velocity, which may facilitate clearance of metabolic by-products and increase the rate and window for re-oxygenation in the working muscles (Arciero et al., 2001, Jäger et al., 2008. ...
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... Thus creatine pyruvate may increase endurance, due to the enhanced activity of the aerobic metabolism. 86 Another study found that creatine pyruvate compared to creatine monohydrate and tri-creatine citrate resulted in significantly greater mean peak concentrations and area under the curve. However, despite these higher elevations, there was no difference between the estimated velocity constants or elimination between the groups. ...
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Purpose: The purpose of this study was to examine the effect of creatine supplementation in conjunction with resistance training on physiological adaptations including muscle fiber hypertrophy and muscle creatine accumulation. Methods: Nineteen healthy resistance-trained men were matched and then randomly assigned in a double-blind fashion to either a creatine (N = 10) or placebo (N = 9) group. Periodized heavy resistance training was performed for 12 wk. Creatine or placebo capsules were consumed (25 g x d(-1)) for 1 wk followed by a maintenance dose (5 g x d(-1)) for the remainder of the training. Results: After 12 wk, significant (P < or = 0.05) increases in body mass and fat-free mass were greater in creatine (6.3% and 6.3%, respectively) than placebo (3.6% and 3.1%, respectively) subjects. After 12 wk, increases in bench press and squat were greater in creatine (24% and 32%, respectively) than placebo (16% and 24%, respectively) subjects. Compared with placebo subjects, creatine subjects demonstrated significantly greater increases in Type I (35% vs 11%), IIA (36% vs 15%), and IIAB (35% vs 6%) muscle fiber cross-sectional areas. Muscle total creatine concentrations were unchanged in placebo subjects. Muscle creatine was significantly elevated after 1 wk in creatine subjects (22%), and values remained significantly greater than placebo subjects after 12 wk. Average volume lifted in the bench press during training was significantly greater in creatine subjects during weeks 5-8. No negative side effects to the supplementation were reported. Conclusion: Creatine supplementation enhanced fat-free mass, physical performance, and muscle morphology in response to heavy resistance training, presumably mediated via higher quality training sessions.
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KAMBER, M., M. KOSTER, R. KREIS, G. WALKER, C. BOESCH, and H. HOPPELER. Creatine supplementation-Part I: performance, clinical chemistry, and muscle volume. Med. Sci. Sports Exerc., Vol. 31, No. 12, pp. 1763-1769, 1999. Purpose: Our purpose was to study the effects and side effects of creatine (Cr) supplementation on high-intensity, short-term muscle work, on biochemical parameters related to Cr metabolism in blood and urine, and on muscle volume of the lower limb muscles. Methods: A cycling ergometer was used in a double-blind, cross-over study on 10 well-trained male physical education students to measure physical performance with 10 repetitive ergometer sprints (6-s duration, 30-s rest) before and after supplementation (5 d, 20 g·d-1, washout period 61 ± 8 d, mean ± SEM, minimum 28 d) with Cr or placebo. Before and after supplementation, blood and urine were taken and the muscle volume of the lower limb was determined by magnetic resonance imaging (MRI). Results: A significant (P ≪ 0.05) increase in performance (+ 7%) at the end [4-6 s] of the later sprints (4-7 and 8-10) was observed combined with a lower production of blood lactate (-1 mmol·L-1) with Cr supplementation. The concentration of Cr was increased significantly in urine (P < 0.001) and serum (P = 0.005), whereas creatinine (Crn) was increased in serum (P < 0.001). Crn in urine and Crn clearance did not change significantly with Cr intake. There were no significant changes in the analyzed blood enzyme activities. A significant gain of body weight (pre-Cr 76.5 ± 1.7 kg to 77.9 ± 1.7 kg post-Cr) with Cr supplementation was measured, but no accompanying increase of muscle mass in a limited volume of the lower limb was observed by MRI. Conclusion: Cr supplementation is effective in improving short-term performance, and the methods used show no detrimental side effects with this supplementation protocol.
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Two intermittent high-intensity exercise protocols were performed before and after the administration of either creatine or a placebo, and performance characteristics and selected physiological responses were studied. Each exercise protocol consisted of 10 6-s bouts of high-intensity cycling at 2 exercise intensities (130 rev/min [EX130]: ∼820 W and 140 rev/min [EX140)]: ∼ 880 W) so that in EX130 the same amount of exercise was performed before and after the administration period, whereas an exercise intensity in EX140 was chosen to induce fatigue over the 10 exercise bouts. Sixteen healthy male subjects were randomly assigned to the 2 experimental groups. A double-blind design was used in this study. There were no significant changes in the placebo group for any of the measured parameters. Performance towards the end of each exercise bout in EX140 was enhanced following creatine supplementation, as shown by a smaller decline in work output from baseline along the 10 trials. Although more work was performed in EX140, after vs before the administration period, blood lactate accumulation decreased (mean and SEM), from 10.8 (0.5) to 9.1 (0.8) mmol·l−1 and plasma accumulation of hypoxanthine decreased from 21.1 (0.4) to 16.7 (0.8) μmol·l−1, but there was no change in oxygen uptake measured during 3 exercise and recovery periods [3.18 (0–1) vs 3.14 (0.1) l·min−1]. In EX130 blood lactate accumulation decreased, from 7.0 (0.5) to 5.1 (0.5) mmol·l−1, and oxygen uptake was also lower, decreasing from 2.84 (0.1) to 2.78 (0.1) l·min−1. A significant increase in body mass (11 kg: range 0.3 to 2.5 kg) was found in the creatine group. The mechanism responsible for the improved performance with creatine supplementation are postulated to be both a higher initial creatine phosphate content availability and an increased rate of creatine phosphate resynthesis during recovery periods. The lower blood lactate and hypoxanthine accumulation can also be explained by these mechanisms.
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We investigated the effect of oral creatine supplementation (20 g d−1 for 7 days) on metabolism during a 1-h cycling performance trial. Twenty endurance-trained cyclists participated in this double-blind placebo controlled study. Five days after familiarization with the exercise test, the subjects underwent a baseline muscle biopsy. Thereafter, a cannula was inserted into a forearm vein before performing the baseline maximal 1-h cycle (test 1 (T1)). Blood samples were drawn at regular intervals during exercise and recovery. After creatine (Cr) loading, the muscle biopsy, 1-h cycling test (test 2 (T2)) and blood sampling were repeated. Resting muscle total creatine (TCr), measured by high performance liquid chromatography, was increased (P < 0.001) in the creatine group from 123.0 ± 3.8 − 159.8 ± 7.9 mmol kg−1 dry wt, but was unchanged in the placebo group (126.7 ± 4.7 − 127.5 ± 3.6 mmol kg−1 dry wt). The extent of Cr loading was unrelated to baseline Cr levels (r=0.33, not significant). Supplementation did not significantly improve exercise performance (Cr group: 39.1 ± 0.9 vs. 39.8 ± 0.8 km and placebo group: 39.3 ± 0.8 vs. 39.2 ± 1.1 km) or change plasma lactate concentrations. Plasma concentrations of ammonia (NH3) (P < 0.05) and hypoxanthine (Hx) (P < 0.01) were lower in the Cr group from T1 to T2. Our results indicate that Cr supplementation alters the metabolic response during sustained high-intensity submaximal exercise. Plasma data suggest that nett intramuscular adenine nucleotide degradation may be decreased in the presence of enhanced intramuscular TCr concentration even during submaximal exercise.
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Our purpose was to study effects of creatine (Cr) supplementation on muscle metabolites noninvasively by means of magnetic resonance spectroscopy (MRS) before and after supplementation with Cr or placebo. 1H-MRS was used in a comprehensive, double-blind, cross-over study in 10 volunteers to measure Cr in m. tibialis anterior and m. rectus femoris at rest. PCr/ATP was observed in m. quadriceps femoris by 31P-MRS at rest and after exercise. A significant increase in total Cr was observed with Cr intake in m. tibialis anterior (+9.6 +/- 1.7%, P = 0.001) and in m. rectus femoris (+18.0 +/- 1.8%, P < 0.001). PCr/ATP showed a significant increase (+23.9 +/- 2.3%, P < 0.001) in m. quadriceps femoris at rest with Cr supplementation. Post-Cr supplementation recovery rates from exercise were significantly lower (k = 0.029 s(-1), P < 0.01) compared with postplacebo consumption (k = 0.034 s(-1)) and presupplementation (k = 0.037 s(-1)). However, higher levels of PCr/ATP at rest compensate for this reduction of the recovery rate after Cr supplementation. The increase of PCr/ATP determined by 31P-MRS correlates with the increase of Cr observed by 1H-MRS (r = 0.824, P < 0.001). Noninvasive observation of Cr and PCr after Cr supplementation shows an increase in a muscle specific manner. Higher preexercise levels of PCr/ATP at rest compensate for significantly slower recovery rates of PCr/ATP after Cr supplementation.
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1. The present study was undertaken to test whether creatine given as a supplement to normal subjects was absorbed, and if continued resulted in an increase in the total creatine pool in muscle. An additional effect of exercise upon uptake into muscle was also investigated. 2. Low doses (1 g of creatine monohydrate or less in water) produced only a modest rise in the plasma creatine concentration, whereas 5 g resulted in a mean peak after 1 h of 795 (sd 104) μmol/l in three subjects weighing 76–87 kg. Repeated dosing with 5 g every 2 h sustained the plasma concentration at around 1000 μmol/l. A single 5 g dose corresponds to the creatine content of 1.1 kg of fresh, uncooked steak. 3. Supplementation with 5 g of creatine monohydrate, four or six times a day for 2 or more days resulted in a significant increase in the total creatine content of the quadriceps femoris muscle measured in 17 subjects. This was greatest in subjects with a low initial total creatine content and the effect was to raise the content in these subjects closer to the upper limit of the normal range. In some the increase was as much as 50%. 4. Uptake into muscle was greatest during the first 2 days of supplementation accounting for 32% of the dose administered in three subjects receiving 6 × 5 g of creatine monohydrate/day. In these subjects renal excretion was 40, 61 and 68% of the creatine dose over the first 3 days. Approximately 20% or more of the creatine taken up was measured as phosphocreatine. No changes were apparent in the muscle ATP content. 5. No side effects of creatine supplementation were noted. 6. One hour of hard exercise per day using one leg augmented the increase in the total creatine content of the exercised leg, but had no effect in the collateral. In these subjects the mean total creatine content increased from 118.1 (sd 3.0) mmol/kg dry muscle before supplementation to 148.5 (sd 5.2) in the control leg, and to 162.2 (sd 12.5) in the exercised leg. Supplementation and exercise resulted in a total creatine content in one subject of 182.8 mmol/kg dry muscle, of which 112.0 mmol/kg dry muscle was in the form of phosphocreatine.
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The in vivo utilization of 3-hydroxybutyrate for lipid and amino acid synthesis in liver, kidney and duodenal mucosa of overnight-starved 15-day-old chicks has been investigated. Lipid synthesis was higher in liver and duodenal mucosa than in kidney. Triglycerides were the main lipids synthesized from 3-hydroxybutyrate in liver and kidney, while in duodenal mucosa a higher amount of phospholipids was observed. This tissue utilized a high percentage of 3-hydroxybutyrate for the synthesis of free cholesterol, in agreement with the major role of intestine in body cholesterogenesis. All of the assayed tissues synthesized amino acids from 3-hydroxybutyrate at a similar rate, glutamate being always the main amino acid formed.