Sports Med. 18 (4): 268-280, 1994
0112-1642/94/00 IQ-0268/S06.50/0
REVIEW ARTICLE
© Adis International Limited. AH rights reserved.
Creatine in Humans with Special
Reference to Creatine Supplementation
Paul D. Balsam, Karin Soderlund and Bjorn Ekblam
Karolinska Institute, Department of Physiology and Pharmacology, Physiology III, and
University College of Physical Education and Sports, Stockholm, Sweden
Contents
Summary
, , , , , , ,
1, Historical Background
2, Creatine
2,1 Biosynthesis '"
2,2 Total Creatine Pool
2,3 Level of Creatine in Skeletal Muscle
2,4 An Energy Substrate for Muscle Contraction
3, Creatine Supplementation
3,1 , Total Creatine Pool , , , , . , , , , .
3.2 Exercise Performance , , , , , , ,
3,3 Creatine Supplementation in Sport
3,4 Treatment of Disease,
3,5 Adverse Effects
4, Conclusions , , , , , , , , ,
Summary
268
269
269
269
270
270
272
273
273
275
276
277
277
277
Since the discovery of creatine in 1832, it has fascinated scientists with its
central role in skeletal muscle metabolism. In humans, over 95% of the total
creatine (Crtot) content is located in skeletal muscle, of which approximately a
third is in its free (Crf) form. The remainder is present in a phosphorylated (Crphos)
form, Crf and Crphos levels in skeletal muscle are subject to indi vidual variations
and are influenced by factors such as muscle fibre type, age and disease, but not
apparently by training or gender. Daily turnover of creatine to creatinine for a
70kg male has been estimated to be around 2g. Part of this turnover can be replaced
through exogenous sources of creatine in foods, especially meat and fish. The
remainder is derived via endogenous synthesis from the precursors arginine, glycine and methionine. A century ago, studies with creatine feeding concluded that
some of the ingested creatine was retained in the body. Subsequent studies have
shown that both Crr and Crphos levels in skeletal muscle can be increased, and
performance of high intensity intermittent exercise enhanced, following a period
of creatine supplementation, However, neither endurance exercise performance
nor maximal oxygen uptake appears to be enhanced, No adverse effects have been
identified with short term creatine feeding . Creatine supplementation has been
used in the treatment of diseases where creatine synthesis is inhibited.
Creatine and Creatine Supplementation
1. Historical Background 1
In 1832, Chevreul, a French scientist, reported
the finding of a new organic constituent of meat to
which he gave the name 'creatine' . However, due
to problems wi th the method for detecting creatine,
it was not until 1847 that Lieberg was able to confirm that creatine was a regular constituent of flesh
extracted from mammals. During this time Lieberg
observed that the flesh of wild foxes killed in the
chase contained 10 times as much creatine as that
of captive creatures and concluded that muscle
work involves an accumulation of creatine. Around
this time, Heintz and Pettenkofer discovered a substance in urine, which Lieberg later confirmed to
be creatinine. Following the observation that creatinine excretion was related to muscle mass, it was
speculated that the creatinine found in urine was derived directly from the creatine stored in muscles.
Early in the twentieth century numerous studies
with creatine feeding were carried out. The creatine was extracted from either fresh meat, which
was a costly process, or more favourably but less
productively, from urine. It was observed that not
all of the creatine ingested by both animals and
humans could be recovered in the urine, which suggested that some of the creatine was retained in the
body. The fate of this exogenous creatine was at
least partly explained by the findings of Folin and
Denis (1912 and 1914), who determined that the
creatine content of the muscles of cats increased by
up to 70% after creatine ingestion. By 1923 Hahn
and Meyer had 'liberally' estimated the total creatine content of a 70kg male to be around 140g, a
figure which is close to that proposed today.
In 1927, Fiske and Subbarow reported the discovery of a 'labile phosphorous' in the resting muscle of cats which they named 'phospho' creatine,
and showed that, during electrical stimulation of
the muscle, phosphocreatine diminished, only to
reappear again during the subsequent recovery period. Since the work of these authors, and that of
Lundsgaard,12] creatine in its free (Crr) and phosI References to works and events prior to 1928 are from
Hunter.[l]
© Adis International Limited. All rights reserved.
269
phorylated (Crphos) forms has been recognised as
a key intermediate of skeletal muscle metabolism.
To learn more of the role of creatine in muscle
metabolism, modem researchers have been helped
by the reintroduction of the needle biopsy technique.!3] This method was first used to study the
breakdown and resynthesis of adenosine triphosphate (ATP) and Crphos with exercise in humans by
Hultman and co-workers in 1967.!4] More recently,
the role of Crphos in skeletal muscle metabolism
has been studied with nuclear magnetic resonance
spectroscopy (NMR) techniques. Although studies
with creatine supplementation can be traced back
to the end of the nineteenth century, it would appear that only recently has the influence of creatine
supplementation on exercise performance in humans been studied.!S· 7] These studies were based
on the finding reported by Harris and co-workers I8 ]
that Crphos content in human muscle could be increased by more than 20% following a regimen of
creatine supplementation.
2. Creatine
2.1 Biosynthesis
2. 1. 1 Biochemistry
There are 3 amino acids involved in the synthesis of creatine: glycine, arginine and methionine
(fig. 1). Synthesis begins with the transfer of the
amidine group from arginine to glycine (transamidination) to form guanidinoacetate and ornithine. The enzyme catalysing this reversible reaction
is transamidinase. Creatine is then formed by the
irreversible addition of a methyl group from Sadenosylmethionine, with a methyltransferase being required for this process (transmethylation).
2. 1.2 De Novo Synthesis
In humans, the enzymes involved in the de novo
synthesis of creatine are located in the liver, pancreas and kidneys. This means that creatine is produced outside of the muscle and transported into
the muscle via the bloodstream. The normal concentration of creatine in plasma is 50 to 100
)lmollL. The different location sites for endogenous
creatine synthesis and utilisation permits an inSports Med. 18 (4) 1994
Balsom et al.
270
r
r
Nfi.;,
+
COOGlycine
I
I
NH
I
+
r+
C=Nfi.;,
C=f11i2
Transanicinase
+
I
I
•
NH
r
r
r
I+
COOGuanidinoacetate
r
r
r
r+
HCNI-i:3
I
coo-
Cfi.;,
Ornithine
r
8-Adenosylrrethionine
COOArginine
+
~
Nfi.;,-C-N-CH.;,-COO-
I
+
AdenosylhofTlOC)'Steine
CI-i:3
Creatine
Fig. 1. Synthesis of creatine (from Devlin,l9) with permission).
dependent regulation of each process (for a review,
see Walker[IOI).
2.2 Total Creatine Pool
2.2. 1 Daily Turnover
The total creatine (Crtot) pool in humans refers
to the combined amount of creatine in its free and
phosphorylated form. In the absence of exogenous
creatine, the rate of turnover of creatine to creatinine has been estimated to be around 1.6% per day
in humansJ II) Thus, with a body weight of 70kg
and a total creatine pool of l20g, this represents a
turnover of approximately 2g per day. This creatine
is replaced through endogenous and exogenous
sources. Endogenous creatine synthesis is believed
to be at least partly regulated by exogenous intake,
most likely by a feedback mechanismJI2)
Creatine is found mostly in meat, fish and other
animal products (see table I), with only trace
amounts found in some plants. The average intake of
creatine from a mixed diet has been estimated to be
19 per dayJI3) Thus, while at least a part of the
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daily creatine requirement can be attained from the
diet, this needs to be complemented by endogenous
synthesis. On a creatine-free diet, as can be the case
with vegetarians, daily needs are met exclusively by
way of endogenous synthesis (see Delanghe and
colleagues[14).
2.2.2 Distribution in the Body
Approximately 95% of the total creatine pool in
humans is found in skeletal muscle. Of the remaining 5%, the highest levels can be found in heart,
brain and testes. In skeletal muscle, Crphos accounts
for approximately two-thirds of the total creatine
pool.
2.3 Level of Creatine in Skeletal Muscle
2.3. 1 Method of Determination
Crr and Crphos levels in a muscle biopsy sample
can be determined enzymatically using a method
modified from that described by BergmeyerJl5]
For a description of this method, together with a
discussion on variance of values, see Harris and
colleaguesJl6] With this method, after the biopsy
Sports Med. 18 (4) 1994
Creatine and Creatine Supplementation
sample has been removed from the muscle it is
immediately frozen in liquid nitrogen and later analysed after freeze drying. A delay in the time from
removal to freezing has been shown to result in an
increase in Crphos level of up to 10 mmol/kg.f171
Changes in Crphos levels during exercise can
also be evaluated using NMR spectroscopy. This
noninvasive method can determine the relative
concentrations of high energy phosphates based on
the behaviour of atomic nuclei exposed to a strong
magnetic field (for review, see McCully and colleagues! 18 1).
2.3.2 Normal Resting Values
A mean Crtot level of 124.4 mmol/kg [standard
deviation (SD) = 11.21], measured using an enzymatic method on freeze dried muscle (dm) biopsy
samples taken from m. quadriceps femoris, has
been reported for a group of 81 untrained male and
female study participants, 18 to 30 years of age.l 161
The respective levels of Crf and Crphos were 49.0
(7.62) and 75.5 (7.63) mmol/kg.
2.3.3 Gender and Age
Only a few studies can be found in the literature
which have compared levels of Crf and Crphos in
the skeletal muscle of males and females.l1 9-221 In
Table I. Approximate creatine content in different foods. The fish
and meat were freeze dried. extracted in percholic acid and
neutralised with potassium hydrogencarbonate (milk and
cranberries were extracted in the same way) . Creatine
concentration was determined enzymatically using a
spectrophotometer (analysed at wavelength of 340nm)
Food type
Creatine content (g/kg)
Fish
Shrimp
Cod
Herring
Plaice
Salmon
Tuna
Meat
Beef
Pork
Other
Milk
Cranberries
Trace
3
6.5-10
2
4.5
4
4.5
5
0.1
0.02
© Adis International Umited. All rights reserved.
271
one of those studies,!221 females were found to have
a higher Crtot level in relation to tissue weight.
However, there does not appear to be further evidence to suggest that any difference exists between
the genders.
In a group of 20 males and 25 females, no significant differences were found in Crtot levels of
m. vastus lateralis, the respective values being [mean
and standard error of the mean (SEM)], 127.7 (2.1)
versus 131.4 (2.4) mmol/(kg dm) [p > 0.05] (K.
SOderlund, unpublished observations).
The effect of aging on the level of Crf and Crphos
in skeletal muscles has been studied by Moller and
co-workers.!20. 23 1 No differences were found in
Crtot level between a group of elderly (52 to 79 years
of age) and young (18 to 36 years of age) study
participants. However, the level of Crphos was
found to be lower and that of Crf higher in the
elderly participants compared with the younger
participants. It was suggested that such discrepancies may be a consequence of inactivity as, in a
subsequent training study with the elderly individuals, changes in Crf and Crphos levels (with no
change in Crtot) towards those of the younger age
group were observed,l231
2.3.4 Different Fibre Types
Using a technique to separate type I and type II
fibres in human freeze dried muscle biopsy samples,
type II fibres of human skeletal muscle in the resting state have been shown to have a higher level
of Crphos than type I fibres.!24- 261 These findings
support the observations made by Edstrom and coworkers! 271 that Crphos level of the soleus muscle
in humans (containing approximately 65% type I
fibres) was significantly lower than that of m. vastus lateralis (approximately 41 % type I).
2.3.5 Effecf of Training
A few studies have compared creatine levels of
skeletal muscle in groups of trained versus untrained participants. In I of these, a higher Crphos
level in a group of trained versus nontrained participants was reported.f 281 However, a recent study
with NMR spectroscopy has failed to show any
such differences,l291 In another study with NMR,
Bemus and co-workers! 301 reported higher levels
Sports Med. 18 (4) 1994
Balsam et al.
272
of Crphos in the quadriceps muscles of sprinters
compared with endurance runners. The explanation offered to explain these findings was that
sprinters would have had a higher percentage of
type II fibres; however, the effect of training cannot be ruled out.
High intensity or heavy resistance training that
induces muscle hypertrophy will increase the absolute size (i .e. amount in grams) of the total creatine pool. However, the evidence from training
studies which have employed this type of exercise
would seem to suggest that Crr and Crphos levels in
skeletal muscle are not increasedJ31-37] Training
with endurance exercise has also failed to show any
changes in Crphos level of m. vastus lateralis,l38]
On the other hand, a few studies have reported increased levels of Crphos in skeletal muscle following training. These include several Russian studies
(see Yakovlev[39]), although no descriptions of the
training or methods of analysis are given, and 2 studies where interpretation of the data can be questioned as wet muscle weight was used as a reference baseJ40,41]
Thus, it appears that, in general, short term
training studies have failed to show any definite
changes in skeletal muscle Crr or Crphos level. Furthermore, there is currently no conclusive evidence
available to suggest that differences exist between
trained and untrained individuals.
2.3.6 Abnormalities with Disease
In the early 1900s it was observed that patients
with muscle diseases retained less creatine than
normal individuals (cited in Hunter[ I]). Lower than
normal levels of Crr and Crphos have been found in
patients with muscle disease (see Fitch( 42 1), rheumatoid arthritis,[43] primary fibromyalgia[44] and
patients with both acute and long term circulatory
or respiratory problems.[4S-49] In patients with muscle disease, it has been suggested that the lower Crr
and Crphos levels may be caused by a fault in the
mechanism that retains creatine in the muscle.l 42 ]
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2.4 An Energy Substrate for
Muscle Contraction
The immediate energy source for skeletal muscle contraction is ATP. During muscle contraction,
ATP is hydrolysed to adenosine diphosphate
(ADP) and must be continuously replenished. With
rapid increases in energy demands, Crphos is degraded and the phosphate donated to the ADP to
regenerate ATP. This reaction is catalysed by the
enzyme creatine kinase (Crphos + ADP + H+ H Crr
+ ATP) and leads to an accumulation of Crr in the
active muscles which during recovery from exercise is rephosphorylated back to Crphos.
In addition to acting as a 'temporal energy
buffer', the Crphos-creatine kinase system also
serves several other main functions for skeletal
muscle metabolism (for a review, see Wallimann et
aLISO]). One of these proposed functions, as a 'spatial energy buffer', has been termed the phosphocreatine energy shuttle (see Bessman[SI] and
Wallimann et aLISO] for a further list of references).
In this concept, Crphos is postulated to act as an
energy carrier, transporting energy from the mitochondria to different ATPase sites in the cytosol.
2.4. 1 High-Intensify Exercise
During a brief bout of high intensity exercise,
the ATP demand in the working muscles can increase to several hundred-fold higher than at rest.
The rate of ATP turnover in different forms of
exercise in humans has been estimated to be approximately 6 mrnol/(kg dm)/sec during a 25-sec
period with electrical stimulation of a quadriceps
muscle;[S2] 13 mmol/(kg dm)/sec during a lO-sec
cycle sprint[S3] and 15 mmol/(kg dm)/sec during 6
sec of all-out cycling.[S4] From these findings it
can be estimated that with high intensity exercise
the Crphos stores could be totally depleted within
10 sec.
The rate of Crphos degradation has been shown
to be higher in type II versus type I fibres,[26,SS]
and the availability of Crphos as an energy substrate
in selected type II muscle fibres is considered to be
a possible limiting factor for maintaining muscle
force during high intensity exercise. The importance
Sports Med. 18 (4) 1994
273
Creatine and Creatine Supplementation
of Crphos for muscle function during high intensity
exercise has been demonstrated recently in a study
by Bogdanis and co-workers[ 561 in which the restoration of peak power output following a 30-sec
cycle sprint was found to proceed in parallel with
the resynthesis of Crphos.
2.4.2 Resynthesis of CrphOS affer
High-Intensify Exercise
The resynthesis of Crphos in human skeletal
muscle is an oxygen-dependent process with a
fast and a slow componentJ57.581 Following high
intensity exercise, approximately half of the preexercise Crphos content is restored within 1 min of
recoveryJ4. 591In these studies by Hultman and colleagues[41 and SOderlund and colleagues,l591 total
resynthesis of Crphos was complete after approximately 5 min; however, in a recent study,l56) 6 min
after a 30-sec cycle sprint, Crphos levels had only
returned to approximately 85% of resting values.
In single muscle fibres the initial rate of resynthesis in type I fibres has been shown to be faster than
for type II fibresJ25.59) This is probably because of
the higher aerobic potential of type I fibres[ 601and
also partly because of an expected smaller decrease in pH of type I versus type II fibres during
exercise.[26)
2.4.3 Endurance Exercise
Although Crphos is not considered to be a primary energy substrate during submaximal exercise, an inverse relation has been reported between
exercise intensity and Crphos level in the working
musclesJ 4l Furthermore, in a study where participants cycled at 60 to 70% of V02max for 75 min,
an increase in inosinemonophosphate (IMP) and a
decrease in Crphos level, to approximately 40% of
resting values, was found at the end of exercise.l 61 )
Similar reductions in Crphos were reported after 80
min of cycling at an intensity corresponding to
68% of V02max.l62) Thus, it appears that Crphos
levels decrease even during submaximal exercise,
however muscle stores are not depleted to the same
extent as during high intensity exercise.
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3. Creatine Supplementation
From studies performed in the beginning of the
twentieth century in both humans and animals
(cited in Hunter[ll) it was concluded that a fraction
of ingested exogenous creatine was retained in the
organism. The majority of these earlier observations were based on the amount of creatine and
creatinine recovered in urine. The mystery surrounding the fate of ingested creatine was at least
partly resolved by Folin and Denis (1912, 1914)
and Myres and Fine (1913) [cited in Hunter[ll],
who found increases of up to 70% in the creatine
content of the muscles of cats and rabbits following a period of creatine ingestion. Further investigations on creatine feeding in humans[8.11.63.641
have since confirmed these earlier findings that the
size of the body pool of creatine can be increased.
Creatine feeding in humans is possible by oral
administration of creatine monohydrate, a white
powder which is soluble in warm water. On ingestion of 5g of creatine monohydrate, the plasma
level of creatine has been shown to rise from between 50 to 100 flmollL to over 500 flmollL 1 hour
after administration.l 81 Creatine is transported into
the muscle from the bloodstream. However, the
exact mechanism by which creatine enters human
skeletal muscle is not clear. In rat muscle this has
been shown to be via a saturable process.l 65 .66 )
3.1 Total Creatine Pool
3.1.1 Changes in Resting Values
In a recent study by Harris and co-workers,l81
with direct measurements from freeze dried muscle biopsy samples, the levels of skeletal muscle
Crr and Crphos were shown to increase in a group
of healthy participants following a series of different regimens of creatine feeding . In this study, a 5g
dose of creatine monohydrate was administered 4
to 6 times a day for 2 or more days. Increases
(mean and SD: n = 17) in Crtot were from 126.8
(11.7) to 148.6 (5.0) mmol/kg. Crphos increased
from 84.2 (7.3) to 90.6 (4.8) mmol/kg. These increases were subject to large individual variances
(for example, for 1 participant, Crphos level increased from 76.7 to 100 mmol/kg) and the uptake
Sports Med. 18 (4) 1994
Balsom et al.
274
SOderlund et alJ731
Greenhaff et aU72J
Unpublished
observations
Unpublished
observations
Comrol
r":
6 days (20 g/day) [n = 7)
Cf::_
5 days (20 g/day) [n
~':
--r::
~:
..,
30 days (3 g/day) [n
14 days (3 g/day) [n = 10)
n=25
~
=8)
= 10)
~
~
~
~
~i~(Ir---~---.---'----.---'----r---.----'--~-110
120
130
140
150
Total creatine (mmoVkg)
Fig. 2. Total creatine level (CrtDt) of m. vastus lateralis after creatine supplementation and without supplementation (control).
of creatine was related to initial Cftol levels. This
latter finding may explain why creatine uptake was
greatest in 2 vegetarians, as lower initial values of
Cftol have been associated with vegetarians.l 14]
Mean increases in skeletal muscle Crlol level from
4 recent creatine supplementation studies are presented in figure 2.
Harris and co-workers[81 have also been able to
confirm an earlier observation by Chanutin (1926;
cited in Hunter[11) that, whereas on the first day
of feeding, creatine uptake was high (70% of a 109
dose was retained in the body of 1 participant),
after a week of feeding almost all of the administered creatine could be retrieved in the urine. In the
study by Harris and co-workers,[81 in which 3 participants were administered six 5g doses per day
for 3 days, 40% (day 1),61 % (day 2) and 68% (day
3) of the administered dose was retrieved in the
urine. Thus, it appears that there is an upper limit
to the amount of creatine which can be stored in
muscle. For most participants this seems to be
around 160 mmol/(kg dm). Preliminary findings
from a recent study show that increases in skeletal
muscle Crlol levels found in a group of participants
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after 6 days of creatine administration (0.3g per
day per kilogram of bodyweight) were maintained
for a subsequent 4-week period, during which time
the dosage was reduced to O.03g per day per kilogram of body weight (unpublished findings).
Increases in the Crlol level of muscle following
creatine feeding have been accompanied by increases in bodyweight. For example, as early as
1923, Benedict and Osterbery (1923), cited in
Hunter,IIl reported a 1.4kg weight gain after 17
weeks of creatine supplementation in a dog that
had initially weighed 14.lkg. Increases in bodyweight were later reported following creatine ingestion in humans. Balsam and co-workers[5,6] reported a mean increase in body weight of around
Ikg (n = 17) for participants administered creatine
monohydrate 20 g/day for 6 days. The most likely
explanation for this weight gain is water retention.
It has, however, been suggested that creatine may
stimulate protein synthesis.[67,68] In a study with
long term small dose supplementation with patients suffering from gyrate atrophy, an increase in
the diameter of type II muscle fibres in m. vastus
lateralis was observed.l 69 ]
Sports Med. 18 (4) 1994
Creatine and Creatine Supplementation
The uptake of creatine has been shown to be
influenced by several factors . For example, during
a period of creatine supplementation in humans,
uptake has been found to be higher in an exercised
leg (1 h/day) compared with a control (nonexercised)
leg. 18 ] This preliminary finding is not readily explainable and may, in future studies, be used to
increase the understanding of the mechanisms by
which creatine enters the muscle from the blood.
Other factors which have been shown to influence
creatine uptake in animals include a reduced uptake with vitamin E deficiencyl70] and an enhanced
uptake when creatine was administered with insulin.!7)]
3.1.2 Effect on Resynthesis of CrphOS After
High-Intensify Exercise
In a study in which the Crphos level in m.
vastus lateralis was depleted to approximately 8
mrnoU(kg dm) by electrical stimulation, the rate of
Crphos resynthesis over the first 2 min of recovery
was compared before and after creatine supplementation (20 g/day for 5 days).I72] This study
found that, in a subgroup of participants who
showed increases in Crtot level as a result of the
supplementation, Crphos resynthesis was accelerated following creatine ingestion.
3.2 Exercise Performance
As early as 1923, Macht observed ' some kind
of beneficial effect' upon the motor control of rats
running in a maze after a period of creatine supplementation. However, despite an abundance of
studies investigating the regulation of endogenous
creatine synthesis, over the last 100 years, little can
be found in the literature that describes the effect of
creatine supplementation on exercise perfonnance.
This is even more surprising considering the central role of creatine in skeletal muscle metabolism
during exercise and considering that the availability of Crphos is believed to be a contributory factor
to fatigue during high intensity exercise.
3.2. 1 High-Intensity Exercise
Following the work of Harris and co-workers,18]
Greenhaff and colleagues l7 ] reported that the ability
© Adis International limited. All rights reserved.
275
to produce muscle torque during 5 bouts of 30
maximal voluntary knee extensions, interspersed
with 60-sec recovery periods, was enhanced following a 5-day period of creatine supplementation
(20 g/day). The finding that creatine supplementation could enhance perfonnance of short duration,
dynamic, high intensity, intermittent exercise was
confirmed in a double-blind study in which 16 participants were randomly assigned to a placebo and
creatine group.!5] In this study, an exercise protocol consisting of ten 6-sec bouts of high intensity
exercise, interspersed with 30-sec recovery periods, was performed on a cycle ergometer. During
each exercise period, study participants were instructed to try to maintain a pedalling frequency
(target speed) of 140 rev Imin. The resistance on the
cycle was detennined so that in the control situation each participant was unable to maintain the
target speed for the entire duration of each 6-sec
period after 4 to 6 exercise periods. The exercise
protocol was performed before and after a 6-day
administration period which consisted of 20 g/day
dosages of either creatine monohydrate or glucose
(placebo group). As can be seen in figure 3, those
in the creatine group were better able to maintain
the target speed along trials towards the end of
each exercise period following creatine supplementation. There were no significant differences
between the 2 groups before the administration
period.
In a follow-up study using a similar exercise
model and the same regimen of creatine feeding,
the ability to sustain a high power output during a
10-sec exercise period, performed 40 sec after the
completion of 5 standardised 6-sec bouts of high
intensity exercise, improved significantly following creatine supplementation.!73] Furthermore, although the same amount of work had been performed over the 5 exercise bouts on both test
occasions, immediately after the fifth exercise period muscle lactate accumulation was 70% lower
after vs before creatine supplementation (p < 0.05).
This suggests that the higher initial Crtot level following creatine supplementation led to a lesser
Sports Med. 18 (4) 1994
Balsom et al.
276
fatigue resistance during the middle part of the test
protocol.
• Creatine (n = 8)
o Placebo (n 8)
=
3.2.2 Endurance Exercise
140
'2
E
">
!
'"
u
c
!g 130
Ien
~
OJ
'0
Ql
a.
120
2
4
6
8
10
Exercise bout (sec)
Fig. 3. Performance data (mean and SEM) for the 4- to 6-sec
interval (Le. last 2 sec) of ten 6-sec periods of high intensity
cycling, for the creatine and placebo groups, following the 6-day
administration period. IS]
dependence on anaerobic glycolysis for the resynthesis of ATP.
Thus, the improvements in performance observed during high intensity, intermittent exercise
following creatine supplementation may be partly
explained by a greater availability of Crphos in the
working muscle before each exercise period, possibly as a result of: (i) a higher pre-exercise concentration; (ii) a smaller decrease in muscle pH;
and (iii) a higher rate of resynthesis during recovery periods.
In another study, the effect of creatine supplementation (6 days, with 20 g/day: n = 8) on the
fatigue resistance of the knee extensor and plantar
flexor muscle groups was investigated using supramaximal, electrically evoked isometric contractions.!7 41Each contraction lasted 300 msec and the
procedure was repeated once per second for 2 min.
The results showed a tendency towards improved
© Adis International Limited. All rights reseNed.
The effects of creatine supplementation on the
performance of continuous endurance type exercise have also been reported.£6, 75 1In a double-blind
study,l751 the effect of creatine supplementation on
performance (time in sec) over 9km of roller-skiing
was investigated. No improvement was found in
either the creatine (n = 10) or the placebo (n = 10)
group folIowing 4 days of either creatine (15g) or
glucose (15g) administration. In another doubleblind study[61 the effect of creatine supplementation (20 g/day for 6 days) on continuous endurance
running was investigated. No improvement in the
time taken to complete a 6km cross-country course
with an undulating terrain was found folIowing
creatine supplementation. In fact, run time was significantly greater folIowing creatine supplementation in the creatine group, whereas no changes
were seen in the placebo group.£61 It was suggested
that this impairment in performance may have
been partly due to the increase in body weight associated with creatine ingestion (see section 3.1.1).
In the same study, neither time to exhaustion nor
peak oxygen uptake for a supramaximal treadmill
run (mean exercise time approximately 4 min)
were different following creatine supplementation.
These results, which fail to show any improvement
in performance of endurance exercise following
creatine supplementation, appear logical because
Crphos is not considered to be a limiting factor for
performance in this type of exercise.
3.3 Creatine Supplementation in Sport
3.3. 1 An Ergogenic Aid
Ingestion of creatine in amounts greatly exceeding those consumed in a normal mixed diet has, in
controlled laboratory experiments, been shown to
enhance the ability to maintain power output during repeated bouts of high intensity exercise (see
section 3.2.1). Thus it can be speculated that, in
sports where performance is in some way influenced by the availability of Crphos, creatine supplementation may be useful as ergogenic aid. The
Sports Med. 18 (4) 1994
277
Creatine and Creatine Supplementation
most obvious examples are in the sprint disciplines of running, swimming and cycling. In sports
with continuous type exercise of a longer duration,
any beneficial effects seem unlikely (see section
3.2.2). In team ball games and racket sports, especially those which have been classified as multiple sprint sports[ 761 (e.g. football, basketball, ice
hockey, tennis) where periods of high intensity exercise are interspersed with periods oflower intensity exercise or standing still, creatine supplementation may be of some benefit if the availability of
Crphos in the working muscles becomes limiting.
However, any isolated short term benefits in these
sports, where game time often exceeds 1 hour, may
be counteracted by an increase in bodyweight (see
section 3.1.1).
Currently, creatine does not appear on the International Olympic Committee (lOC) banned substances list, possibly because of problems with
detecting the ingestion of orally administered
creatine.
3.4 Treatment of Disease
Creatine supplementation with a dosage of 1.5
g/day for 1 year has been shown to stabilise the
condition of some patients suffering from gyrate
atrophy of the choroid retinaJ69] This disease is
characterised by progressive constriction of visual
fields and is attributed to a defect in creatine synthesis. The underlying mechanism is an elevation
of plasma ornithine that is caused by a depressed
activity of the enzyme L-ornithine : 2 oxoacid
aminotransferase which, in turn, decreases creatine synthesis by inhibiting the rate limiting enzyme L-arginine-glycine amidinotransferase. This
condition ultimately results in an atrophy of type
II muscle fibresJ69] The long term administration
of oral creatine in patients suffering from gyrate
atrophy has been shown to result in an increased
diameter of type II muscle fibres in m. vastus
lateralis.l 77 ] Furthermore, it was demonstrated that
atrophy reappeared in a group of patients following cessation of the supplementation. Such findings suggest that creatine supplementation may be
© Adis International Limited. All rights reserved.
used in the treatment of patients with depressed
Crtot levels.
3.5 Adverse Effects
Experiments with creatine feeding date back
well over 100 years. To the best of the authors'
knowledge, the only documented adverse effect
that has been associated with creatine supplementation is an increase in body mass. However, to
date those studies reported have only used high
doses of creatine (up to 25 g/day, i.e. 25 times that
found in a normal mixed diet) for relatively short
periods of time «2 weeks). In a long term study,
where creatine supplementation was maintained
for over a year, a dose similar to the amount of
exogenous creatine found in a normal mixed diet
(i.e. Ig) was usedJ69] Therefore, it must be
stressed that it is not currently known whether
there are any adverse effects caused by long term
high dose supplementation.
As creatine feeding is believed to suppress endogenous creatine synthesis, an important question is raised as to whether this suppression is released when creatine feeding is terminated. While
there is currently no evidence available from human studies to answer this question, there is evidence from animal studies which clearly shows
that transamidinase activities (the enzyme which
catalyses the transfer of the amide group from arginine to glycine), which are suppressed during
creatine feeding, return to normal following the
removal of exogenous creatineV 8]
4. Conclusions
Of the 120 to 140g of creatine found in the human body, around 95% is stored in skeletal muscle.
This creatine plays an important role in the regulation of skeletal muscle metabolism. From the relatively small number of studies available in the
literature it would appear that variations in Crtot
levels in muscle samples of healthy humans, consuming a mixed diet, appear to be relatively small
compared with the increases that have been found
following creatine supplementation. The mechanism
Sports Med. 18 (4) 1994
Balsam et al.
278
by which this exogenous creatine enters the muscle
is not currently known.
Increased Crtot levels in skeletal muscle have
been shown to enhance performance of short duration, high intensity intermittent exercise. The metabolic explanation for this is, as yet, not clear, but
an increased availability of Crphos, due to a faster
resynthesis of Crphos during recovery periods, and
possibly the ability of this substrate to regulate the
rate of muscle glycolysis are factors that have been
postulated. Creatine supplementation may, therefore, be a useful tool that can be used in experimental studies to improve our understanding of key
mechanisms involved in the control of skeletal
muscle metabolism and factors that impair muscle
function during high intensity exercise.
Furthermore, current research is investigating
the use of creatine supplementation for treatment
of 'creatine deficient' diseases which lead to reduced levels of creatine in skeletal muscle. The
theory that creatine stimulates protein synthesis is
also currently being investigated. Creatine supplementation may yet prove to have many exciting
clinincal applications.
Acknowledgements
The authors wish to thank Professor Eric Hultman for
useful comments in the preparation of this manuscript. The
authors also wish to acknowledge the support provided by
the Karolinska Institute Research Fund and the Swedish
Sports Research Council.
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