Mechanisms of muscular adaptations to creatine supplementation

Abstract

Creatine supplementation is a widely used and heavily studied ergogenic aid. Athletes use creatine to increase muscle mass, strength, and muscle endurance. While the performance and muscle- building effects of creatine supplementation have been well documented, the mechanisms responsible for these muscular adaptations have been less studied. Objective: The purpose of this review is to examine studies of the mechanisms underlying muscular adaptations to creatine supplementation. Data sources: PubMed and SPORTDiscus databases were searched from 1992 to 2007 using the terms creatine, creatine supplementation, creatine monohydrate, and phosphocreatine. Study selection: Studies of creatine supplementation in healthy adults were included. Data extraction: Due to the small number of studies identified, a meta-analysis was not performed. Data synthesis: Several potential mechanisms underlying muscular adaptations to creatine supplementation were identified, including: metabolic adaptations, changes in protein turnover, hormonal alterations, stabilization of lipid membranes, molecular modifications, or as a general training aid. The mechanisms with the greatest amount of support (metabolic adaptations, molecular modifications, and general training aid) may work in concert rather than independently. Conclusions: Creatine supplementation may alter skeletal muscle directly, by increased muscle glycogen and phosphocreatine, faster phosphocreatine resynthesis, increased expression of endocrine and growth factor mRNA, or indirectly, through increased training volume. Keywords: dietary supplement, creatine monohydrate, phosphocreatine, muscle, sport nutrition

Full text

Mechanisms of muscular adaptations to creatine supplementation
International SportMed Journal, Vo.8 No.2, 2007,
pp.43-53, http://www.ismj.com
ISMJ
International SportMed Journal
Review article
Mechanisms of muscular adaptations to creatine supplementation
1*Professor Eric S Rawson, PhD, 2Professor Adam M Persky, PhD
1 Department of Exercise Science and Athletics, Bloomsburg University, Bloomsburg, PA USA
2 Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of
North Carolina at Chapel Hill, Chapel Hill, NC USA
Abstract
Creatine supplementation is a widely used and heavily studied ergogenic aid. Athletes use creatine
to increase muscle mass, strength, and muscle endurance. While the performance and muscle-
building effects of creatine supplementation have been well documented, the mechanisms
responsible for these muscular adaptations have been less studied. Objective: The purpose of this
review is to examine studies of the mechanisms underlying muscular adaptations to creatine
supplementation. Data sources: PubMed and SPORTDiscus databases were searched from 1992 to
2007 using the terms creatine, creatine supplementation, creatine monohydrate, and
phosphocreatine. Study selection: Studies of creatine supplementation in healthy adults were
included. Data extraction: Due to the small number of studies identified, a meta-analysis was not
performed. Data synthesis: Several potential mechanisms underlying muscular adaptations to
creatine supplementation were identified, including: metabolic adaptations, changes in protein
turnover, hormonal alterations, stabilization of lipid membranes, molecular modifications, or as a
general training aid. The mechanisms with the greatest amount of support (metabolic adaptations,
molecular modifications, and general training aid) may work in concert rather than independently.
Conclusions: Creatine supplementation may alter skeletal muscle directly, by increased muscle
glycogen and phosphocreatine, faster phosphocreatine resynthesis, increased expression of
endocrine and growth factor mRNA, or indirectly, through increased training volume. Keywords:
dietary supplement, creatine monohydrate, phosphocreatine, muscle, sport nutrition
*Professor Eric S Rawson, PhD
Dr Eric Rawson is an Associate Professor in the Department of Exercise Science and Athletics,
Bloomsburg University, USA. His research focuses on the interactive effects of exercise and nutrition
on muscle function. Dr Rawson has conducted several studies examining peripheral and central
adaptations to creatine supplementation in both young and elderly populations. He is a member of
the American College of Sports Medicine, the National Strength and Conditioning Association, and
the American Society for Nutrition.
Official Journal of FIMS (International Federation of Sports Medicine)
43
*Corresponding author. Address at the end of text.

Mechanisms of muscular adaptations to creatine supplementation
International SportMed Journal, Vo.8 No.2, 2007,
pp.43-53, http://www.ismj.com
Official Journal of FIMS (International Federation of Sports Medicine)
44
Professor Adam M Persky, PhD
Dr Adam Persky is a clinical assistant professor in the Division of Pharmacotherapy and Experimental
Therapeutics, School of Pharmacy, University of North Carolina at Chapel Hill, USA. His research
focuses on the effects of exercise and nutrition on drug disposition and action and pharmacy
education. Dr Persky has conducted studies to characterise the systemic disposition of creatine in
healthy volunteers. He is a member of the American College of Sports Medicine, American
Association of Colleges of Pharmacy, and the American Society of Clinical Pharmacology and
Therapeutics.
Email: apersky@unc.edu
Introduction
Creatine monohydrate is popular dietary
supplement that is used by athletes to
increase muscle mass and strength, and
improve sports performance. The effects of
creatine on exercise performance, strength,
and body composition have been described in
hundreds of studies, with the majority reporting
an ergogenic effect. In the most
comprehensive meta-analysis to date, Branch
1 reported that creatine supplementation
results in increased lean body mass (≈2%),
muscle strength (≈11%), and high-intensity
exercise performance (≈8%). Several
potential mechanisms of how creatine
supplementation exerts an ergogenic effect
have been identified. However, these
mechanisms have not been described
collectively and critically reviewed. The
purpose of this review is to examine studies of
the mechanisms underlying muscular
adaptations to creatine supplementation.
Methods
PubMed and SPORTDiscus databases were
searched from 1992 to 2007 using the terms
creatine, creatine supplementation, creatine
monohydrate, and phosphocreatine. Related
studies were located by reviewing the
reference lists of the articles identified through
the computer database search. There are
many studies of the effects of creatine
supplementation in patient populations (e.g.
Sarcopenic elderly 2, Amyotrophic Lateral
Sclerosis 3, Parkinson’s disease 4, Muscular
Dystrophy 5, etc) and in models of muscle
atrophy/disuse 6, 7. Due to the number of
confounding variables that might influence the
response of these individuals to creatine, the
present authors have chosen to examine
creatine supplementation research that
focused on healthy young subjects under
resting or post-exercise conditions.
Additionally, as there appear to be species
differences in the response to creatine
supplementation 8-11, this review focuses on
data from human trials. Only a small number
of studies were identified, so a meta-analysis
was not performed.
Functions of creatine and phosphocreatine
Creatine and phosphocreatine are often
referred to together as an energy system,
which serves as a temporal energy buffer
under conditions of high energy demand 12.
Since 1981, when the term “phosphocreatine
shuttle” was introduced, creatine and
phosphocreatine have also been studied as a
spatial energy buffer, which acts as an energy
transport system 12, 13. During physical activity,
declines in adenosine triphosphate (ATP) are
prevented when phosphocreatine
phosphorylates adenosine diphosphate (ADP)
to form ATP. For instance, Hirvonen et al. 14
measured muscle phosphocreatine during
sprinting, and found that 88-100% of muscle
phosphocreatine was depleted in about 5.5
seconds 14. Phosphocreatine resynthesis is
an aerobic process that takes approximately 3
to 6 minutes to complete, depending on
exercise intensity, duration, and the number of
bouts 15-18. Because the creatine kinase-
phosphocreatine energy system is so critical to
maintain ATP levels during exercise,
increasing or decreasing basal levels of
muscle creatine must alter energy metabolism.
Muscle creatine and phosphocreatine can be
reduced with a vegetarian diet 19, 20, or
increased approximately 25% following high-
dose short-term (≈20g d-1 for 5 d) or low-dose
long-term (≈3g d-1 for 28d) creatine
supplementation 2, 19, 21-27. The effects of
creatine supplementation on muscle function
(i.e. strength, endurance, power) have been
studied in hundreds of investigations

Mechanisms of muscular adaptations to creatine supplementation
International SportMed Journal, Vo.8 No.2, 2007,
pp.43-53, http://www.ismj.com
Official Journal of FIMS (International Federation of Sports Medicine)
45
(reviewed in 1), 28-31. Generally, if an individual
is able to significantly increase muscle
creatine and phosphocreatine levels with
supplementation there is the potential for an
ergogenic effect. About 70% of creatine
supplementation studies report enhanced
performance subsequent to creatine
supplementation (reviewed in 28). Creatine
appears to be most effective when exercise
time is brief (<30sec), intensity is maximal, and
contractions occur over repeated bouts 1.
Additionally, creatine supplementation may
enhance sprint performance when intense
exercise follows or is interspersed during an
endurance exercise task (i.e. cycling) 32, 33.
Potential mechanisms for the ergogenic
effect of creatine
It is unknown through what mechanism of
action creatine supplementation produces an
ergogenic effect. Potential mechanisms
include: metabolic adaptations, changes in
protein turnover, hormonal alterations,
stabilisation of lipid membranes, molecular
modifications, or as a general training aid
(Figure 1 – see at end of text). These
mechanisms of action are not mutually
exclusive and most likely the mechanism of
action is multifaceted.
Metabolic adaptations
There are several metabolic changes resulting
from creatine supplementation that may
influence exercise performance, including:
increased muscle creatine and
phosphocreatine, increased muscle glycogen,
and faster phosphocreatine resynthesis.
Creatine supplementation is considered by
some to be analogous to carbohydrate
loading. That is, by ingesting large quantities
of creatine during the days before exercise
performance, muscle phosphocreatine is
increased, and subsequently performance will
be improved. Thus creatine supplementation
may simply provide more fuel and enhance the
buffering capacity of skeletal muscle by
increasing basal levels of muscle
phosphocreatine. One would assume that a
caveat of this paradigm would be that the
exercise must rely heavily on the creatine
kinase-phosphocreatine energy system (i.e.
<30sec of maximal intensity exercise).
However, performance-enhancing effects of
creatine supplementation have been noted in
studies with significantly longer exercise tasks
(30-150sec) (reviewed in 1). In a meta-
analysis, Branch 1 reported that creatine
supplementation increased performance
(≈5%) during exercise tasks that rely on
anaerobic glycolysis including bicycle
ergometry, isometric force production, and
isotonic strength. Increased muscle
phosphocreatine is an unlikely explanation for
improved exercise performance in tests >30
seconds in duration, which rely on the
glycolytic pathway for ATP production.
Creatine supplementation, in fact, significantly
increases muscle glycogen (reviewed in 31).
Five of six studies reviewed by Volek and
Rawson 31 showed that creatine
supplementation alone or in combination with
carbohydrate and/or protein, increases muscle
glycogen greater than carbohydrate or placebo
supplementation. This metabolic alteration
may explain the improvement in exercise
performance subsequent to creatine ingestion
in tasks >30 seconds.
Creatine supplementation may also enhance
recovery during repeated bouts of exercise
due to enhanced phosphocreatine resynthesis
22, 34, although this has not been shown in
every case 35. Greenhaff et al. 22 took biopsies
from the vastus lateralis muscle of eight
subjects following 0-, 20-, 6, and 120 seconds
respectively of recovery from electrically
evoked contractions following creatine
supplementation (20g/d for 5d). In responders
(mean 24% increase in basal muscle
creatine), phosphocreatine resynthesis was
increased (35%) during the second minute of
recovery. Yquel et al. 34 used 31P nuclear
magnetic resonance spectroscopy to
demonstrate increased phosphocreatine
resynthesis during recovery from 7 bouts of
plantar flexion exercise. Thus there are
sufficient data to indicate that metabolic
adaptations (i.e. increased muscle glycogen
and phosphocreatine, faster phosphocreatine
resynthesis) are one of the mechanisms
through which creatine exerts an ergogenic
effect. The mechanism for the increased
glycogen storage is not fully understood, but
may be mediated through increased GLUT-4
protein content, as has been described in
creatine-supplemented subjects following
immobilisation and rehabilitation exercise
training 6, 7.
Protein turnover
Prior to creatine becoming a popular dietary
supplement, a series of in vitro and in vivo
investigations by Ingwall and colleagues 36-39

Mechanisms of muscular adaptations to creatine supplementation
International SportMed Journal, Vo.8 No.2, 2007,
pp.43-53, http://www.ismj.com
Official Journal of FIMS (International Federation of Sports Medicine)
46
showed that myosin heavy-chain, actin and
creatine kinase synthesis increased in cardiac
and skeletal muscle subsequent to creatine
exposure. Additionally, Häussinger et al. 40
demonstrated that hyperhydrating a cell, which
may happen during creatine supplementation,
is an anabolic signal which positively impacts
protein turnover. Although the theory for a role
of creatine in protein synthesis is based on
sound logic and data, there appears to be little
effect of creatine supplementation on protein
synthesis in humans
Parise et al. 41 supplemented 27 men and
women with creatine (20g/d for 5d followed by
5g/d for 3-4d) or placebo respectively, and
found no effect on plasma rate of leucine
appearance, leucine oxidation, non-oxidative
rate of leucine disposal, mixed muscle protein
synthesis, nitrogen balance, and fat free mass.
However, creatine reduced plasma leucine
rate of appearance (-7.5%) and leucine
oxidation rate (-19.6%) in men. Because there
was no muscle-specific measure of protein
turnover, and no change in fat free mass
(muscle composes ≈30% of whole body
protein turnover), the authors speculated that
these changes may have occurred in liver or
splanchnic proteins. Subsequently, Louis et al
42, 43 investigated the effects of creatine on
muscle protein turnover at rest, and in post-
absorptive and post-exercise states using [1-
13C] leucine and [2H5] phenylalanine. In the
first study, six males ingested creatine (21g/d
for 5d) and myofibrillar protein synthesis and
muscle protein breakdown were assessed in
post-absorptive and fed states 43. Creatine
had no effect on myofibrillar protein synthesis
or muscle protein breakdown 43. In a second
study, seven males ingested creatine (21g/d
for 5d) and myofibrillar protein synthesis and
muscle protein breakdown were assessed
following 20 sets of 10 repetitions of knee
extension/flexion exercise (75% 1RM) 42.
Again, there was no effect of creatine on
muscle protein turnover 42. Based on these
data, it seems unlikely that the increase in fat-
free mass associated with creatine
supplementation is mediated through
increased protein synthesis or decreased
protein breakdown.
Stabilisation of lipid membranes
There is some indication that creatine
supplementation reduces muscle damage and
enhances recovery from stressful exercise.
Greenwood and colleagues reported fewer 44
instances of muscle dysfunction (cramping,
muscle tightness, strains, injuries, etc)
between creatine and non-creatine users, and
survey data 44, 45 and anecdotal reports 46
indicate that exogenous creatine and
phosphocreatine decrease muscle soreness
and increase recovery between workouts. It is
possible that increased muscle
phosphocreatine levels resulting from creatine
supplementation could reduce muscle
dysfunction, reducing muscle soreness or
enhancing recovery. Exogenous
phosphocreatine reduces muscle damage in
cardiac tissue by stabilising the membrane
phospholipid bilayer, decreasing membrane
fluidity, and turning the membrane into a more
ordered state 47, 48. In cardiac tissue, this
decreases the loss of cardiac muscle proteins,
which indicates less muscle tissue damage 47.
The results of clinical trials of the effects of
oral creatine supplementation on skeletal
muscle damage and recovery from stressful
exercise are discrepant; some data indicate no
effect of creatine on post-exercise muscle
function 49, 50, while other data demonstrate
decreased muscle damage (i.e. reduced
muscle serum proteins) 51. Santos et al. 51
reported a blunted increase in plasma creatine
kinase (19%), prostaglandin E2 (61%), tumour
necrosis factor-α (34%), and plasma lactate
dehydrogenase (100%) in creatine
supplemented athletes following a 30km run.
Rawson et al. 49, 50 found no attenuation of
creatine kinase, lactate dehydrogenase, range
of motion, soreness, or strength following 50
maximal eccentric contractions of the elbow
flexors 49 or a high-repetition squat test (15 to
20 reps at 50% 1RM) 50. Currently, there are
insufficient data to claim that oral creatine
supplementation reduces muscle damage or
enhances recovery from stressful exercise, but
these studies do indicate that creatine
supplementation does not worsen muscle
damage as has been promulgated in the
popular media.
Hormonal alterations
Based on the fact that creatine
supplementation results in a rapid increase in
body mass and fat-free mass, it has been
hypothesised that creatine induces
hypertrophy through endocrine mechanisms.
Volek et al 52 assessed testosterone and
cortisol immediately post-exercise (5 sets of
bench presses and jump squats) in creatine
(25g/d for 7d) and placebo-supplemented
subjects, and found no effect of creatine on
endocrine status. Op‘t Eijnde and Hespel 53

Mechanisms of muscular adaptations to creatine supplementation
International SportMed Journal, Vo.8 No.2, 2007,
pp.43-53, http://www.ismj.com
Official Journal of FIMS (International Federation of Sports Medicine)
47
examined the combined effects of resistance
exercise and an acute creatine bolus (10g) in
creatine-loaded subjects (20g/d for 5d), and
found that the growth hormone response to
exercise was unaltered by creatine. Schedel
et al. 54, however, found increased growth
hormone levels (83%) in response to a 20g
oral creatine bolus. It is difficult to resolve a
practical application for these data, as the
increase in growth hormone was similar to
what is seen following exercise, and athletes
do not typically ingest 20g of creatine per
serving. These available data indicate that
creatine supplementation (20-25g/d for 5-7d),
as it is ordinarily practiced by athletes, does
not alter exercise responses to testosterone,
cortisol, and growth hormone. Thus it seems
unlikely that increases in body mass and fat-
free mass secondary to creatine
supplementation are hormonally mediated.
The fact that a large unaccustomed dose of
creatine (20g/serving) can increase growth
hormone requires further investigation.
Molecular modifications
Creatine researchers have benefited from
advances in laboratory techniques and the
recent surge of interest in genomics. It has
been hypothesised that, if creatine
supplementation itself causes skeletal muscle
adaptations; perhaps, these changes occur at
the molecular level. Willoughby and Rosene 55
demonstrated that creatine supplementation
(6g/d for 12wk) plus resistance training results
in a significantly greater increase in fat-free
mass (4%), muscle volume (21.9%), strength
(65%), myofibrillar protein (58%), Type I
(33%), IIa (31%), and IIx (36%) myosin heavy
chain mRNA expression and Type I (17%) and
Type IIx (16%) myosin heavy chain protein
expression than resistance training alone. In a
subsequent study 57, these researchers
demonstrated that creatine supplementation
(6g/d for 12wk) plus resistance training
increased creatine kinase, myogenin, and
MRF-4 mRNA expression, and myogenin and
MRF-4 protein expression compared with
resistance training and placebo ingestion
More recently, Deldicque and colleagues 56
reported that creatine supplementation (21g/d
for 5d) increased IGF-I (30%) and IGF-II (40%)
mRNA in resting muscle. Whereas the work of
Willoughby and Rosene 55, 57 provides
evidence of a molecular effect of creatine plus
resistance training on skeletal muscle, the
work of Deldicque et al. 56 offers evidence of
an independent effect of creatine. In support
of cell culture 58 and animal research 59, Olsen
et al. 60 demonstrated that 16 weeks of
creatine supplementation, combined with
resistance training, augments increases in
satellite cell number and myonuclei
concentration in healthy males. Collectively,
these studies indicate that creatine alone, or in
combination with resistance training, causes
molecular and cellular adaptations leading to
skeletal muscle hypertrophy.
Training aid
Rawson and Volek 30 reported that creatine
supplementation and concurrent resistance
training result in an 8% greater increase in
strength and a 12% increase in muscular
endurance than does resistance training
alone. It could be hypothesised that chronic
creatine supplementation does not have a
direct effect on skeletal muscle (e.g. protein
synthesis), but simply enhances the ability of
athletes to train hard in the weights room (e.g.
complete more repetitions of each exercise,
faster recovery between sets, etc), via
increased basal muscle phosphocreatine and
glycogen, and faster phosphocreatine
resynthesis. In this manner, creatine
supplementation acts as a training aid, by
allowing athletes to train at higher
volumes/intensities over time. Evidence to
support this includes spontaneously higher
training volumes in creatine- vs. placebo-
supplemented subjects during a 12-week
resistance training intervention 27.
Additionally, others have found that when
training volume is controlled for through
voluntary- (i.e. creatine-supplemented subjects
cannot exceed the prescribed training
programme) 61 or electrically-stimulated
contractions 62, there is no apparent effect of
the creatine. Thus there is evidence to
support the contention that muscular
adaptations to creatine supplementation are
dependent on increased training loads.
However, Arciero et al. 63 showed that chronic
creatine ingestion (20g/d for 5d followed by
10g/d for 23d), with or without resistance
training, result in significant increases in bench
press (creatine no training 8%; creatine plus
resistance training 18%) and leg press
(creatine no training 16%; creatine plus
resistance training 42%) strength. More work
needs to be done in this area as certain
variables, such as creatine supplementation
duration, training load, and training status of
the subjects, may all confound interpretation of
the results.

Mechanisms of muscular adaptations to creatine supplementation
International SportMed Journal, Vo.8 No.2, 2007,
pp.43-53, http://www.ismj.com
Official Journal of FIMS (International Federation of Sports Medicine)
48
Discussion
Supplementation with creatine gained
popularity in the early 1990s and to date
remains one of the most popular performance-
enhancing strategies used by athletes.
Creatine has target effects in tissues with high
metabolic demands, such as skeletal muscle,
brain tissue, and the eye, but the effects of
creatine on skeletal muscle is of primary
interest to athletes. In general, the entry of
creatine into target tissues is capacity-limited,
with movement governed by creatine transport
proteins. Once in the cell, however, the exact
cascade of events that governs performance
enhancement is unresolved, though several
theories have been proposed. Table 1 is a
summary of clinical studies of the mechanisms
through which creatine supplementation
causes muscular adaptations. The strength of
evidence from available clinical trials is ranked
from weak to strong.
Table 1: Summary table of mechanisms supporting muscular adaptations to creatine supplementation
from clinical studies.
9
= weak evidence;
9999
= strong evidence
Mechanism Examples Strength of
support
References
Metabolic
adaptation
↑ muscle glycogen and phosphocreatine;
↑ phosphocreatine resynthesis rate 9999 6, 7, 22, 34, 64-66
Protein turnover ↑ protein synthesis and/or ↓ protein
degradation 9 41-43
Lipid membrane
stabilisation
↓ muscle damage and/or ↑ recovery from
stressful exercise 99 49-51
Hormonal
alterations
↑ growth hormone 9 53, 54
Molecular
modifications
↑ myosin heavy chain mRNA expression;
↑ growth factor (i.e. myogenin and MRF-
4) mRNA expression; ↑ IGF-I and IGF-II
mRNA expression; ↑ satellite cell number
and myonuclei concentration
9999 55-57, 60
Training aid ↑ training volume 9999 27
The metabolic changes resulting from creatine
supplementation appear to be the most logical
mechanism of action and are supported by
observed changes in intramuscular
phosphocreatine and glycogen. Individuals
who consume creatine have increases in
muscle strength and lean body mass, thus
changes in protein turnover have been
proposed. Although potential mechanisms of
muscle gain have been hypothesised (e.g.,
increased cellular hydration), studies to date
have not confirmed a net change in protein
synthesis/degradation. Though changes in
muscle protein turnover have not been found,
changes in satellite cells may, in part, explain
enhanced muscle function. While most
mechanisms proposed focus on muscle as a
target, systemic changes via hormonal

Mechanisms of muscular adaptations to creatine supplementation
International SportMed Journal, Vo.8 No.2, 2007,
pp.43-53, http://www.ismj.com
Official Journal of FIMS (International Federation of Sports Medicine)
49
alterations have not been ruled out; evidence
suggests a role for human growth hormone.
Creatine has been shown to increase training
volume, which may or may not be a function of
the mechanisms proposed in this review.
Conclusions
Creatine supplementation causes adaptations
to skeletal muscle through both direct and
indirect mechanisms. These adaptations
partially explain the increases in fat-free mass
and strength and improvements in exercise
performance following oral creatine ingestion.
While several potential mechanisms identified
that support muscular adaptations to creatine
supplementation have strong support (i.e.
metabolic adaptations, molecular
modifications, and training aid), others (i.e.
protein turnover, lipid membrane stabilisation,
and hormonal alterations) have less support.
Address for correspondence:
Professor Eric S Rawson, 131 Centennial Hall,
Department of Exercise Science and Athletics,
Bloomsburg University, Bloomsburg, PA
17815, USA
Tel.: +1 570 389 5368
Fax: +1 570 389 5047
Email: erawson@bloomu.edu
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Figure 1: Potential mechanisms of action for muscular adaptations to creatine supplementation
include: metabolic adaptations, protein turnover, hormonal alterations, stabilisation of lipid
membranes, molecular modifications, or as a general training aid.