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Nutrition for Health and Performance
SR4S010
Literature Review – Creatine
Word count: 2727
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Creatine is a well-researched dietary supplement which is a non-protein, nitrogenous
compound (Buford et al,. 2007). It was discovered by French scientist Michel Chevrul
whom extracted a substance, now known as creatine, from skeletal muscle in 1832
(Balsom et al., 1994). Due to the area of the body in which it was discovered, the word
“creatine” derives from the Greek word “kreas” meaning “meat” (Feldman, 1999).
Literature states the association of muscular work and the accumulation of creatine
was noticed by Lieberg in the mid-1800s, where the meat in chased wild fox had higher
creatine stores than within captive foxes (Balsom et al., 1994). Proceeding into the
early twentieth century, speculations were made on creatine being stored within the
body, where creatine ingested was more than what was excreted in urine (Seecof et
al., 1934; Balsom et al., 1994). In this time period, a phosphorus compound named
phosphocreatine was observed in cat skeletal muscle, where Fiske and Subbarow
found that with electrical stimulation, phosphocreatine disappeared then gradually
regained to its previous levels (Demant and Rhodes, 1999; Cupp and Tracy, 2003).
The general understanding of creatine has drastically improved, where it is known that
approximately 95% of creatine is stored within skeletal muscle, with small amounts
found in the brain and testes (Buford et al., 2007). These stores are two-thirds
phosphocreatine, with the remaining being stored as free creatine (Balsom et al,.
1994). Creatine can be synthesised within the body, involving amino acids in the liver
and kidneys, or it could be consumed primarily through meat and seafood or via
supplementation (Wyss and Daouk, 2000; Brosnan and Brosnan, 2016).
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Rationale
Creatine supplementation become popular after the 1992 Olympic Games and is now
widely used among recreational and professional athletes (Trexler and Smith-Ryan,
2015; Close et al., 2016). It is established that creatine is beneficial for high-intensity
anaerobic activities, especially in the form of repeated bouts of physical activity
(Kreider et al., 2017). Optimal doses of creatine for physical performance most likely
will not be attained through dietary sources, especially in vegetarian and vegan diets
(Rogerson, 2017; Balestrino and Adriano, 2019). Therefore, it may be of interest to
highlight whether these population types would respond differently to non-vegetarians.
In brief, purpose for creatine consumption is to increase phosphocreatine levels to
postpone fatigue, enhance performance and recovery (Wallimann et al,. 2011). These
aspects and many others have been comprehensively researched by institutions such
as the International Society of Sports Nutrition [ISSN] (Kreider et al., 2017). The aim
of this review is to approach the research of creatine with the intentions of providing a
rationale for its consumption by strength athletes. It will highlight the reasons why
creatine has been denoted as most beneficial for anaerobic-based sports by exploring
the phosphocreatine system, the biological mechanisms in which creatine influences,
the evaluation of the evidence base surrounding the ergogenic value of creatine, risks,
the optimal protocol in supplementing creatine and any potential health benefits.
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Discussion
The Creatine Phosphate (PCr) Energy System (276)
As an introduction to the PCr energy system, it is often referred to as the immediate
energy system that supplies energy through anaerobic processes, and is predominant
in explosive physical activity, which involves fast-twitch muscle fibres contracting for
maximal strength and power (Casey and Greenhaff, 2000). Inherently, the PCr energy
system is generally available for ten seconds, with it taking around thirty seconds of
complete rest to regenerate around half of previous phosphagen stores and between
three to five minutes for full replenishment (Morton, 2008). In regards to the reactions
that comprise the PCr system, there is the creatine kinase, adenylate kinase and the
adenosine monophosphate deaminase reaction which are illustrated in figure 1 (Baker
et al., 2010).
Figure 1 – The combined reactions that make the creatine phosphate energy system
(Baker et al., 2010).
In the creatine kinase and adenylate kinase reactions, there is production of adenosine
triphosphate (ATP), which is the energy molecule within the body that supplies various
cellular and fundamental processes for cell homeostasis (Ferreira-Guimaraes, 2014).
Returning to the idea that having sufficient availability of phosphocreatine, possibly
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through supplementation, is essential for its optimal effects in strength athletes. This
can be demonstrated in the creatine kinase reaction particularly because it involves
phosphocreatine within the reaction and that this reaction has a much larger capacity
for ATP regeneration in comparison to the adenylate kinase reaction (Baker et al.,
2010). During high-intensity activity, phosphocreatine is broken down to form ATP
through the pairing of a phosphate molecule to an adenosine diphosphate molecule,
this reaction also produces free energy through hydrolysis, therefore acting as a buffer
for the resynthesis of ATP, thus providing energy for muscular contraction (Wallimann
et al., 2011; Schlattner et al., 2016). This paired with the knowledge that a normal diet
consists of around one to two grams of creatine per day, muscle creatine stores are
between 60 to 80% saturated, showing that supplementation of creatine could allow
for increases of 20 to 40% in muscle creatine stores, thus more availability of creatine
and phosphocreatine (Kreider et al., 2017).
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Biological Mechanisms behind the Potential Benefits of Creatine (334)
Higher muscle availability of creatine and phosphocreatine allows for more rapid ATP
regeneration between exercise bouts and also delays the time in which
phosphocreatine stores become depleted (Cooper et al., 2012). This delay in depletion
could equate to less dependence on the glycolytic system during intense exercise,
which would be beneficial to reducing muscular fatigue. An explanation to this is that
the process of glycolysis leads to metabolic factors such as hydrogen ions and
inorganic phosphates which play a role in muscular fatigue (Wan et al., 2017). It is
known that exercise-induced muscular acidosis is due to an accumulation of hydrogen
ions, which leads to reductions in muscular force (Metzger and Moss, 1990). In
addition, prolonged intense exercise leads to increased inorganic phosphates which
impair myofibrillar performance, contributing to decreased muscular activation (Allen
and Trajanovska, 2012). It is explained that creatine supplementation reduces reliance
of the glycolytic system through inhibition of the activated protein kinase (AMPK)
pathway (Ponticos et al., 1998), which is consistent with the role of AMPK being a
sensor of cellular energy status (Schimmack et al., 2006). It is suggested that due to
decreases in the concentration of phosphocreatine, it may be key to regulation of
AMPK in short exercise bouts. This has been demonstrated in an animal study, where
transport-stressed chickens were given creatine, which revealed reductions in
glycolysis within the pectoral muscle (Zhang et al., 2017). In terms of the influence of
creatine supplementation on protein synthesis, it is still unclear what mechanisms
would be active to cause an effect (Farshidfar et al., 2017). It is speculated that cellular
swelling can increase the strain on the sarcolemma, stimulating protein synthesis
(Farup et al., 2015). Although a speculation, it does have a suitable rationale for the
water retention effect of creatine. This has been tested, where there is no proof of
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creatine supplementation effecting protein synthesis and degradation (Louis et al.,
2003) however, cellular swelling may be just one factor that is responsible for changes
in protein synthesis. Other factors could be shown within the process of forming
muscle, where creatine supplementation increases expression of mRNA for insulinlike growth factor, resulting in increased satellite cell activation (Hespel et al., 2001;
Deldicque et al., 2005). This evidence indicates the effects of creatine are multifactorial
towards changes in protein synthesis.
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Ergogenic Value of Creatine Supplementation for Sports Performance (526)
It has been established for many years that there is a positive relationship between
exercise performance and creatine uptake (Casey and Greenhaff, 2000). With
reference to the biological mechanisms that creatine supplementation influences, the
main contribution to improvements in physical activity comes from the higher
availability of creatine which allows for more work done during training. Currently, there
are vast amounts of evidence to show that long-term creatine supplementation leads
to greater improvements in gaining strength and muscle mass, leading to improved
exercise capacity and training adaptations (Kreider et al., 2017). This is shown
throughout the age range, from adolescents, young adults and the elderly
(Tarnopolsky, 2000; Juhasz et al., 2009; Claudino et al., 2014).
Moreover, earlier research of the ergogenic value of creatine were somewhat
conflicted, where some studies reported no benefits of creatine supplementation on
exercise performance (Snow et al., 1998; Gilliam et al., 2000; Finn et al., 2001). This
could be explained by the type of study, where all employ a cross-sectional design
which prevents the opportunity for all participants to receive treatment as would in a
crossover design. In addition, other factors could be small sample sizes (Snow et al.,
1998), repeated bouts of maximal-intensity exercise with a small recovery periods
(Gilliam et al., 2000; Finn et al., 2001) or factors that could have an effect, but are not
apparent being non-responders, gender and age. In regards to gender, the majority of
creatine research has been conducted in men, despite this it is suggested that men
see a larger gain in strength and muscle hypertrophy than women (Johannsmeyer et
al., 2016). This may be due to muscle protein catabolism potentially being gender
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specific, where indicators of muscle protein catabolism in urine decreased within
males who supplemented creatine but not females (Parise et al., 2001; Johannsmeyer
et al., 2016). In addition, resting muscle creatine stores may be higher in women,
therefore they may not responding to supplementation as well although, generally
responders possess more type II muscle fibres (Tarnopolsky, 2000; Cooper et al.,
2012).
In terms of strength, systematic reviews of upper and lower-limb strength reveal that
creatine has beneficial effects in exercise that is less than three-minutes in duration,
with improvements in compound exercises shown in the bench press and squat at
5.3% and 8% respectively, with creatine supplementation (Lanhers et al., 2015;
Lanhers et al., 2016). In regard to sports performance, the ISSN provides a list of
creatine benefits and which sports could benefit including increased phosphocreatine
benefitting track or swim sprinting, increased phosphocreatine resynthesis being
advantageous for basketball, field hockey and volleyball, with reduced muscle acidosis
aiding downhill skiing, water sports such as rowing, combat sports such as MMA, with
increased body mass or muscle mass improving American football, bodybuilding,
track/field events such as javelin and discus (Kreider et al., 2017). Regarding
increases in body mass, an interesting study examined the effects of heavy resistance
training alongside creatine supplementation in vegetarian and non-vegetarian,
resistance trained men and women over eight-weeks (Burke et al., 2008). In
comparison, the creatine group gained 2.2kg where the isocaloric-placebo gained
0.6kg, with the vegetarian group gaining the largest amount of lean mass compared
to non-vegetarian by 2.4 to 1.9kg, respectively. A review states that vegetarian diets,
or even more restricted diets such as veganism, may find the greatest increases in
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creatine stores with supplementation where pre-existing creatine stores would be low,
dependant on the time the diet has been followed (Kaviani et al., 2020). Due to the
reported benefits, creatine supplementation has been regarded as the most effective
ergogenic aid since 2007 by the ISSN, and later by the American College of Sports
Medicine [ACSM] (Buford et al., 2007; Thomas et al., 2016).
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Protocol for Creatine Supplementation (351)
Throughout the literature, the most common researched form of creatine is creatinemonohydrate (Kreider et al., 2017). In order for increased creatine muscle stores, it is
advised to start with a loading phase of five to seven days consuming approximately
0.3 grams per kilogram of body mass separated throughout the day, or around 5
grams, four times daily (Hultman et al., 1996; Kreider et al., 2017). This loading-phase
will allow for muscle creatine stores to become fully saturated. Following this,
maintenance of creatine stores is required where a general recommendation is to
ingest 3 to 5 grams daily with some exceptions of larger individuals potentially needing
up to 10 grams per day (Kreider et al., 2017). Alternatively, a loading-phase is not
necessary to reach saturation of muscle creatine stores, where consumption of 3
grams per day for 28 days is suffice (Hultman et al., 1996). However, this is less
effective compared to the loading method, where stores during loading saturate more
quickly and thus, more time for the benefits of saturated creatine stores. The cessation
of creatine ingestion whilst creatine stores are at full capacity, would generally take 4
to 6-weeks for creatine stores to reach baseline, with no evidence to suggest long term
use supresses’ endogenous creatine synthesis, therefore there is no need to cycle on
and off of creatine (Hultman et al., 1996; Kim et al., 2011).
It can be of use to know that dietary or supplementary components could enhance or
hinder the performance benefits associated with creatine. The ISSN state the
consistency of findings that show ingestion of carbohydrates or carbohydrates and
protein alongside creatine consumption will allow greater retention however, acute
effects do not impact performance of anaerobic Wingate tests but long-term
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carbohydrate-protein and creatine combined allows for greater muscle hypertrophy
(Cribb et al., 2007; Kreider et al., 2017; Theodorou et al., 2017). Additionally,
supplementing β-hydroxy β-methylbutyrate (HMB) alongside creatine-monohydrate
has been reviewed, with some evidence to show that three-ten grams creatine with
three grams HMB could provide greater improvements in strength, anaerobic
performance and body-composition instead of consuming either on its own (Landa et
al., 2019). Lastly, consideration should be given on consuming caffeine along with
supplementing creatine with it being hypothesised that high caffeine doses (more than
5mg/kg of body mass) could be competing with the mechanistic pathways of creatine
however, there is a lack of good-quality research (Trexler and Ryan, 2015).
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Common Misconceptions and Potential Side Effects of Creatine (470)
The ISSN, the American Dietetic Association of Canada and the ACSM have reported
the most consistent side effect associated with creatine supplementation is weight gain
(Buford et al., 2007; Rodriguez et al., 2009; Thomas et al., 2016). Literature suggests
this weight gain is due to water retention, which occurs in the first few days of starting
creatine supplementation (Hall and Trojian, 2013). This has led to the acceptance that
increased water retention experienced short-term, attributes to long-term increases
(Francaux and Poortmans, 2006). It is unclear where water retention resides within
the body, with short-term investigations showing that total body water content
increases with extracellular body water (Rosene et al., 2015), and through intracellular
water (Ziegenfuss et al., 1998). Evidence supporting increased water retention is that
creatine is an osmotically active substance (Powers et al., 2003), delivered to the
muscle via a sodium-dependent transporter, where sodium needs water to maintain
intracellular osmolality (Wyss and Daouk, 2000). However, it is likely that due to the
sodium-potassium pumps, intracellular sodium concentration will not be drastically
affected through creatine supplementation (Francaux and Poortmans, 2006). Some
studies also report no increases in total body water, even with a loading-phase, and
were monitoring body water content over 5-weeks of creatine supplementation
(Rawson et al., 2011; Jagim et al., 2012; Andre et al., 2016). Therefore, this conflicting
evidence does warrant further research with a consideration that total body water
measures rely on assumptions (Dasgupta et al., 2019). In summary, there is evidence
to show that creatine supplementation may cause an increase in water retention
however, there are studies that report no effects which indicates water retention may
be an adverse effect for specific populations.
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A necessary well-researched anecdotal claim that has been reported is the association
of creatine supplementation and kidney dysfunction. Creatine and phosphocreatine
are degraded within the body to creatinine, which is transported via the blood and
excreted in urine (Wyss and Daouk, 2000). Creatinine is filtrated by the kidneys, where
increased blood creatinine levels are a marker of kidney dysfunction. However,
creatinine levels are related to lean body mass and creatine intake, where creatine
supplementation causes high-levels of excreted creatine, when usually it is not present
in urine, this has led to unsupported perspectives that creatine supplementation
causes damage to the kidney/renal dysfunction (Hultman et al., 1996; Rawson et al.,
2002). This originated in a case study, where the case had pre-existing kidney disease
for eight years, when the case began supplementing with creatine, blood creatinine
levels increased and despite being in good health, it was concluded that the
individual’s kidney health was declining (Pritchard and Kalra, 1998). Since then,
investigations in the effects of creatine on kidney/renal function show no evidence of
adverse effects in healthy individuals (Perksy and Rawson, 2007; Gualano et al., 2012;
Silva et al., 2019). Interestingly, studies that reported renal dysfunction in those
supplementing with creatine, also found that affected cases had pre-existing kidney
disease, were on additional medications, consumed inappropriate doses of creatine
or used anabolic steroids (Gualano et al., 2012). Other unsupported anecdotal reports
have associated creatine supplementation with musculoskeletal injury, dehydration,
muscle cramping and gastrointestinal upset (Powers et al., 2003; Kreider et al,. 2017;
Antonio et al., 2021). These reports have been disproved, which will be discussed
further in the health benefits associated to creatine supplementation. In summary,
creatine-monohydrate can be deemed safe for consumption in healthy individuals
however, the long-term effects of creatine supplementation remains unknown.
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Health Benefits of Creatine (176)
Continuing from the unsupported claims, it could be argued that much of the peerreviewed evidence involving these aspects of creatine supplementation suggests the
opposite. For example, American collegiate footballers reported that creatine
supplementation lessened the feeling of dehydration, muscle cramping/tightness and
less incidence of injury (Greenwood, Kreider, Melton et al., 2003). Within another
study, similar findings were seen where footballers were monitored over a football
season (over four months), where creatine users experienced significantly less
injuries, feelings of dehydration, and muscle tightness/strain (Greenwood et al., 2003).
Moreover, research provides evidence for the use of creatine in treating muscle
atrophy, whether it would be for those with injury (Hespel and Derave, 2007) or if it
was age-related (Dolan et al., 2019). In immobilised individuals with a leg cast,
creatine supplementation has shown to aid rehabilitation over ten-weeks with
increases of 10% in cross-sectional area of muscle fibre and a 25% increase in peakstrength alongside knee-extension exercise (Hespel and Derave, 2007). Interestingly,
there is some support for creatine consumption improving memory and intelligence
tasks (Avgerinos et al., 2018), with a potential for clinical outcomes in neuromuscular
diseases such as Parkinson and Huntington’s disease (Kreider et al., 2017). More
research is needed in this area, due to conflicting findings (Bender and Klopstock,
2016).
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Conclusion (179)
Throughout the literature, creatine is a well-established supplement in terms of the
consistent reports of associated ergogenic benefits. This is shown within many studies
where creatine supplementation alongside resistance training is associated in greater
improvements in muscle strength, muscle hypertrophy, and sports performance.
There is a vast understanding, beyond the scope of this review, which reveals how
creatine supplementation causes these improvements from a mechanistic view.
Recommendations for optimal creatine supplementation would be to implement a
loading-phase, followed by a maintenance-phase and consume carbohydrate or
combinations or protein and carbohydrate to improve creatine retention. Importantly,
creatine is proven to be a safe, with most reported side-effects being disproved by
research with the exception of weight gain due to water retention. Pairing creatine with
HMB supplementation may provide greater improvements that either supplements
alone, with consideration needed that caffeine could blunt the effects of creatine. In
summary, creatine is safe, has well evidenced benefits for favourable training
adaptations and also has associated health benefits, therefore it would be of interest
for not only strength athletes but for the general population.
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