Creatine—more than just a sports nutrition supplement?


Introduction

Creatine-the basic facts

Creatine is a nonprotein nitrogen-containing compound that is found in the body, stored mainly in skeletal muscle (95%), but also in the brain, testes, liver, and kidney (Cooper et al., 2012). The total creatine pool in a 70-kg individual is about 120 g (Cooper et al., 2012). One of creatine’s main cellular functions is in the operation of the creatine phosphate system, an energy buffer for ATP. The body synthesizes about 1-2 g creatine per day from the amino acids glycine, arginine, and methionine. In addition, dietary sources of creatine (e.g., meats and fish) may provide another 1 g (Cooper et al., 2012). Typically, the body turns over about 1-2 g creatine per day via its conversion to creatinine, which is then excreted in the urine (Buford et al, 2007). Thus, the body requires continuous replenishment of its creatine supply from either diet or endogenous synthesis.

Creatine supplementation protocol

Creatine supplementation has been a popular practice among athletes for over 20 years. Harris et al. (1992) documented that supplementation with 5 g creatine monohydrate 4-6 times per day for 2 days or more resulted in significant elevation (up to 50%) of muscle creatine stores. In a series of experiments, Hultman et al. (1996) observed that: 1) total muscle creatine levels were increased by about 20% with 6 days of creatine monohydrate supplementation (5 g dose 4 times/d); 2) muscle creatine concentrations remained at this high level when the dose was reduced to 2 g/d for 30 d; and 3) a 28-day period of daily ingestion of 3 g creatine monohydrate caused a similar (~20%) increase in muscle creatine as did the 6-day loading period with 20 g/d. Currently, it is generally advised that the loading period (20 g/d, or ~0.3 g/kg body weight) is only needed if an individual wants to rapidly increase muscle creatine stores (in a week or so). For someone who has about a month or more in which to increase muscle creatine stores, a maintenance daily dose of 3-5 g creatine (~0.05 g/kg body weight) per day should suffice (Buford et al., 2007). It appears that there is a fixed limit to the amount of creatine that muscles can store and, as such, larger doses of creatine than those mentioned are not likely to produce additional benefits. This is reflected by the fact that some individuals who already have high baseline muscle creatine levels may be unresponsive to creatine supplementation (Greenhaff et al., 1994).

Creatine supplementation and sports nutrition

Several hundred studies have been conducted regarding the effects of creatine supplementation on athletic performance, with approximately 70% of studies showing positive results (Kreider, 2003a). The following gains are typical of those observed in multiple studies of creatine supplementation (Buford et al., 2007; Kreider, 2003a): 1) gains of an extra 2-4 lbs. of muscle mass during 4-12 weeks of training; 2) 5-15% gains in maximal power/strength; 3) increases of 5-15% in work performed during sets of maximal effort muscle contractions; 4) 1-5% improvement in single effort sprint performance; and 5) 5-15% enhancement in work performed during repetitive sprint performance. Probably the major explanation for these benefits is the ability of creatine supplementation to markedly increase intracellular levels of total and phosphocreatine (Harris et al, 1992). The transfer of a phosphate group from phosphocreatine to adenosine diphosphate (ADP), a reaction catalyzed by the creatine kinase enzyme, allows for rapid formation of adenosine triphosphate (ATP), the ultimate fuel source for powering muscle contraction.

However, it is now recognized that creatine plays a number of other roles that could influence muscle mass, strength, and training adaptations. In combination with resistance training, creatine supplementation augmented the training-induced increase in satellite cells and myonuclei number (Olsen et al., 2006), both of which are important precursors to muscle fiber hypertrophy. Creatine supplementation also can increase the messenger RNA (mRNA) and/or protein expression for a multitude of factors that promote muscular hypertrophy (e.g., collagen 1(α1), myosin heavy chains I and IIA, myogenin, myogenic regulatory factor 4, Myo D, insulin-like growth factor-I) (Deldicque et al, 2008; Deldicque et al., 2005; Willoughby and Rosene, 2003). Not only does creatine help promote muscle hypertrophy, but its use during resistance training also appears to downregulate the expression of myostatin, an inhibitor of muscle growth, above and beyond the effects of resistance training itself (Saremi et al., 2010). Finally, Deldicque et al. (2008) observed an increase in the mRNA for the GLUT-4 transporter in response to a bout of resistance training following 5 days of creatine supplementation at 21 g/d. Because the GLUT-4 transporter is involved in moving glucose from the blood into muscle cells, an intervention that might potentially increase GLUT-4 expression or activity could have implications for not only muscle fuel status, but also regulation of blood glucose in conditions such as diabetes (more on this later).
Creatine and health benefits outside of muscle

The multiple cellular effects of creatine, coupled with the presence of the creatine phosphate energy system in a wide variety of body cells, increase the potential that creatine supplementation may have health benefits that occur outside of just the muscles. Further, in some cases, there are therapeutic uses of creatine. For example, patients with gyrate atrophy of the choroid and retina have a defect in ornithine metabolism that secondarily impairs the body’s ability to synthesize creatine (normal synthesis in adults is about 1-2 g/d) (Persky and Brazeau, 2001; Walker, 1979). These patients experience atrophy of type II muscle fibers, degenerative brain changes, and progressive constriction of the visual fields that can ultimately end in total blindness by early to mid-adulthood (Evangeliou et al, 2009). Creatine supplementation in these patients helps increase muscle creatine levels, reverses muscular atrophy, and may help slow the progression of the visual changes in some patients (Vannas-Sulonen et al., 1985).

Creatine and brain function

The brain has high energy requirements and brain creatine levels are high relative to other tissues. The cytosolic and mitochondrial creatine kinase enzyme isoforms needed for the metabolism of creatine/creatine phosphate are found throughout the brain (Pan and Takahashi, 2007), thus making the creatine phosphate system a viable energy pathway. There is evidence that creatine from supplementation can cross the blood-brain barrier and raise brain creatine and creatine phosphate levels (Stöckler et al., 1996; Lyoo et al., 2003; Dechent et al., 1999; Pan and Takahashi, 2007). Interestingly, brain creatine levels measured by magnetic resonance spectroscopy have been found to be reduced in patients with severe vs. mild depression, panic disorder, and schizophrenia (Kato et al., 1992; Massana et al., 2002; Öngur et al., 2009). Thus, the question has arisen whether creatine supplementation may help restore normal creatine status in the brain and improve markers of cognitive status or mental health.

Several studies of short-term creatine supplementation in doses of 5-20 g creatine monohydrate/d for 5-15 d in young adults have shown improvements in cognitive performance and reaction time (measured via computer tasks), cerebral oxygen utilization, and mental fatigue during calculation tasks (Ling et al., 2009; Watanabe et al., 2002; McMorris et al., 2006; McMorris et al., 2007a; Rae et al., 2003; Benton and Donohoe, 2011). Of these studies, 2 involved vegetarian subjects (Rae et al., 2003; Benton and Donohoe, 2011) and 1 (Benton and Donahoe, 2011) showed benefits only in vegetarian subjects. This is an important consideration, as vegetarians generally have reduced body creatine stores relative to omnivores due to lack of dietary creatine intake (Burke et al., 2003). It should also be noted that the studies by McMorris et al. (2006, 2007a) employed sleep-deprived subjects. Thus, it may be that creatine benefits on cognitive function are more likely to be observed in individuals with low creatine stores or those undergoing a stressful situation such as sleep deprivation. Dose may be an issue as well, as Rawson et al. (2008) showed no improvement in cognitive function with a lower dose of about 2.1 g creatine/d for 6 weeks.

With regard to potential cognitive improvement by creatine supplementation in older individuals, results have been mixed. One study of non-exercising individuals (mean age 76 y) employing 20 g creatine/d for 7 days reported improved number and spatial recall and long-term memory tasks vs. placebo (McMorris et al., 2007b). However, another study incorporating a 20 g/d loading and 5 g/d maintenance creatine dosing protocol over the course of a 24-week strength program did not result in any significant cognitive or mood benefits above and beyond those of exercise alone (Alves et al., 2013).

Use of creatine as an augmentation to medical therapy for depression has also been investigated. Lyoo et al. (2012) studied 52 women with major depressive disorder in which their standard treatment with escitalopram (the selective serotonin reuptake inhibitor Lexapro) was augmented with either creatine (3 g/d for 1 week, then 5 g/d for 7 weeks) or placebo. The response to therapy, as quantified via the Hamilton Depression Rating Scale (HAM-D), was evaluated at baseline and at weeds 1, 2, 4, and 8 of therapy. The results are shown in Figure 1.

creatine-more-than-sports-supplement_chart_1
Figure 1. Percentage change in HAM-D score in patients with major depressive disorder on standard escitalopram therapy augmented with either creatine or placebo for 8 weeks. More negative scores indicate greater improvement in symptoms. bSignificant difference between groups in intent-to-treat analysis (P<0.001). Figure re-drawn from Lyoo et al. (2012).

Several other preliminary studies and case reports support additive benefits of creatine supplementation to medical depression therapy (Amital et al., 2006a; Amital et al., 2006b; Kondo et al., 2011; Roitman et al., 2007). The mechanism for how creatine may be helpful in these circumstances has not been defined, but it may have something to do with creatine’s role in improving brain energetics.

Creatine and diabetes

Skeletal muscle is a major site of insulin-mediated glucose uptake from the blood and, as such, its metabolic activity plays a key role in maintaining healthy glucose tolerance. Individuals with type 2 diabetes typically experience some degree of insulin resistance. As a result, uptake of glucose from the blood is reduced, leading to chronic elevation in blood glucose that is associated with macro and microvascular damage. A key pathway by which insulin exerts its effects is via its docking with the insulin receptor on the muscle cell membrane. This docking stimulates a series of intracellular steps that ultimately promote the migration of a glucose transporter protein, known as GLUT-4, from cytosolic vesicles to the cell membrane in order to facilitate glucose entry into the cell.

Regular exercise improves insulin sensitivity and GLUT-4 content in muscle cells (Dela et al., 1992; Houmard et al., 1995). However, creatine supplementation may also impact either the GLUT4 content of muscle or its cellular localization. In two different studies involving immobilization of the leg in a cast, it was found that this immobilization significantly decreased leg muscle GLUT4 content (Eijinde et al., 2001; Derave et al., 2003). Daily creatine supplementation during a 2-week immobilization period and 6-10 weeks of rehabilitation training caused a greater rebound in muscle GLUT4 content vs. a carbohydrate placebo, in some cases elevating it greater than the pre-study baseline value. Building upon this information, Gualano et al. (2011a) supplemented 25 subjects with type 2 diabetes with either 5 g/d creatine monohydrate (N=13) or dextrose (N=12) during a 12-week exercise program. The creatine feeding elevated muscle phosphocreatine levels by almost 60%, versus no change in the placebo group. Training with creatine vs. placebo did not improve body composition, strength, aerobic fitness, or blood lipids beyond the effects of training alone. However, in the creatine group, the blood level of hemoglobin A1c (higher values of which indicate chronic elevation in blood glucose over the previous 4 months or so) fell by 1.1 percentage points (Figure 2). This reduction, according to the authors, was superior to that typically observed with exercise or metformin medical treatment alone. Further, subjects in the creatine group experienced a significant reduction in the postprandial blood glucose area under the curve in response to an oral glucose challenge in comparison with no change, and even a slight increase, in the placebo group. Finally, creatine supplementation did not affect total levels of GLUT-4 in the muscle, but it did increase the amount of GLUT-4 found in the muscle cell membrane in relation to that observed in either the placebo group or age-matched healthy controls (untreated). This finding indicates a potential mechanism by which creatine exerted its effect. Although this human study is quite provocative and the findings potentially clinical relevant for management of type 2 diabetes, it should be noted that it has not been replicated as of yet.

creatine-more-than-sports-supplement_chart_2

Figure 2. Effects of creatine vs. placebo supplementation on hemoglobin A1c levels in patients with type 2 diabetes over the course of a 12-week training program. The difference between pre- and post- supplementation values in the creatine group was statistically significant (P = 0.004) (Re-drawn from: Gualano et al., 2011a).

Creatine and bone health

Bone and cartilage-building cells (e.g., osteoblasts and chondrocytes) can have high energy requirements during growth and development or during repair of injuries. These cells express the creatine kinase enzyme necessary for synthesis of ATP from creatine phosphate. It is possible, then, that creatine supplementation may benefit bone health via the enhancement of cellular reserves of creatine phosphate. Gerber et al. (2005) found increases in metabolic activity, mineralization, and alkaline phosphatase activity in cell culture studies of rat osteoblast-like cells grown in the presence vs. absence of creatine-containing media. This stimulation of osteoblasts could also lead to the production of osteoprotegerin, a cytokine that has inhibitory actions on the differentiation of osteoclasts, the cells responsible for bone resorption (Candow and Chilibeck, 2010). Thus, creatine supplementation might improve bone building while, at the same time, reducing bone breakdown, contributing to overall positive net mineral balance in bone.

A recent clinical study (Chilibeck et al., 2014) explored the effects of supplementing creatine monohydrate or an isocaloric maltodextrin placebo (0.1 g/kg body weight/d) in 47 postmenopausal women (mean age 57 y) during a 12-month resistance training program. The subjects performed fully supervised resistance training 3 times per week, utilizing 17 exercises for different body parts. Subjects performed 3 sets of 10 repetitions to failure with either 80% of the 1-repetition maximum (hack squat and bench press) or at the 10 repetition maximum for the other exercises. The daily dose of creatine was subdivided into two equal doses of 0.05 g/kg body weight, given before and after training on training days, or with 2 meals on non-training days. As would typically be expected with creatine supplementation, bench press strength increased to a greater degree in the creatine group (64%) vs. the placebo group (34%) (P<0.05). With regard to bone health, Figure 3 shows that creatine supplementation significantly blunted the expected decrease in bone mineral density at the hip and actually increased femoral shaft subperiosteal width (a marker of increased bone strength).

creatine-more-than-sports-supplement_chart_3

Figure 3. Effect of 12 months of resistance training with either creatine or placebo supplementation in postmenopausal women. Error bars represent 95% confidence intervals. For both variables, the difference between creatine and placebo was significant (P<0.05). Re-drawn from: Chilibeck et al. (2014).

Support for the potential positive effects of creatine supplementation on bone health is not limited to this particular study. Another study from the same research group (Chilibeck et al, 2005) showed that 6 g creatine/d during 12 weeks of resistance training in elderly men resulted in increased arm bone mineral content versus a placebo. Two investigations in boys with Duchenne muscular dystrophy showed that creatine monohydrate supplementation (3-4 g/d for 3-4 months) decreased urinary excretion of collagen type I cross-linking N-telopeptide (Louis et al., 2003; Tarnopolsky et al., 2004), which is a marker of bone resorption. Further, one of these studies (Louis et al., 2003) reported significant gains in lumbar and whole body bone mineral density with creatine supplementation vs. placebo.

It should be noted, however, that not all studies of creatine supplementation for bone have had positive outcomes. Cornish et al. (2009) and Tarnopolsky et al. (2007) observed no significant changes in urinary N-telopeptides in young or old subjects supplemented with a combination of creatine monohydrate and conjugated linoleic acid. Further, a review paper (Candow and Chilibeck, 2010) summarized three other studies that did not associate creatine supplementation with bone benefits. A critical point of consideration, though, is that the duration of two of these investigations (4-12 weeks) was likely too short to expect to see significant improvements in their reported outcome variables (bone mineral content and bone mass) (Kreider et al., 1998; Kerksick et al., 2007).

Creatine safety

There have been anecdotal reports and isolated case studies linking creatine supplementation to dehydration, venous thrombotic effects, muscle cramping, kidney disorders, and liver dysfunction (Tan et al., 2014; Pritchard and Kalra, 1998; Koshy and Griswold, 1999; Hariri et al., 2012). However, such case reports have a number of limitations that seriously limit their validity. Common problems include: 1) individuals taking a larger than recommended dose of creatine for an extended period of time; 2) use of other dietary supplements or drugs in addition to creatine that may have been the more likely cause of the adverse effect; 3) presence of pre-existing kidney disease. There is no evidence from controlled clinical trials that use of daily maintenance doses of creatine (3-5 g/d) is associated with any significant adverse effects in athletes and healthy individuals (Kreider et al., 2003b; Kim et al., 2011) or kidney dysfunction in persons with type 2 diabetes (Gualano et al., 2011b). Some confusion may arise because the excretory product of creatine metabolism, creatinine, is often elevated in the blood of those with kidney disease. For those with kidney disease, creatine supplementation might not be recommended (Kim et al., 2011). However, multiple studies show that creatine use at the maintenance level is safe for those who have healthy kidneys to start with (Gualano et al., 2008; Lugaresi et al., 2013; Kreider et al., 2003b; Kim et al., 2011). Thorough safety assessments by the European Food Safety Authority (EFSA, 2004) and the Norwegian Scientific Committee for Food Safety (VKM, 2010) have found no safety issues with the use of up to 3 g/d in healthy individuals. Further, a risk assessment by Hathcock and Shao (2006) determined that the Observed Safe Level for chronic creatine monohydrate supplementation is 5 g/d.

Summary

In summary, creatine supplementation may have promise outside the world of sports nutrition for improving blood glucose control in diabetes, various markers of brain function, and bone health. Further studies are needed for confirmation of these benefits, but the strong data observed from multiple studies, coupled with some mechanistic evidence for why creatine should be helpful, tends to put creatine supplementation in a positive light. Given its low cost and its excellent safety profile, creatine supplementation appears to be a low risk dietary strategy for achieving potential health benefits.

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