Research

The following research* study was compiled and edited by Dr. Richard Kreider, Pd.D. In addition to serving as the Chairman of our Scientific Advisory Board, Dr. Kreider serves as Professor, Executive Director of the Human Clinical Research Facility, and Director of the Exercise & Sport Nutrition Lab at Texas A&M University. Dr. Richard Kreider states, “We all agree that the best source of creatine for dietary supplements is the same active ingredient found in Encour - pure creatine monohydrate from Germany.”

Pure German Creatine from Germany is the primary active ingredient in Encour. 

 

*THIS STUDY IS SHARED WITH PERMISSION FROM THE AUTHOR.

 

 

 

CREATINE IN HEALTH

AND DISEASE

December 1, 2020

Richard B. Kreider, PhD, FACSM, FISSN, FACN, FNAK

Abstract

Although creatine has been mostly studied as an ergogenic aid for exercise, training, and sport; several health and potential therapeutic benefits have been reported. The reason for this is that creatine plays a critical role in cellular metabolism particularly during metabolically stressed states and limitations in the ability to transport and/or store creatine can impair metabolism. Moreover, increasing availability of creatine in tissue may enhance cellular metabolism and thereby lessen the severity of injury and/or disease conditions, particularly when oxygen availability is compromised. This systematic review assesses the peer-reviewed scientific and medical evidence related to the role of creatine in promoting general health as we age as well as how creatine supplementation has been used as a nutritional strategy to help individuals recover from injury and/or manage chronic disease. Additionally, it suggests reasonable structure and function claims that can be made based on the scientific literature. Based on this analysis, it can be concluded that the creatine supplementation has a number of health and therapeutic benefits throughout the lifespan.

Methods

 

A systematic review of the scientific and medical literature was conducted to assess the state of science related to creatine supplementation on metabolism, performance, health, and disease management. This was accomplished by doing key word searches related to creatine supplementation on each topic summarized using the National Institutes for Health National Library of Medicine PubMed.gov search engine. A total of 1,322 articles were reviewed with relevant research highlighted in this systematic review.

 

Metabolic Role

 

Creatine (N-aminoiminomethyl-N-methyl glycine) is a member of the guanidine phosphagen family [1, 2] and is a naturally occurring nitrogen containing compound found primarily in red meat and fish [3-6]. It is also processed and manufactured as a dietary supplement and used by a variety of populations [2, 7, 8]. The majority of creatine is found in skeletal muscle (~95%) with about 5% found in the brain and testes [9, 10]. About two thirds of intramuscular creatine is stored as phosphocreatine (PCr) with the remaining is free creatine. The total creatine pool (PCr + Cr) in the muscle averages about 120 mmol/kg of dry muscle mass for a 70 kg individual on a normal diet while vegetarians have been reported to have muscle creatine and PCr stores about 20-30% lower than non-vegetarians [11, 12]. About 1–2% of intramuscular creatine is degraded each day into creatinine and excreted in the urine [11, 13, 14]. Degradation of creatine to creatinine is greater in individuals with larger muscle mass and individuals with higher physical activity levels.

 

About half of the daily need for creatine is obtained from the diet primarily from meat and fish [15]. The remaining amount of daily creatine needed to maintain tissue creatine concentrations is synthesized primarily in the liver and kidneys from arginine and glycine by the enzyme arginine:glycine amidinotransferase (AGAT) to guanidinoacetate (GAA), which is then methylated by guanidinoacetate N-methyltransferase (GAMT) using S-adenosyl methionine to form creatine [16]. Therefore, normal sized individuals need to consume about 2-3 grams/day of creatine to maintain normal creatine stores depending on diet, muscle mass, and physical activity levels. Consequently, it has been recommended that people ingest 3 grams/day of creatine in their diet to promote general health [2, 17]. The most effective way to increase muscle creatine stores is to ingest five grams of creatine monohydrate four times daily (or 0.3 grams/kg body weight) for 5 – 7 days [11, 14]. However, higher levels of creatine supplementation (e.g., 20 – 30 grams/day) for longer periods of time may be needed to increase brain concentrations of creatine, offset creatine synthesis deficiencies, or influence disease states [18-20].

 

Creatine and phosphagens are prevalent in all species and play an important role in maintaining cellular energy

availability [3, 4, 21, 22]. The primary metabolic role of creatine is to combine with a phosphoryl group (Pi) to form PCr through the enzymatic reaction of creatine kinase (CK). Wallimann and colleagues [17, 23, 24] suggested that the physiological and biochemical effects of Cr are mostly related to the functions of CK and PCr (i.e., CK/PCr system). As adenosine triphosphate (ATP) is degraded into adenosine diphosphate (ADP) and Pi to provide free energy for metabolic activity, the free energy released from the hydrolysis of PCr into Cr + Pi can be used as a buffer to resynthesize ATP [21, 22]. This helps maintain ATP availability particularly during maximal effort anaerobic sprint-type exercise. The CK/PCr system also plays an important role in shuttling intracellular energy from the mitochondria into the cytosol. This creatine phosphate shuttle connects sites of ATP production (glycolysis and mitochondrial oxidative phosphorylation) with subcellular sites of ATP utilization (ATPases) [17, 21, 22]. In this regard, creatine enters the cytosol through a creatine transporters (CRTR) [25-28]. In the cytosol, creatine and associated cytosolic and glycolytic CK isoforms help maintain glycolytic ATP levels, the cytosolic ATP/ADP ratio, and cytosolic ATP-consumption [17]. Additionally, creatine diffuses into the mitochondria and couples with ATP produced from oxidative phosphorylation and the adenine nucleotide translocator (ANT) via mitochondrial CK. ATP and PCr can then diffuse back into the cytosol and help buffer energy needs. This coupling also reduces the formation of reactive oxygen species (ROS) and can therefore act as a direct and/or indirect antioxidant [29-32]. The creatine phosphate shuttle thereby connects sites of ATP production (glycolysis and mitochondrial oxidative phosphorylation) with subcellular sites of ATP utilization (ATPases) in order to fuel energy metabolism [17, 21, 22]. In this way, the CK/PCr system serves as an important regulator of metabolism. The role of CK/PCr system in normal metabolism as well as disease states help explain the ergogenic, health, and potential therapeutic benefits of creatine supplementation [6, 17, 30, 33-42].

 

General Health Benefits

 

Most research on creatine initially focused on the role of creatine on exercise performance, training adaptations, and safety in untrained and trained healthy individuals [2]. Creatine supplementation has been reported to increase muscle creatine and PCr levels, enhance acute exercise capacity, and improve training adaptations in adolescents [43-47], younger adults [48-59], and older individuals [9, 37, 40, 60-67]. These adaptations allow an athlete to do more work over a series of sets or sprints leading to greater gains in strength, muscle mass, and/or performance due to an improvement in the quality of training. After creatine loading, performance of high intensity and/or repetitive exercise is generally increased by 10-20% depending on the magnitude of increase in muscle PCr [68]. This includes many lifetime fitness activities like fitness/weight training [48, 55, 62, 69-79], golf [80], volleyball [81], soccer [53, 82, 83], softball [84], ice hockey [85], running [86-90], and swimming [44, 45, 91-94] among others. Benefits have been reported in men and women from children to elderly populations although the majority of studies have been conducted on men and some studies suggest that women may not see as much gain in strength and/or muscle mass during training in response to creatine supplementation [45, 82, 84, 95-99]. In terms of performance, the International Society of Sports Nutrition (ISSN) has concluded that creatine monohydrate is the most effective ergogenic nutritional supplement currently available to athletes in terms of increasing high-intensity exercise capacity and lean body mass during training [2, 7, 9, 60]. Position stands by the American Dietetic Association, Dietitians of Canada, and the American College of Sports Medicine on nutrition for athletic performance have drawn similar conclusions [100, 101]. Thus, there is wide-spread consensus creatine supplementation can serve as an effective nutritional ergogenic aid that may benefit athletes involved in numerous sports as well as individuals initiating exercise training to promote health and fitness.

 

As performance-related studies assessed markers of health and safety, evidence began to that creatine supplementation may improve health status and/or reduce risk to chronic disease as individuals age [38, 40-42, 102-105]. In this regard, creatine supplementation has been reported to help lower cholesterol, triglycerides and/or manage blood lipid levels [48, 106, 107]; reduce fat accumulation in the liver [107, 108]; reduce homocysteine levels and thereby risk to heart disease [109, 110]; serve as an antioxidant [110-114]; enhance glycemic control [2, 115-119]; slow tumor growth in some types of cancers [29, 109, 120-125]; increase strength and/or muscle mass [34, 38, 41, 42, 64, 70, 72, 126-134]; minimize bone loss in some studies [70, 103, 104, 128, 129, 135-141]; improve functional capacity in patients with knee osteoarthritis [142, 143] and fibromyalgia [144] in some studies; enhance cognitive function particularly in older populations [40, 65, 98, 102, 140, 145-153]; and, in some instances improve the efficacy of some anti-depressant medications [154-160]. These findings support contentions that it is prudent for individuals to consume at least 3 g/day of creatine in their diet to support general health as one ages [2, 17].

 

Benefits of Creatine in Aging Populations

 

Since creatine has been reported to increase muscle mass and strength, a number of studies have evaluated the effects of creatine supplementation in older populations in an attempt to prevent sarcopenia, maintain strength, and/or reduce risk to chronic disease. The following discusses some of these potential applications.

 

Reduce Muscle Loss and Sarcopenia

 

Sarcopenia is an age-related muscle condition characterized by a reduction in muscle quantity, muscle strength, and functional capacity. Although multifactorial, sarcopenia may be caused by changes in muscle protein kinetics, neuromuscular function, inflammation, physical activity and nutrition [104, 105]. A number of nutritional and exercise interventions have been suggested to counteract sarcopenia in older individuals including creatine supplementation during resistance-training [104, 105]. For example, Chrusch et al. [77] reported that older participants ( 60 – 84 years) who supplemented their diet with creatine (0.3 g/kg/day for 5 days,0.07 g/kg/day for 79 days) during supervised resistance training (3 days/week for 12-weeks) experienced greater gains in lean tissue mass,lower-body maximal strength and endurance, and isokinetic knee flexion/extension average power compared to controls.

 

Candow and colleagues [70] reported that low-dose creatine (0.1 g/kg/day) combined with protein supplementation (0.3 g/kg/day) increased lean tissue mass and upper body strength while decreasing markers of muscle protein degradation and bone resorption in older men (59-77 yr). Chilibeck et al. [128] reported that 12 months of creatine supplementation (0.1 g/kg/day) during resistance training increased strength and preserved femoral neck bone mineral density and increased femoral shaft subperiosteal width in postmenopausal women. Gualano and coworkers [69] reported that creatine supplementation (20 g/day for 5 days and 5 g/day for 161 days) during resistance training improved appendicular lean mass and muscle function in older vulnerable women and that creatine supplementation alone resulted in similar gains in muscle mass compared to those engaged in resistance training alone. Aguiar et al [67] reported that 12-weeks of creatine supplementation (5 g/day) combined with resistance training improved muscle endurance, ability to perform functional tasks, maximal strength, and muscle mass in older women. McMorris et al [161] reported that creatine supplementation (20 g/day for 7-days) after sleep deprivation improved balance measures.

 

Bernat and colleagues [162] reported that creatine supplementation (0.1 g/kg/day) during 8-weeks of high velocity resistance training in untrained healthy aging men promoted significantly greater gains in leg press and total lower-body strength, muscle thickness, and some measures of peak torque and physical performance. Moreover, a meta-analysis [62] of 357 elderly individuals (64 years) participating in an average of 12.6 weeks of resistance training found that participants supplementing their diet with creatine experienced greater gains in muscle mass, strength, and functional capacity. These findings were corroborated in a meta-analysis of 405 elderly participants (64 years) who experienced greater gains in muscle mass and upper body strength with creatine supplementation during resistance-training compared to training alone [34]. While not all studies report statistically significant effects, the preponderance of available research supports contentions that creatine supplementation, particularly when combined with resistance-exercise, can help maintain or increase muscle mass, strength, and balance in older individuals and therefore serve as an effective countermeasure to prevent sarcopenia.

 

Additionally, given that creatine supplementation has been reported to increase muscle mass and older adults often diet to lose weight, creatine supplementation during energy-restriction induced weight loss may be an effective way to preserve muscle while dieting and thereby help manage adult onset obesity.

 

Cognitive Function

 

Creatine supplementation has been reported to increase brain PCr content by 5% - 15% and thereby enhance brain bioenergetics [163-165]. For this reason, there has been interest in assessing the effects of creatine supplementation on cognition, memory, and executive function in older individuals as well as patients with mild cognitive impairment [140, 146, 148, 149]\. A number of studies have shown that creatine supplementation can reduce mental fatigue [145, 149, 166] and/or improve cognitive function [65, 140, 145, 146, 148, 149, 153, 161, 167, 168].

 

For example, Watanabe et al. [166] reported that creatine supplementation (8 g/day for 5-days) reduced mental fatigue when subjects repeatedly performed a simple mathematical calculation as well as increased oxygen utilization in the brain. Rae and colleagues [167] reported that creatine supplementation (5 g/day for 6-weeks) significantly improved working memory and intelligence tests requiring speed of processing. McMorris and coworkers [161] found that creatine supplementation (20 g/day for 7-days) after sleep deprivation resulted in significantly less decrement in performance in random movement generation, choice reaction time, balance, and mood state. This group also examined the effects of creatine supplementation (20 g/day for 7-days) on cognitive function in elderly participants and found that creatine supplementation significantly improved performance on random number generation, forward spatial recall, and long-term memory tasks. Ling and associates [168] reported that creatine supplementation (5 g/day for 15-days) improved cognition on some tasks.

 

More recently, VAN Cutsem and colleagues [145], reported that creatine supplementation (20 g/day for 7-days) prior to performing a simulated soccer match improved muscular endurance and prolonged cognitive performance. Although not all studies show benefits, there is clear evidence that creatine supplementation can increase brain creatine and/or improve cognitive function [40, 140, 146].

 

Glucose Management and Diabetes

 

It is well-known that creatine uptake into tissue is influenced by glucose and insulin [117, 169, 170]. Additionally, that creatine supplementation prevents declines in the GLUT-4 transporter during immobilization while increasing GLUT-4 by 40% during rehabilitation after atrophy [115]. Moreover, that co-ingestion of creatine with carbohydrate [12, 171] or creatine with carbohydrate and protein [172] enhanced creatine uptake and/or muscle glycogen levels [12, 172, 173]. For this reason, there has been interest in determining whether creatine supplementation may help diabetics manage blood glucose levels [115-119, 174].

 

For example, Gualano and associates [116] supplemented patients with type 2 diabetes with a placebo or creatine (5 g/day) for 12-weeks during training. Creatine supplementation significantly decreased HbA1c and glycemic response to standardized meal as well as increased GLUT-4 translocation. These researchers also reported [118] that the AMPK-alpha protein content tended to be higher after Creatine supplementation and were significantly related to the changes in GLUT-4 translocation and Hb1Ac levels suggesting that AMPK signaling may be implicated in the effects of supplementation on glucose uptake in type 2 diabetes.

 

These findings suggest that creatine supplementation combined with an exercise program improves glycemic control and glucose disposal in type 2 diabetic patients. Thus, there is evidence indicating that creatine supplementation enhances glucose uptake and insulin sensitivity and therefore can help individuals manage glucose and HbA1c levels particularly when initiating and exercise program [119, 174, 175].

 

Ischemic Heart Disease

 

Coronary heart disease limits blood supply to the heart thereby increasing susceptibility to ischemic events, arrhythmias, and/or heart failure. Creatine and PCr play an important role in maintaining myocardial bioenergetics during ischemic events [30]. For this reason, there has been interest in assessing the role of creatine or PCr administration in reducing arrhythmias, ischemia related damage, and/or heart function in individuals with chronic heart failure [176-186]. For example, Anyukhovsky et al. [184] reported that intravenous administration of PCr and PCr-nine (300 mg/kg) in canines prevented accumulation of lysophosphoglycerides in the ischemic zone of the heart which is associated with increase prevalence of arrhythmias.

 

The researchers concluded that this may explain the antiarrhythmic action of PCr and PCr-nine in acute myocardial ischemia. Sharov and coworkers [183] reported that exogenous PCr administration provided protection against ischemia in the heart. Likewise, Balestrino and colleagues [30] concluded that

phosphocreatine administration, primarily as an addition to cardioplegic solutions, may improve energy availability during myocardial ischemia, prevent ischemia-induced arrhythmias, and improve cardiac function.

 

As noted below, there is also evidence that creatine supplementation may maintain energy availability during brain ischemia and thereby reduce stroke related damage. Thus, prophylactic creatine supplementation may be beneficial for patients at risk for myocardial and/or cerebral ischemia.

 

Potential Therapeutic Uses of Creatine

 

Given the role of creatine in metabolism, a number of researchers have been investigating the potential therapeutic benefits of creatine supplementation in various clinical populations. The following highlights some of these applications.

 

Creatine Synthesis Deficiencies

 

Creatine deficiency syndromes are a group of inborn errors (e.g., AGAT deficiency, GAMT deficiency, and CRTR deficiency) that reduce or eliminate the ability to synthesize creatine or effectively transport creatine into the cell [187]. There is also recent evidence [188] that human genome encodes 19 genes of the solute carrier 6 (SLC6) family and that non-synonymous changes in the coding sequence give rise to mutated or misfolded transporters that cause diseases in affected individuals. This includes transporters for creatine (CT1, SLC6A8).

 

Individuals with creatine synthesis deficiencies and creatine transporter mutations have low levels of creatine and PCr in the muscle and the brain [20, 28, 188-193]. As a result, they often have clinical manifestations of muscle myopathies, gyrate atrophy, movement disorders, speech delay, autism, mental retardation, epilepsy, and/or developmental problems [20, 28, 187-193]. For this reason, a number of studies have investigated the use of relatively high doses of creatine monohydrate supplementation (e.g., 0.3 – 0.8 g/kg/day equivalent to 21 – 56 g/day of creatine for a 70 kg person) throughout the lifespan as a nutritional strategy of increasing muscle and brain in children and adults with creatine synthesis deficiencies [20, 28, 187-197]. These studies generally show some improvement in clinical outcomes particularly for AGAT and GAMT with less consistent effects on CRTR deficiencies [190].

 

For example, Bianchi et al. [198] reported that creatine supplementation (200 – 800 mg/kg/day divided into 5 servings per day) significantly increased brain creatine and PCr levels in patients with GAMT-d and AGAT-d creatine synthesis deficiencies. Battini et al. [199] reported that a patient diagnosed at birth with AGAT deficiency who was treated with creatine supplementation beginning at four months of age experienced normal psychomotor development at eighteen months compared to siblings who did not have the deficiency. Stockler-Ipsiroglu and coworkers [200] evaluated the effects of creatine monohydrate supplementation (0.3 – 0.8 g/kg/day) in 48 children with GMAT deficiency with clinical manifestations of global developmental delay/intellectual disability (DD/ID) with speech/language delay and behavioral problems (n=44), epilepsy (n=35), or movement disorder (n=13). The median age at treatment was 25.5 months, 39 months, and 11 years in patients with mild, moderate, and severe DD/ID, respectively. The researchers found that creatine supplementation increased brain creatine levels and improved or stabilized clinical symptoms. Moreover,

four patients treated younger than nine months had normal or almost normal developmental outcomes. Long-term creatine supplementation has also been used to treat patients with creatine deficiency-related gyrate atrophy [201-205].

 

These findings and others provide promise that high-dose creatine monohydrate supplementation may be an effective adjunctive therapy for children and adults with creatine synthesis and/or transporter deficiencies [190, 206-209]. Additionally, these reports provide strong evidence regarding the long-term safety and tolerability of high-dose creatine supplementation in pediatric populations with creatine synthesis deficiencies, including infants less than one year of age [206].

 

Neurodegenerative Diseases.

 

A number of studies have investigated the short and long-term therapeutic benefit of creatine supplementation in children and adults with various neuromuscular diseases like muscular dystrophies [210-215], Huntington's disease [18, 216-221]; Parkinson disease [18, 37, 71, 216, 222-224]; mitochondria-related diseases [25, 224-228]; amyotrophic lateral sclerosis or Lou Gehrig’s Disease [216, 229-235]; and, spinal and bulbar muscular atrophy [236]. These studies have provided some evidence that creatine supplementation may improve exercise capacity and/or clinical outcomes in these patient populations. However, Bender and colleagues [18] reported results of several large clinical trials evaluating the effects of creatine supplementation in patients with Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). A total of 1,687 patients took an average of 9.5 g/day of creatine for a total of 5,480 patient years. Results revealed no clinical benefit on patient outcomes in patients with PD or ALS.

 

However, there was some evidence that creatine supplementation slowed down progression of brain atrophy in patients with HD (although clinical markers were unaffected). Whether creatine supplementation may have a role in mediating other clinical markers in these patient populations and/or whether individual patients may respond more positively to creatine supplementation than others remains to be determined. Nevertheless, these studies show that creatine supplementation has been used to treat children and adults with neurodegenerative conditions and is apparently safe and well-tolerated when taking up to 30 g/day for five years in these populations.

 

Brain and Spinal Cord Neuroprotection

 

It is well-known that creatine supplementation increases brain bioenergetics [30, 151, 165, 198, 224, 237] and has neuroprotective benefits particularly in response to injury and/or ischemic conditions [25, 35, 37, 238]. For this reason, a number of studies have examined the effects of creatine supplementation on cerebral ischemia, traumatic brain injury (TBI), and spinal cord injury (SCI).

 

For example, Adcock et al. [239] reported that neonatal rats fed 3 g/kg of creatine for three days observed a significant increase in the ratio of brain PCr to Pi and a 25% reduction in the volume of edemic brain tissue following cerebral hypoxic ischemia. The authors concluded that creatine supplementation appears to improve brain bioenergetics thereby helping minimize the amount of brain damage in response to brain ischemia.

 

Prass and colleagues [240] reported that creatine administration reduced the brain infarct size following an ischemic event by 40%. Zhu and colleagues [241] reported that oral creatine administration resulted in a marked reduction in ischemic brain infarction size, neuronal cell death, and provided neuroprotection after cerebral ischemia in mice.

 

Allah et al. [242] reported that creatine monohydrate supplementation for ten weeks reduced infarction size and improved learning/memory following neonatal hypoxia ischemia encephalopathy in female mice.

 

Finally, Turner and coworkers [151] reported that 7-days of creatine supplementation increased brain creatine content by 9.2%, increased corticomotor excitability, and prevented the decline in attention during hypoxia in healthy adults. Collectively, these findings suggest that creatine supplementation may reduce the severity of brain ischemia and therefore may have some therapeutic benefits in individuals at risk to stroke [30, 120, 186].

 

In terms of injury, several studies have evaluated the effects of creatine supplementation on response to mild TBI and SCI in animal models [33, 146, 157, 243-247]. For example, Sullivan et al. [245] reported that five days of creatine administration prior to a controlled TBI in rats and mice reduced the amount of cortical damage by 36% to 50%, respectively. The researchers attributed the reduction in cortical damage to a creatine-induced maintenance of neuronal mitochondrial bioenergetics. Hausmann and associates [246] reported that rats fed creatine (5 g/100 g dry food) before and after a moderate SCI reduced the size of scar tissue and improved locomotor function test performance. The authors suggested that pretreatment of patients with creatine may provide neuroprotection in patients undergoing spinal surgery who are at risk to SCI. Rabchevsky and associates [248] examined the efficacy of creatine-supplemented diets on hind limb functional recovery and tissue sparing in adult rats. Rats were fed a control diet or 2% creatine-supplemented chow for 4-5 weeks prior to and following SCI. Results revealed that creatine feeding significantly reduced loss of gray matter after SCI. Creatine supplementation has also been reported to enhance training adaptations in patients recovering from spinal cord injury.

 

For example, Jacobs et al. [249] reported that creatine supplementation (20 g/day for 7-days) enhanced aerobic exercise capacity and ventilator anaerobic threshold in individuals with complete cervical-level SCI. Moreover, Amorim et al. [247] reported that individuals with SCI who consumed creatine (3 g/day) with vitamin D (25,000 IU/day) while participating in a resistance-training program for 8-weeks experienced significantly greater improvements in arm muscle area, strength, and function capacity. While some studies report no benefit of creatine supplementation on maximal voluntary contractions [250] or 800-m wheel chair performance [251] in individuals with SCI, collective findings provide strong evidence that creatine supplementation may limit damage from concussions, TBI, and/or SCI [30, 244]. In fact, this evidence is so strong the International Society of Sports Nutrition has recommended that all athletes who are involved in sports with risk to TBI and/or SCI should take creatine to reduce the severity of TBI and/or SCI.

 

Enhanced Rehabilitation Outcomes

 

Since creatine supplementation has been reported to promote gains in muscle mass and improved strength, there has been interest in examining the effects of creatine supplementation on preserving muscle mass during limb immobilization and/or enhancing rehabilitation outcomes in a variety of populations [140, 157, 236, 252]. For example, Hespel and coworkers [253] examined the effects of creatine supplementation (20 g/day, then 5 g/day) on atrophy rates and 10-week rehabilitation outcomes in individuals who had their right leg casted for two weeks.

 

The researchers reported that individuals in the creatine group experienced greater changes in the crosssectional area of muscle fiber (+10%) and peak strength (+25%) during the rehabilitation period. These changes were associated with greater changes in myogenic regulating factor 4 (MRF4) and myogenic protein expression. Jacobs and associates [249] examined the effects of creatine supplementation (20 g/d for seven days) on upper extremity work capacity in individuals with cervical-level spinal cord injury (SCI). Results revealed that peak oxygen uptake and ventilatory anaerobic threshold were increased following creatine supplementation.

 

Although findings are mixed, several studies reported that creatine supplementation in chronic heart failure patient’s enhanced rehabilitative outcomes [254- 258]. Fuld et al. [259] reported that creatine supplementation (17.1 g/day for 2-weeks prior to rehabilitation and 5.7 g/day for 16-weeks during rehabilitation) increased fat-free mass, peripheral muscle strength and endurance, and health status in patients with chronic obstructive pulmonary disease (COPD).

 

Hass and colleagues [71] reported that creatine supplementation (20 g/day for 5-days; 5 g/day for 12-weeks) during resistance training in Parkinson’s patients promoted greater gains in muscle strength and ability to perform the functional chair sit to rise test. Cooke and assistants [260] reported that creatine supplementation (0.3 g/kg/day for 5-days prior to performing a eccentric-only resistance exercise bout to promote muscle damage/injury and 0.1 g/kg/day for 14-days following the bout) significantly reduced markers of muscle damage and improved the rate of recovery of knee extension muscle function after creatine supplementation following injury. Finally, Neves et al. [142] reported that creatine supplementation (20 g/day for 5-days and 5 g/day for 79-days) improved physical function, lower limb lean mass, and quality of life in postmenopausal women with knee OA

undergoing strengthening exercises.

 

While not all studies show benefit to rehabilitative outcomes, there is evidence that creatine supplementation may help lessen muscle atrophy following immobilization and promote recovery during exercise-related rehabilitation in some populations.

 

Pregnancy.

 

Since creatine supplementation has been shown to improve brain and heart bioenergetics during ischemic conditions and possess neuroprotective properties, there has been recent interest in use of creatine during pregnancy to promote neural development and reduce complications resulting from birth asphyxia [261-270]. The rationale for creatine supplementation during pregnancy is that the fetus relies upon placental transfer of maternal creatine until late in pregnancy and significant changes in creatine synthesis and excretion occur as pregnancy progresses [263, 265]. Consequently, there is an increased demand for and utilization of creatine during pregnancy.

 

Maternal creatine supplementation has been reported to improve neonatal survival and organ function following birth asphyxia in animals [261, 262, 264, 266-268, 270]. Human studies show changes in the maternal urine and plasma creatine levels across pregnancy and association to maternal diet [263, 265]. Consequently, it has been postulated that there may be benefit to creatine supplementation during pregnancy on fetal growth, development, and health [263, 265]. This area of research may have broad implications for fetal and child development and health. 

 

Immune Support

 

One of the more novel potential uses of creatine is its influence on the immune system. A number of in vitro and animal studies indicate that creatine has immunomodulatory effects [33]. In this regard, several studies have reported that creatine supplementation may alter production and/or the expression of molecules involved in recognizing infections like toll-like receptors (TLR) [33].

 

For example, Leland and colleagues [271] reported that creatine down regulated expression of TLR-2, TLR-3, TLR-4, and TLR-7 in a mouse macrophage cell line (RAW 254.7). While this could reduce the ability to sense some infections in immunocompromised individuals, TLR-4 downregulation may also alter Parkinson’s disease pathology and inhibit neuronal death as the disease progresses [272, 273]. There is also evidence that creatine influences cytokines possibly via the NF-κB signaling pathway thereby affecting cytokines, receptors, and/or growth factors that can positively or negatively influence immune response [33, 271]. A creatine-induced reduction of pro-inflammatory cytokines (e.g., IL-6) and other markers of inflammation (e.g., TNFα, PGE2) may help explain some of the neuroprotective benefits observed in patients with central nervous system related diseases [33]. It may also explain reports that creatine supplementation attenuates inflammatory and/or muscle damage in response to intense exercise [260, 274-276]. On the other hand, there have been several studies in mice suggesting that creatine supplementation may impair airway inflammation thereby exacerbating exercise-induced asthma [277, 278]. However, other studies suggest creatine attenuates pulmonary and systemic effects of lung ischemia and reperfusion injury in rats [279]; improves rehabilitative outcomes in patients with cystic fibrosis [280] and COPD [259]; or, has no statistically significant effects on pulmonary rehabilitation outcomes [281, 282] and youth soccer players with allergies [283].

 

Additional research is needed to understand the anti-inflammatory and immunomodulating effects of creatine but it is clear that creatine can affect these pathways.

 

Anticancer Properties:

 

Another emerging area related to creatine supplementation is the potential anti-cancer effects. As noted above, creatine and phosphagens play and important role in maintaining energy availability [3, 4, 21, 22] particularly in relation to the role of the CK/PRr system and shuttling of ATP, ADP and Pi in and out of the mitochondria for cellular metabolism [17, 23, 24]. Prior studies have shown that creatine content and energy availability is low in several types of malignant cells as well as T cells that mediate the immune responses against cancer [29, 121, 122, 124, 125]. Additionally, that the expression of the creatine transport Slc6a8 gene, which encodes a surface transporter controlling the uptake of creatine into a cell, markedly increases in tumor-infiltrating immune cells [124].

 

It has been known for some time that creatine and its related compound cyclocreatine have anticancer properties [121, 284, 285]. For example, Patra et al. [121] also noted that the efficacy of the anticancer medication methylglyoxal (MG) is significantly augmented in the presence of creatine and that administration of creatine, methylglyoxal, and ascorbic acid provided greater efficacy and eliminated visible signs of tumor growth. Moreover, creatine and CK, which were very low in sarcoma tissue, were significantly elevated with the concomitant regression of tumor cells. Similarly, Pal and colleagues [125] reported that MG efficacy was improved with co-administration of creatine and ascorbic acid in muscle cells in vitro as well as in sarcoma animal model in vivo suggesting that creatine supplementation may serve as an adjunctive anticancer therapeutic intervention with MG. Di Biase and coworkers [124] also reported that creatine uptake deficiency severely impaired CD8 T cell responses to tumor challenge in vivo and to antigen stimulation in vitro, while supplementation of creatine through either direct administration or dietary supplementation significantly suppressed tumor growth in multiple mouse tumor models. Moreover, that the energy-buffering function of creatine goes beyond regulating CD8 T cells in that reduced energy capacity has also been reported in multiple immune cells in various mouse tumor models in creatine transporter knockout mice [124]. The researchers concluded creatine is an important metabolic regulator controlling antitumor T cell immunity and that creatine supplementation may improve T cell–based cancer immunotherapies [124].

 

Collectively, these findings indicate that creatine supplementation may have anti-cancer properties.

 

Chronic Fatigue

 

Chronic fatigue syndrome (CFS), also known as postviral fatigue syndrome (PFS) or myalgic encephalomyelitis (ME), is characterized by fatigue and associated symptoms (e.g., muscle and joint pains, anxiety, cognitive and sleep disorders, intolerance to physical exertion) persisting more than six months in duration [286]. Although the etiology is not completely understood, there is some evidence that a lack creatine availability and/or impaired creatine metabolism may play a role in CFS related diseases.

 

For example, Malatji et al. [287] reported a significant relationship between urinary creatine levels and symptoms of pain, fatigue and energy levels in patients with the CFS related chronic pain syndrome, fibromyalgia. Mueller and associates [288] reported that creatine levels and energy metabolite ratios were lower in several areas of the brain in patients with ME/CFS and that the levels correlated with fatigue severity. Moreover, reduced creatine ratio in the prefrontal region of the brain was associated with greater pain of CFS patients [289]. Puri et al. [290] reported that mean ratio of choline to creatine in the occipital cortex of the brain was significantly higher in CFS patients most likely due to an increase in choline peak. Additionally, there a loss of the normal spatial variation of the choline peak. Similarly, Chaudhuri and associates [291, 292] reported that the ratio of choline:creatine was also altered in CFS patients.

 

Given these potential relationships, a couple of studies have examined the effects of creatine related compounds on patient outcomes in CFS patients. Ostojic and colleagues [293] reported that GAA supplementation (2.4 g/day for 3 months) positively affected creatine metabolism and work capacity in women with CFS but did not affect symptoms of general fatigue and musculoskeletal soreness. Finally, Alves and colleagues [144] reported that creatine supplementation (20 g/day for 5-days; 5 g/day for 107-days) increased intramuscular phosphorylcreatine content and improved lower- and upper-body muscle function, with minor changes in other fibromyalgia features. The authors concluded that creatine supplementation may serve as a useful dietary intervention to improve muscle function in fibromyalgia patients. While more studies are needed, these findings provide some support that creatine and/or GAA may have some therapeutic benefit for patients with CFS, PFS, EM, and/or fibromyalgia.

 

Anti-Depressive

There are several studies indicating that creatine and/or creatine precursors like S-adenosyl-Lmethionine (SAMe) and GAA affect brain phosphagen levels and may have anti-depressive effects and/or increase the therapeutic efficacy of anti-depressant medications [120, 154, 155].

 

For example, the creatine precursor SAMe has been reported to be an effective treatment for clinical depression. Silveri et al [294] reported that SAMe supplementation (1,600 mg/day) increase brain creatine and PCr levels higher after treatment as well as lowered transverse relaxation time in women compared to men. Allen and colleagues [295] reported that rats fed creatine diets (4%) for 5-weeks altered depression-like behavior in response to force swim training in a sex-dependent manner with female rats displaying an antidepressant-like response. Ahn and coworkers [296] reported that a single treatment of creatine or exercise has partial effects as an antidepressant in mice with chronic mild stress-induced depression and that combining creatine and exercise promoted greater benefits. Pazini et al. [297] reported that creatine administration (21-days, 10 mg/kg, p.o.) abolished  corticosterone induced depressive-like behaviors in mice. Similarly, Leem and colleagues [298] reported that mice exposed to mild chronic stress for 4-weeks had a greater effect on hippocampal neurogenesis via the Wnt/GSK3beta/betacatenin pathway activation when creatine and exercise was combined compared with each treatment in chronic mild stress-induced behavioral depression.

 

There is some support in human trials that creatine supplementation may affect depression. For example, Roitman et al. [154] reported in an open label study that creatine monohydrate supplementation (3-5 g/day for 4-wks) improved outcomes in a small sample of patients with unipolar depression. Toniolo and colleagues [156] evaluated the effects of creatine supplementation (6 g/day for 6-wks) in bipolar patients and reported that Montgomery-Asberg Depression Rating Scale (MADRS) remission rates (i.e., 66.7% remission in the creatine group vs. 18.2% in the placebo group). Although more research is needed, there is evidence suggesting that creatine may help individuals manage some types of depression and/or anxiety disorders particularly when combined with choline [164, 299].

 

Fertility

 

Creatine has been used to improve fertility in men and women. The rationale in men is that sperm motility is dependent on ATP availability and CK activity has been associated with greater sperm quality and function [17, 300-302]. Additionally, creatine has been added to medium during intrauterinal insemination to increase viability of sperm and success of fertility treatments [300-305]. These findings suggest that creatine plays an important role in fertility.

Skin Health

 

Since availability of creatine has been reported to affect energy status and in the dermis and is an antioxidant, several studies have evaluated whether topical application of creatine influences skin health and/or may serve as an effective anti-wrinkle intervention [306]. For example, Lenz et al.[306] reported that stress decreases CK activity in cutaneous cells and that topical creatine application improved cellular energy availability and markedly protected against a variety of cellular stress conditions, like oxidative and UV damage, which are involved in premature skin aging and skin damage.

 

Peirano and coworkers [307] found that topically applied creatine rapidly penetrates the dermis, stimulates

collagen synthesis, and influences gene expression and at the protein level. Additionally, that topical application of a creatine-containing formulation for 6-wks significantly reduced the sagging cheek intensity in the jowl area, crow's feet wrinkles, and wrinkles under the eyes. The researchers concluded that creatine represents a beneficial active ingredient for topical use in the prevention and treatment of human skin aging.

 

Summary

The benefits of creatine supplementation go well-beyond serving to increase muscle Cr and PCr levels and thereby enhance high-intensity exercise and training adaptations. Research has clearly shown a number of health and/or potential therapeutic benefits as we age and in clinical populations that may benefit by enhancing Cr and PCr levels. Although additional research is needed to further explore the clinical benefits of creatine supplementation, the following structure and function claims can be reasonably made:

 

1. Creatine supplementation can increase cellular energy availability and support general health, fitness, and wellbeing throughout the lifespan.

 

2. Creatine supplementation, particularly when combined with resistance-training, can promote gains in strength and help maintain or increase muscle mass in older individuals. Additionally, creatine supplementation during energy restriction induced weight loss may be an effective way to preserve muscle while dieting and thereby help manage adult onset obesity.

 

3. Creatine supplementation supports cognitive function particularly as one ages.

 

4. Creatine supplementation supports healthy glucose management.

 

5. Creatine supplementation supports heart metabolism and health particularly during ischemic challenges.

 

6. Long-term, high-dose creatine supplementation in individuals with creatine synthesis and/or transport deficiencies can increase brain creatine and PCr levels and reduce the severity of deficits associated with these disorders.

 

7. Although creatine supplementation has been shown to have neuroprotective properties and improve strength and endurance, the efficacy of long-term, high-dose creatine supplementation in individuals with neurological diseases is equivocal.

 

8. Creatine supplementation can increase brain creatine content, enhance energy availability during ischemic events, and provide neuroprotection from TBI and/or SCI.

 

9. Creatine supplementation prior to and following injury may reduce immobilization related atrophy and/or enhance rehabilitative outcomes in a number of populations.

 

10. Creatine supplementation during the third trimester of pregnancy may help support health of the mother and child.

 

11. Creatine supplementation may have anti-inflammatory and immunomodulating effects.

 

12. Creatine is an important energy source for immune cells, can help support a healthy immune system, and may have some anticancer properties.

 

13. Creatine and/or GAA may increase brain bioenergetics and provide some therapeutic benefit for patients with chronic fatigue related syndromes such as post viral fatigue syndrome (PFS) or myalgic encephalomyelitis (ME).

 

14. Creatine supports mental health.

 

15. Creatine supports reproductive health.

 

16. Creatine supports skin health.

 

References

1. Jager, R., et al., Analysis of the efficacy, safety, and regulatory status of novel forms of creatine. Amino Acids, 2011. 40(5): p. 1369-83.

2. Kreider, R.B., et al., International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine. J Int Soc Sports Nutr, 2017. 14: p. 18.

3. Bertin, M., et al., Origin of the genes for the isoforms of creatine kinase. Gene, 2007. 392(1-2): p. 273-82.

4. Suzuki, T., et al., Evolution and divergence of the genes for cytoplasmic, mitochondrial, and flagellar creatine kinases. J Mol Evol, 2004.59(2): p. 218-26.

5. Sahlin, K. and R.C. Harris, The creatine kinase reaction: a simple reaction with functional complexity. Amino Acids, 2011. 40(5): p. 1363-7.

6. Harris, R., Creatine in health, medicine and sport: an introduction to a meeting held at Downing College, University of Cambridge, July 2010. Amino Acids, 2011. 40(5): p. 1267-70.

7. Kerksick, C.M., et al., ISSN exercise & sports nutrition review update: research & recommendations. J Int Soc Sports Nutr, 2018. 15(1): p. 38.

8. Meyers, S. Sports nutrition market growth watch. Natural Products Insidier, 2016.

9. Buford, T.W., et al., International Society of Sports Nutrition position stand: creatine supplementation and exercise. J Int Soc Sports Nutr, 2007. 4: p. 6.

10. Kreider, R.B. and Y.P. Jung, Creatine supplementation in exercise, sport, and medicine. . J Exerc Nutr Biochem, 2011. 15(2): p. 53-69.

11. Hultman, E., et al., Muscle creatine loading in men. J Appl Physiol (1985), 1996. 81(1): p. 232-7.

12. Green, A.L., et al., Carbohydrate ingestion augments skeletal muscle creatine accumulation during creatine supplementation in humans. Am J Physiol, 1996. 271(5 Pt 1): p. E821-6.

13. Balsom, P.D., K. Soderlund, and B. Ekblom, Creatine in humans with special reference to creatine supplementation. Sports Med, 1994. 18(4): p. 268-80.

14. Harris, R.C., K. Soderlund, and E. Hultman, Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin Sci (Lond), 1992. 83(3): p. 367-74.

15. Brosnan, M.E. and J.T. Brosnan, The role of dietary creatine. Amino Acids, 2016. 48(8): p. 1785-91.

16. Paddon-Jones, D., E. Borsheim, and R.R. Wolfe, Potential ergogenic effects of arginine and creatine supplementation. J Nutr, 2004. 134(10 Suppl): p. 2888S-2894S; discussion 2895S.

17. Wallimann, T., M. Tokarska-Schlattner, and U. Schlattner, The creatine kinase system and pleiotropic effects of creatine. Amino Acids, 2011. 40(5): p. 1271-96.

18. Bender, A. and T. Klopstock, Creatine for neuroprotection in neurodegenerative disease: end of story? Amino Acids, 2016. 48(8): p. 1929-40.

19. Hanna-El-Daher, L. and O. Braissant, Creatine synthesis and exchanges between brain cells: What can be learned from human creatine deficiencies and various experimental models? Amino Acids, 2016. 48(8): p. 1877-95.

20. Braissant, O., et al., Creatine deficiency syndromes and the importance of creatine synthesis in the brain. Amino Acids, 2011. 40(5): p. 1315-24.

21. Schlattner, U., et al., Cellular compartmentation of energy metabolism: creatine kinase microcompartments and recruitment of B-type

creatine kinase to specific subcellular sites. Amino Acids, 2016. 48(8): p. 1751-74.

22. Ydfors, M., et al., Modelling in vivo creatine/phosphocreatine in vitro reveals divergent adaptations in human muscle mitochondrial respiratory control by ADP after acute and chronic exercise. J Physiol, 2016. 594(11): p. 3127-40.

23. Wallimann, T., T. Schlosser, and H.M. Eppenberger, Function of M-line-bound creatine kinase as intramyofibrillar ATP regenerator at the receiving end of the phosphorylcreatine shuttle in muscle. J Biol Chem, 1984. 259(8): p. 5238-46.

24. Wallimann, T., et al., Some new aspects of creatine kinase (CK): compartmentation, structure, function and regulation for cellular and mitochondrial bioenergetics and physiology. Biofactors, 1998. 8(3-4): p. 229-34.

25. Tarnopolsky, M.A., et al., Creatine transporter and mitochondrial creatine kinase protein content in myopathies. Muscle Nerve, 2001. 24(5): p. 682-8.

26. Santacruz, L. and D.O. Jacobs, Structural correlates of the creatine transporter function regulation: the undiscovered country. Amino Acids, 2016. 48(8): p. 2049-55.

27. Braissant, O., Creatine and guanidinoacetate transport at blood-brain and blood-cerebrospinal fluid barriers. J Inherit Metab Dis, 2012. 35(4): p. 655-64.

28. Beard, E. and O. Braissant, Synthesis and transport of creatine in the CNS: importance for cerebral functions. J Neurochem, 2010. 115(2): p. 297-313.

29. Campos-Ferraz, P.L., et al., Exploratory studies of the potential anti-cancer effects of creatine. Amino Acids, 2016. 48(8): p. 1993-2001.

30. Balestrino, M., et al., Potential of creatine or phosphocreatine supplementation in cerebrovascular disease and in ischemic heart disease. Amino Acids, 2016. 48(8): p. 1955-67.

31. Saraiva, A.L., et al., Creatine reduces oxidative stress markers but does not protect against seizure susceptibility after severe traumatic brain injury. Brain Res Bull, 2012. 87(2-3): p. 180-6.

32. Rahimi, R., Creatine supplementation decreases oxidative DNA damage and lipid peroxidation induced by a single bout of resistance exercise. J Strength Cond Res, 2011. 25(12): p. 3448-55.

33. Riesberg, L.A., et al., Beyond muscles: The untapped potential of creatine. Int Immunopharmacol, 2016. 37: p. 31-42.

34. Candow, D.G., P.D. Chilibeck, and S.C. Forbes, Creatine supplementation and aging musculoskeletal health. Endocrine, 2014. 45(3): p. 354-61.

35. Tarnopolsky, M.A., Clinical use of creatine in neuromuscular and neurometabolic disorders. Subcell Biochem, 2007. 46: p. 183-204.

36. Kley, R.A., M.A. Tarnopolsky, and M. Vorgerd, Creatine for treating muscle disorders. Cochrane Database Syst Rev, 2011(2): p. CD004760.

37. Tarnopolsky, M.A., Potential benefits of creatine monohydrate supplementation in the elderly. Curr Opin Clin Nutr Metab Care, 2000. 3(6): p. 497-502.

38. Candow, D.G., et al., Strategic creatine supplementation and resistance training in healthy older adults. Appl Physiol Nutr Metab, 2015. 40(7): p. 689-94.

39. Moon, A., et al., Creatine supplementation: can it improve quality of life in the elderly without associated resistance training? Curr Aging Sci, 2013. 6(3): p. 251-7.

40. Rawson, E.S. and A.C. Venezia, Use of creatine in the elderly and evidence for effects on cognitive function in young and old. Amino Acids, 2011. 40(5): p. 1349-62.

41. Candow, D.G., Sarcopenia: current theories and the potential beneficial effect of creatine application strategies. Biogerontology, 2011.12(4): p. 273-81.

42. Candow, D.G. and P.D. Chilibeck, Potential of creatine supplementation for improving aging bone health. J Nutr Health Aging, 2010. 14(2):p. 149-53.

43. Cornish, S.M., P.D. Chilibeck, and D.G. Burke, The effect of creatine monohydrate supplementation on sprint skating in ice-hockey players. J Sports Med Phys Fitness, 2006. 46(1): p. 90-8.

44. Dawson, B., T. Vladich, and B.A. Blanksby, Effects of 4 weeks of creatine supplementation in junior swimmers on freestyle sprint and swim bench performance. J Strength Cond Res, 2002. 16(4): p. 485-90.

45. Grindstaff, P.D., et al., Effects of creatine supplementation on repetitive sprint performance and body composition in competitive swimmers. Int J Sport Nutr, 1997. 7(4): p. 330-46.

46. Juhasz, I., et al., Creatine supplementation improves the anaerobic performance of elite junior fin swimmers. Acta Physiol Hung, 2009. 96(3): p. 325-36.

47. Silva, A.J., et al., Effect of creatine on swimming velocity, body composition and hydrodynamic variables. J Sports Med Phys Fitness, 2007. 47(1): p. 58-64.

48. Kreider, R.B., et al., Effects of creatine supplementation on body composition, strength, and sprint performance. Med Sci Sports Exerc, 1998. 30(1): p. 73-82.

49. Stone, M.H., et al., Effects of in-season (5 weeks) creatine and pyruvate supplementation on anaerobic performance and body composition in American football players. Int J Sport Nutr, 1999. 9(2): p. 146-65.

50. Bemben, M.G., et al., Creatine supplementation during resistance training in college football athletes. Med Sci Sports Exerc, 2001. 33(10): p. 1667-73.

51. Hoffman, J., et al., Effect of creatine and beta-alanine supplementation on performance and endocrine responses in strength/power athletes. Int J Sport Nutr Exerc Metab, 2006. 16(4): p. 430-46.

52. Chilibeck, P.D., C. Magnus, and M. Anderson, Effect of in-season creatine supplementation on body composition and performance in rugby union football players. Appl Physiol Nutr Metab, 2007. 32(6): p. 1052-7.

53. Claudino, J.G., et al., Creatine monohydrate supplementation on lower-limb muscle power in Brazilian elite soccer players. J Int Soc Sports Nutr, 2014. 11: p. 32.

54. Kerksick, C.M., et al., Impact of differing protein sources and a creatine containing nutritional formula after 12 weeks of resistance training. Nutrition, 2007. 23(9): p. 647-56.

55. Kerksick, C.M., et al., The effects of creatine monohydrate supplementation with and without D-pinitol on resistance training adaptations. J Strength Cond Res, 2009. 23(9): p. 2673-82.

56. Galvan, E., et al., Acute and chronic safety and efficacy of dose dependent creatine nitrate supplementation and exercise performance. J Int Soc Sports Nutr, 2016. 13: p. 12.

57. Volek, J.S., et al., Creatine supplementation enhances muscular performance during high-intensity resistance exercise. J Am Diet Assoc, 1997. 97(7): p. 765-70.

58. Volek, J.S., et al., Physiological responses to short-term exercise in the heat after creatine loading. Med Sci Sports Exerc, 2001. 33(7): p. 1101-8.

59. Volek, J.S., et al., The effects of creatine supplementation on muscular performance and body composition responses to short-term resistance

training overreaching. Eur J Appl Physiol, 2004. 91(5-6): p. 628-37.

60. Kreider, R.B., et al., ISSN exercise & sport nutrition review: research & recommendations. J Int Soc Sports Nutr, 2010. 7: p. 7.

61. Branch, J.D., Effect of creatine supplementation on body composition and performance: a meta-analysis. Int J Sport Nutr Exerc Metab, 2003. 13(2): p. 198-226.

62. Devries, M.C. and S.M. Phillips, Creatine supplementation during resistance training in older adults-a meta-analysis. Med Sci Sports Exerc, 2014. 46(6): p. 1194-203.

63. Lanhers, C., et al., Creatine Supplementation and Lower Limb Strength Performance: A Systematic Review and Meta-Analyses. Sports Med, 2015. 45(9): p. 1285-94.

64. Wiroth, J.B., et al., Effects of oral creatine supplementation on maximal pedalling performance in older adults. Eur J Appl Physiol, 2001. 84(6): p. 533-9.

65. McMorris, T., et al., Creatine supplementation and cognitive performance in elderly individuals. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn, 2007. 14(5): p. 517-28.

66. Rawson, E.S. and P.M. Clarkson, Acute creatine supplementation in older men. Int J Sports Med, 2000. 21(1): p. 71-5.

67. Aguiar, A.F., et al., Long-term creatine supplementation improves muscular performance during resistance training in older women. Eur J Appl Physiol, 2013. 113(4): p. 987-96.

68. Kreider, R.B., Effects of creatine supplementation on performance and training adaptations. Mol Cell Biochem, 2003. 244(1-2): p. 89-94.

69. Gualano, B., et al., Creatine supplementation and resistance training in vulnerable older women: a randomized double-blind placebo controlled

clinical trial. Exp Gerontol, 2014. 53: p. 7-15.

70. Candow, D.G., et al., Low-dose creatine combined with protein during resistance training in older men. Med Sci Sports Exerc, 2008. 40(9): p. 1645-52.

71. Hass, C.J., M.A. Collins, and J.L. Juncos, Resistance training with creatine monohydrate improves upper-body strength in patients with Parkinson disease: a randomized trial. Neurorehabil Neural Repair, 2007. 21(2): p. 107-15.

72. Candow, D.G. and P.D. Chilibeck, Effect of creatine supplementation during resistance training on muscle accretion in the elderly. J Nutr Health Aging, 2007. 11(2): p. 185-8.

73. Chilibeck, P.D., et al., Creatine monohydrate and resistance training increase bone mineral content and density in older men. J Nutr Health Aging, 2005. 9(5): p. 352-3.

74. Burke, D.G., et al., Effect of creatine and weight training on muscle creatine and performance in vegetarians. Med Sci Sports Exerc, 2003. 35(11): p. 1946-55.

75. Wilder, N., et al., The effects of a 10-week, periodized, off-season resistance-training program and creatine supplementation among collegiate football players. J Strength Cond Res, 2002. 16(3): p. 343-52.

76. Izquierdo, M., et al., Effects of creatine supplementation on muscle power, endurance, and sprint performance. Med Sci Sports Exerc, 2002. 34(2): p. 332-43.

77. Chrusch, M.J., et al., Creatine supplementation combined with resistance training in older men. Med Sci Sports Exerc, 2001. 33(12): p. 2111-7.

78. Becque, M.D., J.D. Lochmann, and D.R. Melrose, Effects of oral creatine supplementation on muscular strength and body composition. Med Sci Sports Exerc, 2000. 32(3): p. 654-8.

79. Volek, J.S., et al., Performance and muscle fiber adaptations to creatine supplementation and heavy resistance training. Med Sci Sports Exerc, 1999. 31(8): p. 1147-56.

80. Ziegenfuss, T.N., et al., Effects of a dietary supplement on golf drive distance and functional indices of golf performance. J Int Soc Sports Nutr, 2015. 12(1): p. 4.

81. Lamontagne-Lacasse, M., R. Nadon, and E.D. Goulet, Effect of creatine supplementation on jumping performance in elite volleyball players. Int J Sports Physiol Perform, 2011. 6(4): p. 525-33.

82. Ramirez-Campillo, R., et al., Effects of plyometric training and creatine supplementation on maximal-intensity exercise and endurance in female soccer players. J Sci Med Sport, 2016. 19(8): p. 682-7.

83. Yanez-Silva, A., et al., Effect of low dose, short-term creatine supplementation on muscle power output in elite youth soccer players. J Int Soc Sports Nutr, 2017. 14: p. 5.

84. Ayoama, R., E. Hiruma, and H. Sasaki, Effects of creatine loading on muscular strength and endurance of female softball players. J Sports Med Phys Fitness, 2003. 43(4): p. 481-7.

85. Jones, A.M., T. Atter, and K.P. Georg, Oral creatine supplementation improves multiple sprint performance in elite ice-hockey players. J Sports Med Phys Fitness, 1999. 39(3): p. 189-96.

86. Ahmun, R.P., R.J. Tong, and P.N. Grimshaw, The effects of acute creatine supplementation on multiple sprint cycling and running performance in rugby players. J Strength Cond Res, 2005. 19(1): p. 92-7.

87. Cox, G., et al., Acute creatine supplementation and performance during a field test simulating match play in elite female soccer players. Int J Sport Nutr Exerc Metab, 2002. 12(1): p. 33-46.

88. Preen, D., et al., Effect of creatine loading on long-term sprint exercise performance and metabolism. Med Sci Sports Exerc, 2001. 33(5): p. 814-21.

89. Aaserud, R., et al., Creatine supplementation delays onset of fatigue during repeated bouts of sprint running. Scand J Med Sci Sports, 1998. 8(5 Pt 1): p. 247-51.

90. Bosco, C., et al., Effect of oral creatine supplementation on jumping and running performance. Int J Sports Med, 1997. 18(5): p. 369-72.

91. Dabidi Roshan, V., et al., The effect of creatine supplementation on muscle fatigue and physiological indices following intermittent swimming bouts. J Sports Med Phys Fitness, 2013. 53(3): p. 232-9.

92. Selsby, J.T., et al., Swim performance following creatine supplementation in Division III athletes. J Strength Cond Res, 2003. 17(3): p. 421-4.

93. Leenders, N.M., D.R. Lamb, and T.E. Nelson, Creatine supplementation and swimming performance. Int J Sport Nutr, 1999. 9(3): p. 251-62.

94. Peyrebrune, M.C., et al., The effects of oral creatine supplementation on performance in single and repeated sprint swimming. J Sports Sci, 1998. 16(3): p. 271-9.

95. Vandenberghe, K., et al., Long-term creatine intake is beneficial to muscle performance during resistance training. J Appl Physiol (1985), 1997. 83(6): p. 2055-63.

96. Tarnopolsky, M.A. and D.P. MacLennan, Creatine monohydrate supplementation enhances high-intensity exercise performance in males and females. Int J Sport Nutr Exerc Metab, 2000. 10(4): p. 452-63.

97. Ziegenfuss, T.N., et al., Effect of creatine loading on anaerobic performance and skeletal muscle volume in NCAA Division I athletes. Nutrition, 2002. 18(5): p. 397-402.

98. Benton, D. and R. Donohoe, The influence of creatine supplementation on the cognitive functioning of vegetarians and omnivores. Br J Nutr, 2011. 105(7): p. 1100-5.

99. Johannsmeyer, S., et al., Effect of creatine supplementation and drop-set resistance training in untrained aging adults. Exp Gerontol, 2016. 83: p. 112-9.

100. Rodriguez, N.R., et al., Position of the American Dietetic Association, Dietitians of Canada, and the American College of Sports Medicine: Nutrition and athletic performance. J Am Diet Assoc, 2009. 109(3): p. 509-27.

101. Thomas, D.T., K.A. Erdman, and L.M. Burke, Position of the Academy of Nutrition and Dietetics, Dietitians of Canada, and the American College of Sports Medicine: Nutrition and Athletic Performance. J Acad Nutr Diet, 2016. 116(3): p. 501-28.

102. Gualano, B., et al., Creatine supplementation in the aging population: effects on skeletal muscle, bone and brain. Amino Acids, 2016. 48(8):

p. 1793-805.

103. Dolan, E., et al., Muscular Atrophy and Sarcopenia in the Elderly: Is There a Role for Creatine Supplementation? Biomolecules, 2019. 9(11).

104. Candow, D.G., et al., Effectiveness of Creatine Supplementation on Aging Muscle and Bone: Focus on Falls Prevention and Inflammation. J Clin Med, 2019. 8(4).

105. Candow, D.G., et al., Variables Influencing the Effectiveness of Creatine Supplementation as a Therapeutic Intervention for Sarcopenia. Front Nutr, 2019. 6: p. 124.

106. Earnest, C.P., A.L. Almada, and T.L. Mitchell, High-performance capillary electrophoresis-pure creatine monohydrate reduces blood lipids in men and women. Clin Sci (Lond), 1996. 91(1): p. 113-8.

107. da Silva, R.P., K.A. Leonard, and R.L. Jacobs, Dietary creatine supplementation lowers hepatic triacylglycerol by increasing lipoprotein secretion in rats fed high-fat diet. J Nutr Biochem, 2017. 50: p. 46-53.

108. Deminice, R., et al., Creatine supplementation prevents fatty liver in rats fed choline-deficient diet: a burden of one-carbon and fatty acid metabolism. J Nutr Biochem, 2015. 26(4): p. 391-7.

109. Deminice, R., et al., Creatine supplementation prevents hyperhomocysteinemia, oxidative stress and cancer-induced cachexia progression in Walker-256 tumor-bearing rats. Amino Acids, 2016. 48(8): p. 2015-24.

110. Van Bavel, D., R. de Moraes, and E. Tibirica, Effects of dietary supplementation with creatine on homocysteinemia and systemic microvascular endothelial function in individuals adhering to vegan diets. Fundam Clin Pharmacol, 2019. 33(4): p. 428-440.

111. Lawler, J.M., et al., Direct antioxidant properties of creatine. Biochem Biophys Res Commun, 2002. 290(1): p. 47-52.

112. Rakpongsiri, K. and S. Sawangkoon, Protective effect of creatine supplementation and estrogen replacement on cardiac reserve function and antioxidant reservation against oxidative stress in exercise-trained ovariectomized hamsters. Int Heart J, 2008. 49(3): p. 343-54.

113. Rahimi, R., et al., Effects of creatine monohydrate supplementation on exercise-induced apoptosis in athletes: A randomized, double-blind, and placebo-controlled study. J Res Med Sci, 2015. 20(8): p. 733-8.

114. Deminice, R. and A.A. Jordao, Creatine supplementation decreases plasma lipid peroxidation markers and enhances anaerobic performance in rats. Redox Rep, 2015.

115. Op 't Eijnde, B., et al., Effect of oral creatine supplementation on human muscle GLUT4 protein content after immobilization. Diabetes, 2001. 50(1): p. 18-23.

116. Gualano, B., et al., Creatine in type 2 diabetes: a randomized, double-blind, placebo-controlled trial. Med Sci Sports Exerc, 2011. 43(5): p. 770-8.

117. Op't Eijnde, B., et al., Creatine supplementation increases soleus muscle creatine content and lowers the insulinogenic index in an animal model of inherited type 2 diabetes. Int J Mol Med, 2006. 17(6): p. 1077-84.

118. Alves, C.R., et al., Creatine-induced glucose uptake in type 2 diabetes: a role for AMPK-alpha? Amino Acids, 2012. 43(4): p. 1803-7.

119. Pinto, C.L., et al., Creatine supplementation and glycemic control: a systematic review. Amino Acids, 2016. 48(9): p. 2103-29.

120. Smith, R.N., A.S. Agharkar, and E.B. Gonzales, A review of creatine supplementation in age-related diseases: more than a supplement for athletes. F1000Res, 2014. 3: p. 222.

121. Patra, S., et al., A short review on creatine-creatine kinase system in relation to cancer and some experimental results on creatine as adjuvant in cancer therapy. Amino Acids, 2012. 42(6): p. 2319-30.

122. Soares, J.D.P., et al., Dietary Amino Acids and Immunonutrition Supplementation in Cancer-Induced Skeletal Muscle Mass Depletion: A Mini-Review. Curr Pharm Des, 2020. 26(9): p. 970-978.

123. Cella, P.S., et al., Creatine supplementation in Walker-256 tumor-bearing rats prevents skeletal muscle atrophy by attenuating systemic inflammation and protein degradation signaling. Eur J Nutr, 2020. 59(2): p. 661-669.

124. Di Biase, S., et al., Creatine uptake regulates CD8 T cell antitumor immunity. J Exp Med, 2019. 216(12): p. 2869-2882.

125. Pal, A., A. Roy, and M. Ray, Creatine supplementation with methylglyoxal: a potent therapy for cancer in experimental models. Amino Acids, 2016. 48(8): p. 2003-13.

126. Canete, S., et al., Does creatine supplementation improve functional capacity in elderly women? J Strength Cond Res, 2006. 20(1): p. 22-8.

127. Candow, D.G., et al., Comparison of creatine supplementation before versus after supervised resistance training in healthy older adults. Res Sports Med, 2014. 22(1): p. 61-74.

128. Chilibeck, P.D., et al., Effects of Creatine and Resistance Training on Bone Health in Postmenopausal Women. Med Sci Sports Exerc, 2015. 47(8): p. 1587-95.

129. Stares, A. and M. Bains, The Additive Effects of Creatine Supplementation and Exercise Training in an Aging Population: A Systematic Review of Randomized Controlled Trials. J Geriatr Phys Ther, 2020. 43(2): p. 99-112.

130. O'Bryan, K.R., et al., Do multi-ingredient protein supplements augment resistance training-induced gains in skeletal muscle mass and strength? A systematic review and meta-analysis of 35 trials. Br J Sports Med, 2020. 54(10): p. 573-581.

131. Nilsson, M.I., et al., A Five-Ingredient Nutritional Supplement and Home-Based Resistance Exercise Improve Lean Mass and Strength in Free-Living Elderly. Nutrients, 2020. 12(8).

132. Gielen, E., et al., Nutritional interventions to improve muscle mass, muscle strength, and physical performance in older people: an umbrella review of systematic reviews and meta-analyses. Nutr Rev, 2020.

133. Evans, M., et al., Efficacy of a novel formulation of L-Carnitine, creatine, and leucine on lean body mass and functional muscle strength in healthy older adults: a randomized, double-blind placebo-controlled study. Nutr Metab (Lond), 2017. 14: p. 7.

134. Chilibeck, P.D., et al., Effect of creatine supplementation during resistance training on lean tissue mass and muscular strength in older adults: a meta-analysis. Open Access J Sports Med, 2017. 8: p. 213-226.

135. Sales, L.P., et al., Creatine Supplementation (3 g/d) and Bone Health in Older Women: A 2-Year, Randomized, Placebo-Controlled Trial. J Gerontol A Biol Sci Med Sci, 2020. 75(5): p. 931-938.

136. Castoldi, R.C., et al., Effects of muscular strength training and growth hormone (GH) supplementation on femoral bone tissue: analysis by Raman spectroscopy, dual-energy X-ray absorptiometry, and mechanical resistance. Lasers Med Sci, 2020. 35(2): p. 345-354.

137. Laskou, F. and E. Dennison, Interaction of Nutrition and Exercise on Bone and Muscle. Eur Endocrinol, 2019. 15(1): p. 11-12.

138. Fairman, C.M., et al., The potential therapeutic effects of creatine supplementation on body composition and muscle function in cancer. Crit Rev Oncol Hematol, 2019. 133: p. 46-57.

139. Candow, D.G., S.C. Forbes, and E. Vogt, Effect of pre-exercise and post-exercise creatine supplementation on bone mineral content and density in healthy aging adults. Exp Gerontol, 2019. 119: p. 89-92.

140. Rawson, E.S., M.P. Miles, and D.E. Larson-Meyer, Dietary Supplements for Health, Adaptation, and Recovery in Athletes. Int J Sport Nutr Exerc Metab, 2018. 28(2): p. 188-199.

141. Forbes, S.C., P.D. Chilibeck, and D.G. Candow, Creatine Supplementation During Resistance Training Does Not Lead to Greater Bone Mineral Density in Older Humans: A Brief Meta-Analysis. Front Nutr, 2018. 5: p. 27.

142. Neves, M., Jr., et al., Beneficial effect of creatine supplementation in knee osteoarthritis. Med Sci Sports Exerc, 2011. 43(8): p. 1538-43.

143. Cornish, S.M. and J.D. Peeler, No effect of creatine monohydrate supplementation on inflammatory and cartilage degradation biomarkers in individuals with knee osteoarthritis. Nutr Res, 2018. 51: p. 57-66.

144. Alves, C.R., et al., Creatine supplementation in fibromyalgia: a randomized, double-blind, placebo-controlled trial. Arthritis Care Res (Hoboken), 2013. 65(9): p. 1449-59.

145. J, V.A.N.C., et al., Can Creatine Combat the Mental Fatigue-associated Decrease in Visuomotor Skills? Med Sci Sports Exerc, 2020. 52(1): p. 120-130.

146. Dolan, E., B. Gualano, and E.S. Rawson, Beyond muscle: the effects of creatine supplementation on brain creatine, cognitive processing, and traumatic brain injury. Eur J Sport Sci, 2019. 19(1): p. 1-14.

147. Bell, K.E., et al., A Multi-Ingredient Nutritional Supplement in Combination With Resistance Exercise and High-Intensity Interval Training Improves Cognitive Function and Increases N-3 Index in Healthy Older Men: A Randomized Controlled Trial. Front Aging Neurosci, 2019. 11: p. 107.

148. Scholey, A., Nutrients for neurocognition in health and disease: measures, methodologies and mechanisms. Proc Nutr Soc, 2018. 77(1): p. 73-83.

149. Avgerinos, K.I., et al., Effects of creatine supplementation on cognitive function of healthy individuals: A systematic review of randomized controlled trials. Exp Gerontol, 2018. 108: p. 166-173.

150. Merege-Filho, C.A., et al., Does brain creatine content rely on exogenous creatine in healthy youth? A proof-of-principle study. Appl Physiol Nutr Metab, 2017. 42(2): p. 128-134.

151. Turner, C.E., W.D. Byblow, and N. Gant, Creatine supplementation enhances corticomotor excitability and cognitive performance during oxygen deprivation. J Neurosci, 2015. 35(4): p. 1773-80.

152. Rawson, E.S., et al., Creatine supplementation does not improve cognitive function in young adults. Physiol Behav, 2008. 95(1-2): p. 130-4.

153. McMorris, T., et al., Creatine supplementation, sleep deprivation, cortisol, melatonin and behavior. Physiol Behav, 2007. 90(1): p. 21-8.

154. Roitman, S., et al., Creatine monohydrate in resistant depression: a preliminary study. Bipolar Disord, 2007. 9(7): p. 754-8.

155. D'Anci, K.E., P.J. Allen, and R.B. Kanarek, A potential role for creatine in drug abuse? Mol Neurobiol, 2011. 44(2): p. 136-41.

156. Toniolo, R.A., et al., Cognitive effects of creatine monohydrate adjunctive therapy in patients with bipolar depression: Results from a randomized, double-blind, placebo-controlled trial. J Affect Disord, 2016.

157. Balestrino, M. and E. Adriano, Beyond sports: Efficacy and safety of creatine supplementation in pathological or paraphysiological conditions of brain and muscle. Med Res Rev, 2019. 39(6): p. 2427-2459.

158. Toniolo, R.A., et al., A randomized, double-blind, placebo-controlled, proof-of-concept trial of creatine monohydrate as adjunctive treatment for bipolar depression. J Neural Transm (Vienna), 2018. 125(2): p. 247-257.

159. Wallimann, T., U. Riek, and M. Moddel, Intradialytic creatine supplementation: A scientific rationale for improving the health and quality of life of dialysis patients. Med Hypotheses, 2017. 99: p. 1-14.

160. Toniolo, R.A., et al., Cognitive effects of creatine monohydrate adjunctive therapy in patients with bipolar depression: Results from a randomized, double-blind, placebo-controlled trial. J Affect Disord, 2017. 224: p. 69-75.

161. McMorris, T., et al., Effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol. Psychopharmacology (Berl), 2006. 185(1): p. 93-103.

162. Bernat, P., et al., Effects of high-velocity resistance training and creatine supplementation in untrained healthy aging males. Appl Physiol Nutr Metab, 2019. 44(11): p. 1246-1253.

163. Dechent, P., et al., Increase of total creatine in human brain after oral supplementation of creatine-monohydrate. Am J Physiol, 1999. 277(3 Pt 2): p. R698-704.

164. Lyoo, I.K., et al., Multinuclear magnetic resonance spectroscopy of high-energy phosphate metabolites in human brain following oral supplementation of creatine-monohydrate. Psychiatry Res, 2003. 123(2): p. 87-100.

165. Pan, J.W. and K. Takahashi, Cerebral energetic effects of creatine supplementation in humans. Am J Physiol Regul Integr Comp Physiol, 2007. 292(4): p. R1745-50.

166. Watanabe, A., N. Kato, and T. Kato, Effects of creatine on mental fatigue and cerebral hemoglobin oxygenation. Neurosci Res, 2002. 42(4): p. 279-85.

167. Rae, C., et al., Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial. Proc Biol Sci, 2003. 270(1529): p. 2147-50.

168. Ling, J., M. Kritikos, and B. Tiplady, Cognitive effects of creatine ethyl ester supplementation. Behav Pharmacol, 2009. 20(8): p. 673-9.

169. Rooney, K., et al., Creatine supplementation alters insulin secretion and glucose homeostasis in vivo. Metabolism, 2002. 51(4): p. 518-22.

170. Newman, J.E., et al., Effect of creatine ingestion on glucose tolerance and insulin sensitivity in men. Med Sci Sports Exerc, 2003. 35(1): p. 69-74.

171. Greenwood, M., et al., Differences in creatine retention among three nutritional formulations of oral creatine supplements. J Exerc Physiol Online, 2003. 6(2): p. 37-43.

172. Steenge, G.R., E.J. Simpson, and P.L. Greenhaff, Protein- and carbohydrate-induced augmentation of whole body creatine retention in humans. J Appl Physiol (1985), 2000. 89(3): p. 1165-71.

173. Nelson, A.G., et al., Muscle glycogen supercompensation is enhanced by prior creatine supplementation. Med Sci Sports Exerc, 2001. 33(7): p. 1096-100.

174. Gualano, B., et al., In sickness and in health: the widespread application of creatine supplementation. Amino Acids, 2012. 43(2): p. 519-29.

175. Gualano, B., et al., Exploring the therapeutic role of creatine supplementation. Amino Acids, 2010. 38(1): p. 31-44.

176. Hultman, J., et al., Myocardial energy restoration of ischemic damage by administration of phosphoenolpyruvate during reperfusion. A study in a paracorporeal rat heart model. Eur Surg Res, 1983. 15(4): p. 200-7.

177. Thelin, S., et al., Metabolic and functional effects of creatine phosphate in cardioplegic solution. Studies on rat hearts during and after normothermic ischemia. Scand J Thorac Cardiovasc Surg, 1987. 21(1): p. 39-45.

178. Osbakken, M., et al., Creatine and cyclocreatine effects on ischemic myocardium: 31P nuclear magnetic resonance evaluation of intact heart. Cardiology, 1992. 80(3-4): p. 184-95.

179. Thorelius, J., et al., Biochemical and functional effects of creatine phosphate in cardioplegic solution during aortic valve surgery--a clinical study. Thorac Cardiovasc Surg, 1992. 40(1): p. 10-3.

180. Boudina, S., et al., Alteration of mitochondrial function in a model of chronic ischemia in vivo in rat heart. Am J Physiol Heart Circ Physiol, 2002. 282(3): p. H821-31.

181. Laclau, M.N., et al., Cardioprotection by ischemic preconditioning preserves mitochondrial function and functional coupling between adenine nucleotide translocase and creatine kinase. J Mol Cell Cardiol, 2001. 33(5): p. 947-56.

182. Conorev, E.A., V.G. Sharov, and V.A. Saks, Improvement in contractile recovery of isolated rat heart after cardioplegic ischaemic arrest with endogenous phosphocreatine: involvement of antiperoxidative effect? Cardiovasc Res, 1991. 25(2): p. 164-71.

183. Sharov, V.G., et al., Protection of ischemic myocardium by exogenous phosphocreatine. I. Morphologic and phosphorus 31-nuclear magnetic resonance studies. J Thorac Cardiovasc Surg, 1987. 94(5): p. 749-61.

184. Anyukhovsky, E.P., et al., Effect of phosphocreatine and related compounds on the phospholipid metabolism of ischemic heart. Biochem Med Metab Biol, 1986. 35(3): p. 327-34.

185. Sharov, V.G., et al., Protection of ischemic myocardium by exogenous phosphocreatine (neoton): pharmacokinetics of phosphocreatine, reduction of infarct size, stabilization of sarcolemma of ischemic cardiomyocytes, and antithrombotic action. Biochem Med Metab Biol, 1986. 35(1): p. 101-14.

186. Perasso, L., et al., Therapeutic use of creatine in brain or heart ischemia: available data and future perspectives. Med Res Rev, 2013. 33(2): p. 336-63.

187. Sykut-Cegielska, J., et al., Biochemical and clinical characteristics of creatine deficiency syndromes. Acta Biochim Pol, 2004. 51(4): p. 875- 82.

188. Freissmuth, M., T. Stockner, and S. Sucic, SLC6 Transporter Folding Diseases and Pharmacochaperoning. Handb Exp Pharmacol, 2018. 245: p. 249-270.

189. Mercimek-Mahmutoglu, S. and G.S. Salomons, Creatine Deficiency Syndromes, in GeneReviews(R), R.A. Pagon, et al., Editors. 1993: Seattle (WA).

190. Stockler-Ipsiroglu, S. and C.D. van Karnebeek, Cerebral creatine deficiencies: a group of treatable intellectual developmental disorders. Semin Neurol, 2014. 34(3): p. 350-6.

191. Joncquel-Chevalier Curt, M., et al., Creatine biosynthesis and transport in health and disease. Biochimie, 2015. 119: p. 146-65.

192. Cameron, J.M., et al., Variability of Creatine Metabolism Genes in Children with Autism Spectrum Disorder. Int J Mol Sci, 2017. 18(8).

193. Salazar, M.D., et al., Classification of the Molecular Defects Associated with Pathogenic Variants of the SLC6A8 Creatine Transporter. Biochemistry, 2020. 59(13): p. 1367-1377.

194. Longo, N., et al., Disorders of creatine transport and metabolism. Am J Med Genet C Semin Med Genet, 2011. 157C(1): p. 72-8.

195. Nasrallah, F., M. Feki, and N. Kaabachi, Creatine and creatine deficiency syndromes: biochemical and clinical aspects. Pediatr Neurol, 2010. 42(3): p. 163-71.

196. Mercimek-Mahmutoglu, S., et al., GAMT deficiency: features, treatment, and outcome in an inborn error of creatine synthesis. Neurology, 2006. 67(3): p. 480-4.

197. Stromberger, C., O.A. Bodamer, and S. Stockler-Ipsiroglu, Clinical characteristics and diagnostic clues in inborn errors of creatine metabolism. J Inherit Metab Dis, 2003. 26(2-3): p. 299-308.

198. Bianchi, M.C., et al., Treatment monitoring of brain creatine deficiency syndromes: a 1H- and 31P-MR spectroscopy study. AJNR Am J Neuroradiol, 2007. 28(3): p. 548-54.

199. Battini, R., et al., Arginine:glycine amidinotransferase (AGAT) deficiency in a newborn: early treatment can prevent phenotypic expression of the disease. J Pediatr, 2006. 148(6): p. 828-30.

200. Stockler-Ipsiroglu, S., et al., Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring. Mol Genet Metab, 2014. 111(1): p. 16-25.

201. Valtonen, M., et al., Central nervous system involvement in gyrate atrophy of the choroid and retina with hyperornithinaemia. J Inherit Metab Dis, 1999. 22(8): p. 855-66.

202. Nanto-Salonen, K., et al., Reduced brain creatine in gyrate atrophy of the choroid and retina with hyperornithinemia. Neurology, 1999. 53(2): p. 303-7.

203. Heinanen, K., et al., Creatine corrects muscle 31P spectrum in gyrate atrophy with hyperornithinaemia. Eur J Clin Invest, 1999. 29(12): p. 1060-5.

204. Vannas-Sulonen, K., et al., Gyrate atrophy of the choroid and retina. A five-year follow-up of creatine supplementation. Ophthalmology, 1985. 92(12): p. 1719-27.

205. Sipila, I., et al., Supplementary creatine as a treatment for gyrate atrophy of the choroid and retina. N Engl J Med, 1981. 304(15): p. 867-70.

206. Evangeliou, A., et al., Clinical applications of creatine supplementation on paediatrics. Curr Pharm Biotechnol, 2009. 10(7): p. 683-90.

207. Verbruggen, K.T., et al., Global developmental delay in guanidionacetate methyltransferase deficiency: differences in formal testing and clinical observation. Eur J Pediatr, 2007. 166(9): p. 921-5.

208. Ganesan, V., et al., Guanidinoacetate methyltransferase deficiency: new clinical features. Pediatr Neurol, 1997. 17(2): p. 155-7.

209. Ensenauer, R., et al., Guanidinoacetate methyltransferase deficiency: differences of creatine uptake in human brain and muscle. Mol Genet Metab, 2004. 82(3): p. 208-13.

210. Ogborn, D.I., et al., Effects of creatine and exercise on skeletal muscle of FRG1-transgenic mice. Can J Neurol Sci, 2012. 39(2): p. 225-31.

211. Louis, M., et al., Beneficial effects of creatine supplementation in dystrophic patients. Muscle Nerve, 2003. 27(5): p. 604-10.

212. Banerjee, B., et al., Effect of creatine monohydrate in improving cellular energetics and muscle strength in ambulatory Duchenne muscular dystrophy patients: a randomized, placebo-controlled 31P MRS study. Magn Reson Imaging, 2010. 28(5): p. 698-707.

213. Felber, S., et al., Oral creatine supplementation in Duchenne muscular dystrophy: a clinical and 31P magnetic resonance spectroscopy study. Neurol Res, 2000. 22(2): p. 145-50.

214. Radley, H.G., et al., Duchenne muscular dystrophy: focus on pharmaceutical and nutritional interventions. Int J Biochem Cell Biol, 2007. 39(3): p. 469-77.

215. Tarnopolsky, M.A., et al., Creatine monohydrate enhances strength and body composition in Duchenne muscular dystrophy. Neurology, 2004. 62(10): p. 1771-7.

216. Adhihetty, P.J. and M.F. Beal, Creatine and its potential therapeutic value for targeting cellular energy impairment in neurodegenerative diseases. Neuromolecular Med, 2008. 10(4): p. 275-90.

217. Verbessem, P., et al., Creatine supplementation in Huntington's disease: a placebo-controlled pilot trial. Neurology, 2003. 61(7): p. 925-30.

218. Dedeoglu, A., et al., Creatine therapy provides neuroprotection after onset of clinical symptoms in Huntington's disease transgenic mice. J Neurochem, 2003. 85(6): p. 1359-67.

219. Andreassen, O.A., et al., Creatine increase survival and delays motor symptoms in a transgenic animal model of Huntington's disease. Neurobiol Dis, 2001. 8(3): p. 479-91.

220. Ferrante, R.J., et al., Neuroprotective effects of creatine in a transgenic mouse model of Huntington's disease. J Neurosci, 2000. 20(12): p. 4389-97.

221. Matthews, R.T., et al., Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington's disease. J Neurosci, 1998. 18(1): p. 156-63.

222. Bender, A., et al., Long-term creatine supplementation is safe in aged patients with Parkinson disease. Nutr Res, 2008. 28(3): p. 172-8.

223. Bender, A., et al., Creatine supplementation in Parkinson disease: a placebo-controlled randomized pilot trial. Neurology, 2006. 67(7): p. 1262-4.

224. Duarte-Silva, S., et al., Neuroprotective Effects of Creatine in the CMVMJD135 Mouse Model of Spinocerebellar Ataxia Type 3. Mov Disord, 2018. 33(5): p. 815-826.

225. Komura, K., et al., Effectiveness of creatine monohydrate in mitochondrial encephalomyopathies. Pediatr Neurol, 2003. 28(1): p. 53-8.

226. Tarnopolsky, M.A. and G. Parise, Direct measurement of high-energy phosphate compounds in patients with neuromuscular disease. Muscle Nerve, 1999. 22(9): p. 1228-33.

227. Tarnopolsky, M.A., B.D. Roy, and J.R. MacDonald, A randomized, controlled trial of creatine monohydrate in patients with mitochondrial cytopathies. Muscle Nerve, 1997. 20(12): p. 1502-9.

228. Gowayed, M.A., et al., Enhanced mitochondrial biogenesis is associated with the ameliorative action of creatine supplementation in rat soleus and cardiac muscles. Exp Ther Med, 2020. 19(1): p. 384-392.

229. Andreassen, O.A., et al., Increases in cortical glutamate concentrations in transgenic amyotrophic lateral sclerosis mice are attenuated by creatine supplementation. J Neurochem, 2001. 77(2): p. 383-90.

230. Choi, J.K., et al., Magnetic resonance spectroscopy of regional brain metabolite markers in FALS mice and the effects of dietary creatine supplementation. Eur J Neurosci, 2009. 30(11): p. 2143-50.

231. Derave, W., et al., Skeletal muscle properties in a transgenic mouse model for amyotrophic lateral sclerosis: effects of creatine treatment. Neurobiol Dis, 2003. 13(3): p. 264-72.

232. Drory, V.E. and D. Gross, No effect of creatine on respiratory distress in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord, 2002. 3(1): p. 43-6.

233. Ellis, A.C. and J. Rosenfeld, The role of creatine in the management of amyotrophic lateral sclerosis and other neurodegenerative disorders. CNS Drugs, 2004. 18(14): p. 967-80.

234. Mazzini, L., et al., Effects of creatine supplementation on exercise performance and muscular strength in amyotrophic lateral sclerosis: preliminary results. J Neurol Sci, 2001. 191(1-2): p. 139-44.

235. Vielhaber, S., et al., Effect of creatine supplementation on metabolite levels in ALS motor cortices. Exp Neurol, 2001. 172(2): p. 377-82.

236. Hijikata, Y., et al., Treatment with Creatine Monohydrate in Spinal and Bulbar Muscular Atrophy: Protocol for a Randomized, Double-Blind, Placebo-Controlled Trial. JMIR Res Protoc, 2018. 7(3): p. e69.

237. Ipsiroglu, O.S., et al., Changes of tissue creatine concentrations upon oral supplementation of creatine-monohydrate in various animal species. Life Sci, 2001. 69(15): p. 1805-15.

238. Kley, R.A., M. Vorgerd, and M.A. Tarnopolsky, Creatine for treating muscle disorders. Cochrane Database Syst Rev, 2007(1): p. CD004760.

239. Adcock, K.H., et al., Neuroprotection of creatine supplementation in neonatal rats with transient cerebral hypoxia-ischemia. Dev Neurosci, 2002. 24(5): p. 382-8.

240. Prass, K., et al., Improved reperfusion and neuroprotection by creatine in a mouse model of stroke. J Cereb Blood Flow Metab, 2007. 27(3): p. 452-9.

241. Zhu, S., et al., Prophylactic creatine administration mediates neuroprotection in cerebral ischemia in mice. J Neurosci, 2004. 24(26): p. 5909-12.

242. Allah Yar, R., A. Akbar, and F. Iqbal, Creatine monohydrate supplementation for 10 weeks mediates neuroprotection and improves learning/memory following neonatal hypoxia ischemia encephalopathy in female albino mice. Brain Res, 2015. 1595: p. 92-100.

243. Ainsley Dean, P.J., et al., Potential for use of creatine supplementation following mild traumatic brain injury. Concussion, 2017. 2(2): p. CNC34.

244. Freire Royes, L.F. and G. Cassol, The Effects of Creatine Supplementation and Physical Exercise on Traumatic Brain Injury. Mini Rev Med Chem, 2016. 16(1): p. 29-39.

245. Sullivan, P.G., et al., Dietary supplement creatine protects against traumatic brain injury. Ann Neurol, 2000. 48(5): p. 723-9.

246. Hausmann, O.N., et al., Protective effects of oral creatine supplementation on spinal cord injury in rats. Spinal Cord, 2002. 40(9): p. 449-56.

247. Amorim, S., et al., Creatine or vitamin D supplementation in individuals with a spinal cord injury undergoing resistance training: A doubleblinded, randomized pilot trial. J Spinal Cord Med, 2018. 41(4): p. 471-478.

248. Rabchevsky, A.G., et al., Creatine diet supplement for spinal cord injury: influences on functional recovery and tissue sparing in rats. J Neurotrauma, 2003. 20(7): p. 659-69.

249. Jacobs, P.L., et al., Oral creatine supplementation enhances upper extremity work capacity in persons with cervical-level spinal cord injury. Arch Phys Med Rehabil, 2002. 83(1): p. 19-23.

250. Kendall, R.W., et al., Creatine supplementation for weak muscles in persons with chronic tetraplegia: a randomized double-blind placebo controlled crossover trial. J Spinal Cord Med, 2005. 28(3): p. 208-13.

251. Perret, C., G. Mueller, and H. Knecht, Influence of creatine supplementation on 800 m wheelchair performance: a pilot study. Spinal Cord,2006. 44(5): p. 275-9.

252. Hespel, P. and W. Derave, Ergogenic effects of creatine in sports and rehabilitation. Subcell Biochem, 2007. 46: p. 245-59.

253. Hespel, P., et al., Oral creatine supplementation facilitates the rehabilitation of disuse atrophy and alters the expression of muscle myogenic factors in humans. J Physiol, 2001. 536(Pt 2): p. 625-33.

254. Carvalho, A.P., et al., Influence of creatine supplementation on the functional capacity of patients with heart failure. Arq Bras Cardiol, 2012. 99(1): p. 623-9.

255. Cornelissen, V.A., et al., Effect of creatine supplementation as a potential adjuvant therapy to exercise training in cardiac patients: a randomized controlled trial. Clin Rehabil, 2010. 24(11): p. 988-99.

256. Kuethe, F., et al., Creatine supplementation improves muscle strength in patients with congestive heart failure. Pharmazie, 2006. 61(3): p. 218-22.

257. Andrews, R., et al., The effect of dietary creatine supplementation on skeletal muscle metabolism in congestive heart failure. Eur Heart J, 1998. 19(4): p. 617-22.

258. Gordon, A., et al., Creatine supplementation in chronic heart failure increases skeletal muscle creatine phosphate and muscle performance. Cardiovasc Res, 1995. 30(3): p. 413-8.

259. Fuld, J.P., et al., Creatine supplementation during pulmonary rehabilitation in chronic obstructive pulmonary disease. Thorax, 2005. 60(7): p. 531-7.

260. Cooke, M.B., et al., Creatine supplementation enhances muscle force recovery after eccentrically-induced muscle damage in healthy individuals. J Int Soc Sports Nutr, 2009. 6: p. 13.

261. Ellery, S.J., et al., Renal dysfunction in early adulthood following birth asphyxia in male spiny mice, and its amelioration by maternalcreatine supplementation during pregnancy. Pediatr Res, 2017.

262. LaRosa, D.A., et al., Maternal creatine supplementation during pregnancy prevents acute and long-term deficits in skeletal muscle after birth asphyxia: a study of structure and function of hind limb muscle in the spiny mouse. Pediatr Res, 2016. 80(6): p. 852-860.

263. Ellery, S.J., D.W. Walker, and H. Dickinson, Creatine for women: a review of the relationship between creatine and the reproductive cycle and female-specific benefits of creatine therapy. Amino Acids, 2016. 48(8): p. 1807-17.

264. Ellery, S.J., et al., Dietary creatine supplementation during pregnancy: a study on the effects of creatine supplementation on creatine homeostasis and renal excretory function in spiny mice. Amino Acids, 2016. 48(8): p. 1819-30.

265. Dickinson, H., et al., Creatine supplementation during pregnancy: summary of experimental studies suggesting a treatment to improve fetal and neonatal morbidity and reduce mortality in high-risk human pregnancy. BMC Pregnancy Childbirth, 2014. 14: p. 150.

266. Bortoluzzi, V.T., et al., Co-administration of creatine plus pyruvate prevents the effects of phenylalanine administration to female rats during pregnancy and lactation on enzymes activity of energy metabolism in cerebral cortex and hippocampus of the offspring. Neurochem Res, 2014. 39(8): p. 1594-602.

267. Vallet, J.L., J.R. Miles, and L.A. Rempel, Effect of creatine supplementation during the last week of gestation on birth intervals, stillbirth, and preweaning mortality in pigs. J Anim Sci, 2013. 91(5): p. 2122-32.

268. Ellery, S.J., et al., Creatine pretreatment prevents birth asphyxia-induced injury of the newborn spiny mouse kidney. Pediatr Res, 2013. 73(2): p. 201-8.

269. Dickinson, H., et al., Maternal dietary creatine supplementation does not alter the capacity for creatine synthesis in the newborn spiny mouse. Reprod Sci, 2013. 20(9): p. 1096-102.

270. Ireland, Z., et al., A maternal diet supplemented with creatine from mid-pregnancy protects the newborn spiny mouse brain from birth hypoxia. Neuroscience, 2011. 194: p. 372-9.

271. Leland, K.M., T.L. McDonald, and K.M. Drescher, Effect of creatine, creatinine, and creatine ethyl ester on TLR expression in macrophages. Int Immunopharmacol, 2011. 11(9): p. 1341-7.

272. Beraud, D. and K.A. Maguire-Zeiss, Misfolded alpha-synuclein and Toll-like receptors: therapeutic targets for Parkinson's disease. Parkinsonism Relat Disord, 2012. 18 Suppl 1: p. S17-20.

273. De Paola, M., et al., Synthetic and natural small molecule TLR4 antagonists inhibit motoneuron death in cultures from ALS mouse model. Pharmacol Res, 2016. 103: p. 180-7.

274. Bassit, R.A., R. Curi, and L.F. Costa Rosa, Creatine supplementation reduces plasma levels of pro-inflammatory cytokines and PGE2 after a\ half-ironman competition. Amino Acids, 2008. 35(2): p. 425-31.

275. Deminice, R., et al., Effects of creatine supplementation on oxidative stress and inflammatory markers after repeated-sprint exercise in humans. Nutrition, 2013. 29(9): p. 1127-32.

276. Santos, R.V., et al., The effect of creatine supplementation upon inflammatory and muscle soreness markers after a 30km race. Life Sci, 2004. 75(16): p. 1917-24.

277. Garcia, M., et al., Creatine supplementation impairs airway inflammation in an experimental model of asthma involving P2 x 7 receptor. Eur J Immunol, 2019. 49(6): p. 928-939.

278. Vieira, R.P., et al., Creatine supplementation exacerbates allergic lung inflammation and airway remodeling in mice. Am J Respir Cell Mol Biol, 2007. 37(6): p. 660-7.

279. Almeida, F.M., et al., Creatine supplementation attenuates pulmonary and systemic effects of lung ischemia and reperfusion injury. J Heart Lung Transplant, 2016. 35(2): p. 242-50.

280. Braegger, C.P., et al., Effects of creatine supplementation in cystic fibrosis: results of a pilot study. J Cyst Fibros, 2003. 2(4): p. 177-82.

281. Al-Ghimlas, F. and D.C. Todd, Creatine supplementation for patients with COPD receiving pulmonary rehabilitation: a systematic review and meta-analysis. Respirology, 2010. 15(5): p. 785-95.

282. Faager, G., et al., Creatine supplementation and physical training in patients with COPD: a double blind, placebo-controlled study. Int J Chron Obstruct Pulmon Dis, 2006. 1(4): p. 445-53.

283. Simpson, A.J., et al., Effect of Creatine Supplementation on the Airways of Youth Elite Soccer Players. Med Sci Sports Exerc, 2019. 51(8): p. 1582-1590.

284. Miller, E.E., A.E. Evans, and M. Cohn, Inhibition of rate of tumor growth by creatine and cyclocreatine. Proc Natl Acad Sci U S A, 1993. 90(8): p. 3304-8.

285. Wyss, M. and R. Kaddurah-Daouk, Creatine and creatinine metabolism. Physiol Rev, 2000. 80(3): p. 1107-213.

286. Ostojic, S.M., Postviral fatigue syndrome and creatine: a piece of the puzzle? Nutr Neurosci, 2020: p. 1-2.

287. Malatji, B.G., et al., A diagnostic biomarker profile for fibromyalgia syndrome based on an NMR metabolomics study of selected patients and controls. BMC Neurol, 2017. 17(1): p. 88.

288. Mueller, C., et al., Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy. Brain Imaging Behav, 2020. 14(2): p. 562-572.

289. van der Schaaf, M.E., et al., Prefrontal Structure Varies as a Function of Pain Symptoms in Chronic Fatigue Syndrome. Biol Psychiatry, 2017. 81(4): p. 358-365.

290. Puri, B.K., Proton and 31-phosphorus neurospectroscopy in the study of membrane phospholipids and fatty acid intervention in schizophrenia, depression, chronic fatigue syndrome (myalgic encephalomyelitis) and dyslexia. Int Rev Psychiatry, 2006. 18(2): p. 145-7.

291. Chaudhuri, A., et al., Proton magnetic resonance spectroscopy of basal ganglia in chronic fatigue syndrome. Neuroreport, 2003. 14(2): p. 225-8.

292. Chaudhuri, A. and P.O. Behan, In vivo magnetic resonance spectroscopy in chronic fatigue syndrome. Prostaglandins Leukot Essent Fatty Acids, 2004. 71(3): p. 181-3.

293. Ostojic, S.M., et al., Supplementation with Guanidinoacetic Acid in Women with Chronic Fatigue Syndrome. Nutrients, 2016. 8(2): p. 72.

294. Silveri, M.M., et al., S-adenosyl-L-methionine: effects on brain bioenergetic status and transverse relaxation time in healthy subjects. Biol Psychiatry, 2003. 54(8): p. 833-9.

295. Allen, P.J., et al., Chronic creatine supplementation alters depression-like behavior in rodents in a sex-dependent manner. Neuropsychopharmacology, 2010. 35(2): p. 534-46.

296. Ahn, N.R., et al., Effects of creatine monohydrate supplementation and exercise on depression-like behaviors and raphe 5-HT neurons in mice. J Exerc Nutrition Biochem, 2016. 20(3): p. 24-31.

297. Pazini, F.L., et al., Creatine Prevents Corticosterone-Induced Reduction in Hippocampal Proliferation and Differentiation: Possible  Implication for Its Antidepressant Effect. Mol Neurobiol, 2017. 54(8): p. 6245-6260.

298. Leem, Y.H., M. Kato, and H. Chang, Regular exercise and creatine supplementation prevent chronic mild stress-induced decrease in hippocampal neurogenesis via Wnt/GSK3beta/beta-catenin pathway. J Exerc Nutrition Biochem, 2018. 22(2): p. 1-6.

299. Lyoo, I.K., et al., Oral choline decreases brain purine levels in lithium-treated subjects with rapid-cycling bipolar disorder: a double-blind trial using proton and lithium magnetic resonance spectroscopy. Bipolar Disord, 2003. 5(4): p. 300-6.

300. Sbracia, M., et al., Sperm function and choice of preparation media: comparison of Percoll and Accudenz discontinuous density gradients. J Androl, 1996. 17(1): p. 61-7.

301. Huszar, G., L. Vigue, and M. Corrales, Sperm creatine kinase activity in fertile and infertile oligospermic men. J Androl, 1990. 11(1): p. 40-6.

302. Fakih, H., et al., Enhancement of human sperm motility and velocity in vitro: effects of calcium and creatine phosphate. Fertil Steril, 1986.

46(5): p. 938-44.

303. Oehninger, S. and N.J. Alexander, Male infertility: the focus shifts to sperm manipulation. Curr Opin Obstet Gynecol, 1991. 3(2): p. 182-90.

304. Gergely, A., et al., Sperm creatine kinase activity in normospermic and oligozospermic Hungarian men. J Assist Reprod Genet, 1999. 16(1): p. 35-40.

305. Froman, D.P. and A.J. Feltmann, A new approach to sperm preservation based on bioenergetic theory. J Anim Sci, 2010. 88(4): p. 1314-20.

306. Lenz, H., et al., The creatine kinase system in human skin: protective effects of creatine against oxidative and UV damage in vitro and in vivo. J Invest Dermatol, 2005. 124(2): p. 443-52.

307. Peirano, R.I., et al., Dermal penetration of creatine from a face-care formulation containing creatine, guarana and glycerol is linked to effective antiwrinkle and antisagging efficacy in male subjects. J Cosmet Dermatol, 2011. 10(4): p. 273-81.