Creatine O'Clock: Does Timing of Ingestion Really Influence Muscle Mass and Performance?

It is well-established that creatine supplementation augments the gains in muscle mass and performance during periods of resistance training. However, whether the timing of creatine ingestion influences these physical and physiological adaptations is unclear. Muscle contractions increase blood flow and possibly creatine transport kinetics which has led some to speculate that creatine in close proximity to resistance training sessions may lead to superior improvements in muscle mass and performance. Furthermore, creatine co-ingested with carbohydrates or a mixture of carbohydrates and protein that alter insulin enhance creatine uptake. The purpose of this narrative review is to (i) discuss the purported mechanisms and variables that possibly justify creatine timing strategies, (ii) to critically evaluate research examining the strategic ingestion of creatine during a resistance training program, and (iii) provide future research directions pertaining to creatine timing.

Effects of Creatine Supplementation on Brain Function and Health.

While the vast majority of research involving creatine supplementation has focused on skeletal muscle, there is a small body of accumulating research that has focused on creatine and the brain. Preliminary studies indicate that creatine supplementation (and guanidinoacetic acid; GAA) has the ability to increase brain creatine content in humans. Furthermore, creatine has shown some promise for attenuating symptoms of concussion, mild traumatic brain injury and depression but its effect on neurodegenerative diseases appears to be lacking. The purpose of this narrative review is to summarize the current body of research pertaining to creatine supplementation on total creatine and phophorylcreatine (PCr) content, explore GAA as an alternative or adjunct to creatine supplementation on brain creatine uptake, assess the impact of creatine on cognition with a focus on sleep deprivation, discuss the effects of creatine supplementation on a variety of neurological and mental health conditions, and outline recent advances on creatine supplementation as a neuroprotective supplement following traumatic brain injury or concussion.

A Bioinformatics-Assisted Review on Iron Metabolism and Immune System to Identify Potential Biomarkers of Exercise Stress-Induced Immunosuppression.

The immune function is closely related to iron (Fe) homeostasis and allostasis. The aim of this bioinformatics-assisted review was twofold; (i) to update the current knowledge of Fe metabolism and its relationship to the immune system, and (ii) to perform a prediction analysis of regulatory network hubs that might serve as potential biomarkers during stress-induced immunosuppression. Several literature and bioinformatics databases/repositories were utilized to review Fe metabolism and complement the molecular description of prioritized proteins. The Search Tool for the Retrieval of Interacting Genes (STRING) was used to build a protein-protein interactions network for subsequent network topology analysis. Importantly, Fe is a sensitive double-edged sword where two extremes of its nutritional status may have harmful effects on innate and adaptive immunity. We identified clearly connected important hubs that belong to two clusters: (i) presentation of peptide antigens to the immune system with the involvement of redox reactions of Fe, heme, and Fe trafficking/transport; and (ii) ubiquitination, endocytosis, and degradation processes of proteins related to Fe metabolism in immune cells (e.g., macrophages). The identified potential biomarkers were in agreement with the current experimental evidence, are included in several immunological/biomarkers databases, and/or are emerging genetic markers for different stressful conditions. Although further validation is warranted, this hybrid method (human-machine collaboration) to extract meaningful biological applications using available data in literature and bioinformatics tools should be highlighted.

A Convergent Functional Genomics Analysis to Identify Biological Regulators Mediating Effects of Creatine Supplementation.

Creatine (Cr) and phosphocreatine (PCr) are physiologically essential molecules for life, given they serve as rapid and localized support of energy- and mechanical-dependent processes. This evolutionary advantage is based on the action of creatine kinase (CK) isozymes that connect places of ATP synthesis with sites of ATP consumption (the CK/PCr system). Supplementation with creatine monohydrate (CrM) can enhance this system, resulting in well-known ergogenic effects and potential health or therapeutic benefits. In spite of our vast knowledge about these molecules, no integrative analysis of molecular mechanisms under a systems biology approach has been performed to date; thus, we aimed to perform for the first time a convergent functional genomics analysis to identify biological regulators mediating the effects of Cr supplementation in health and disease. A total of 35 differentially expressed genes were analyzed. We identified top-ranked pathways and biological processes mediating the effects of Cr supplementation. The impact of CrM on miRNAs merits more research. We also cautiously suggest two dose-response functional pathways (kinase- and ubiquitin-driven) for the regulation of the Cr uptake. Our functional enrichment analysis, the knowledge-based pathway reconstruction, and the identification of hub nodes provide meaningful information for future studies. This work contributes to a better understanding of the well-reported benefits of Cr in sports and its potential in health and disease conditions, although further clinical research is needed to validate the proposed mechanisms.

The Application of Creatine Supplementation in Medical Rehabilitation.

Numerous health conditions affecting the musculoskeletal, cardiopulmonary, and nervous systems can result in physical dysfunction, impaired performance, muscle weakness, and disuse-induced atrophy. Due to its well-documented anabolic potential, creatine monohydrate has been investigated as a supplemental agent to mitigate the loss of muscle mass and function in a variety of acute and chronic conditions. A review of the literature was conducted to assess the current state of knowledge regarding the effects of creatine supplementation on rehabilitation from immobilization and injury, neurodegenerative diseases, cardiopulmonary disease, and other muscular disorders. Several of the findings are encouraging, showcasing creatine's potential efficacy as a supplemental agent via preservation of muscle mass, strength, and physical function; however, the results are not consistent. For multiple diseases, only a few creatine studies with small sample sizes have been published, making it difficult to draw definitive conclusions. Rationale for discordant findings is further complicated by differences in disease pathologies, intervention protocols, creatine dosing and duration, and patient population. While creatine supplementation demonstrates promise as a therapeutic aid, more research is needed to fill gaps in knowledge within medical rehabilitation.

Metabolic Basis of Creatine in Health and Disease: A Bioinformatics-Assisted Review.

Creatine (Cr) is a ubiquitous molecule that is synthesized mainly in the liver, kidneys, and pancreas. Most of the Cr pool is found in tissues with high-energy demands. Cr enters target cells through a specific symporter called Na+/Cl--dependent Cr transporter (CRT). Once within cells, creatine kinase (CK) catalyzes the reversible transphosphorylation reaction between [Mg2+:ATP4-]2- and Cr to produce phosphocreatine (PCr) and [Mg2+:ADP3-]-. We aimed to perform a comprehensive and bioinformatics-assisted review of the most recent research findings regarding Cr metabolism. Specifically, several public databases, repositories, and bioinformatics tools were utilized for this endeavor. Topics of biological complexity ranging from structural biology to cellular dynamics were addressed herein. In this sense, we sought to address certain pre-specified questions including: (i) What happens when creatine is transported into cells? (ii) How is the CK/PCr system involved in cellular bioenergetics? (iii) How is the CK/PCr system compartmentalized throughout the cell? (iv) What is the role of creatine amongst different tissues? and (v) What is the basis of creatine transport? Under the cellular allostasis paradigm, the CK/PCr system is physiologically essential for life (cell survival, growth, proliferation, differentiation, and migration/motility) by providing an evolutionary advantage for rapid, local, and temporal support of energy- and mechanical-dependent processes. Thus, we suggest the CK/PCr system acts as a dynamic biosensor based on chemo-mechanical energy transduction, which might explain why dysregulation in Cr metabolism contributes to a wide range of diseases besides the mitigating effect that Cr supplementation may have in some of these disease states.

Common questions and misconceptions about creatine supplementation: what does the scientific evidence really show?

Supplementing with creatine is very popular amongst athletes and exercising individuals for improving muscle mass, performance and recovery. Accumulating evidence also suggests that creatine supplementation produces a variety of beneficial effects in older and patient populations. Furthermore, evidence-based research shows that creatine supplementation is relatively well tolerated, especially at recommended dosages (i.e. 3-5 g/day or 0.1 g/kg of body mass/day). Although there are over 500 peer-refereed publications involving creatine supplementation, it is somewhat surprising that questions regarding the efficacy and safety of creatine still remain. These include, but are not limited to: 1. Does creatine lead to water retention? 2. Is creatine an anabolic steroid? 3. Does creatine cause kidney damage/renal dysfunction? 4. Does creatine cause hair loss / baldness? 5. Does creatine lead to dehydration and muscle cramping? 6. Is creatine harmful for children and adolescents? 7. Does creatine increase fat mass? 8. Is a creatine 'loading-phase' required? 9. Is creatine beneficial for older adults? 10. Is creatine only useful for resistance / power type activities? 11. Is creatine only effective for males? 12. Are other forms of creatine similar or superior to monohydrate and is creatine stable in solutions/beverages? To answer these questions, an internationally renowned team of research experts was formed to perform an evidence-based scientific evaluation of the literature regarding creatine supplementation.

Creatine Supplementation and Brain Health.

There is a robust and compelling body of evidence supporting the ergogenic and therapeutic role of creatine supplementation in muscle. Beyond these well-described effects and mechanisms, there is literature to suggest that creatine may also be beneficial to brain health (e.g., cognitive processing, brain function, and recovery from trauma). This is a growing field of research, and the purpose of this short review is to provide an update on the effects of creatine supplementation on brain health in humans. There is a potential for creatine supplementation to improve cognitive processing, especially in conditions characterized by brain creatine deficits, which could be induced by acute stressors (e.g., exercise, sleep deprivation) or chronic, pathologic conditions (e.g., creatine synthesis enzyme deficiencies, mild traumatic brain injury, aging, Alzheimer's disease, depression). Despite this, the optimal creatine protocol able to increase brain creatine levels is still to be determined. Similarly, supplementation studies concomitantly assessing brain creatine and cognitive function are needed. Collectively, data available are promising and future research in the area is warranted.

Beyond muscle: the effects of creatine supplementation on brain creatine, cognitive processing, and traumatic brain injury.

The ergogenic and therapeutic effects of increasing muscle creatine by supplementation are well-recognized. It appears that similar benefits to brain function and cognitive processing may also be achieved with creatine supplementation, however research in this area is more limited, and important knowledge gaps remain. The purpose of this review is to provide a comprehensive overview of the current state of knowledge about the influence of creatine supplementation on brain function in healthy individuals. It appears that brain creatine is responsive to supplementation, however higher, or more prolonged dosing strategies than those typically used to increase muscle creatine, may be required to elicit an increase in brain creatine. The optimal dosing strategy to induce this response, is currently unknown, and there is an urgent need for studies investigating this. When considering the influence of supplementation strategies on cognitive processes, it appears that creatine is most likely to exert an influence in situations whereby cognitive processes are stressed, e.g. during sleep deprivation, experimental hypoxia, or during the performance of more complex, and thus more cognitively demanding tasks. Evidence exists indicating that increased brain creatine may be effective at reducing the severity of, or enhancing recovery from mild traumatic brain injury, however, only limited data in humans are available to verify this hypothesis, thus representing an exciting area for further research.

IOC consensus statement: dietary supplements and the high-performance athlete.

Nutrition usually makes a small but potentially valuable contribution to successful performance in elite athletes, and dietary supplements can make a minor contribution to this nutrition programme. Nonetheless, supplement use is widespread at all levels of sport. Products described as supplements target different issues, including (1) the management of micronutrient deficiencies, (2) supply of convenient forms of energy and macronutrients, and (3) provision of direct benefits to performance or (4) indirect benefits such as supporting intense training regimens. The appropriate use of some supplements can benefit the athlete, but others may harm the athlete's health, performance, and/or livelihood and reputation (if an antidoping rule violation results). A complete nutritional assessment should be undertaken before decisions regarding supplement use are made. Supplements claiming to directly or indirectly enhance performance are typically the largest group of products marketed to athletes, but only a few (including caffeine, creatine, specific buffering agents and nitrate) have good evidence of benefits. However, responses are affected by the scenario of use and may vary widely between individuals because of factors that include genetics, the microbiome and habitual diet. Supplements intended to enhance performance should be thoroughly trialled in training or simulated competition before being used in competition. Inadvertent ingestion of substances prohibited under the antidoping codes that govern elite sport is a known risk of taking some supplements. Protection of the athlete's health and awareness of the potential for harm must be paramount; expert professional opinion and assistance is strongly advised before an athlete embarks on supplement use.

IOC Consensus Statement: Dietary Supplements and the High-Performance Athlete.

Nutrition usually makes a small but potentially valuable contribution to successful performance in elite athletes, and dietary supplements can make a minor contribution to this nutrition program. Nonetheless, supplement use is widespread at all levels of sport. Products described as supplements target different issues, including the management of micronutrient deficiencies, supply of convenient forms of energy and macronutrients, and provision of direct benefits to performance or indirect benefits such as supporting intense training regimens. The appropriate use of some supplements can offer benefits to the athlete, but others may be harmful to the athlete's health, performance, and/or livelihood and reputation if an anti-doping rule violation results. A complete nutritional assessment should be undertaken before decisions regarding supplement use are made. Supplements claiming to directly or indirectly enhance performance are typically the largest group of products marketed to athletes, but only a few (including caffeine, creatine, specific buffering agents and nitrate) have good evidence of benefits. However, responses are affected by the scenario of use and may vary widely between individuals because of factors that include genetics, the microbiome, and habitual diet. Supplements intended to enhance performance should be thoroughly trialed in training or simulated competition before implementation in competition. Inadvertent ingestion of substances prohibited under the anti-doping codes that govern elite sport is a known risk of taking some supplements. Protection of the athlete's health and awareness of the potential for harm must be paramount, and expert professional opinion and assistance is strongly advised before embarking on supplement use.

Dietary Supplements for Health, Adaptation, and Recovery in Athletes.

Some dietary supplements are recommended to athletes based on data that supports improved exercise performance. Other dietary supplements are not ergogenic per se, but may improve health, adaptation to exercise, or recovery from injury, and so could help athletes to train and/or compete more effectively. In this review, we describe several dietary supplements that may improve health, exercise adaptation, or recovery. Creatine monohydrate may improve recovery from and adaptation to intense training, recovery from periods of injury with extreme inactivity, cognitive processing, and reduce severity of or enhance recovery from mild traumatic brain injury (mTBI). Omega 3-fatty acid supplementation may also reduce severity of or enhance recovery from mTBI. Replenishment of vitamin D insufficiency or deficiency will likely improve some aspects of immune, bone, and muscle health. Probiotic supplementation can reduce the incidence, duration, and severity of upper respiratory tract infection, which may indirectly improve training or competitive performance. Preliminary data show that gelatin and/or collagen may improve connective tissue health. Some anti-inflammatory supplements, such as curcumin or tart cherry juice, may reduce inflammation and possibly delayed onset muscle soreness (DOMS). Beta-hydroxy beta-methylbutyrate (HMB) does not consistently increase strength and/or lean mass or reduce markers of muscle damage, but more research on recovery from injury that includes periods of extreme inactivity is needed. Several dietary supplements, including creatine monohydrate, omega 3-fatty acids, vitamin D, probiotics, gelatin, and curcumin/tart cherry juice could help athletes train and/or compete more effectively.

Selected In-Season Nutritional Strategies to Enhance Recovery for Team Sport Athletes: A Practical Overview.

Team sport athletes face a variety of nutritional challenges related to recovery during the competitive season. The purpose of this article is to review nutrition strategies related to muscle regeneration, glycogen restoration, fatigue, physical and immune health, and preparation for subsequent training bouts and competitions. Given the limited opportunities to recover between training bouts and games throughout the competitive season, athletes must be deliberate in their recovery strategy. Foundational components of recovery related to protein, carbohydrates, and fluid have been extensively reviewed and accepted. Micronutrients and supplements that may be efficacious for promoting recovery include vitamin D, omega-3 polyunsaturated fatty acids, creatine, collagen/vitamin C, and antioxidants. Curcumin and bromelain may also provide a recovery benefit during the competitive season but future research is warranted prior to incorporating supplemental dosages into the athlete's diet. Air travel poses nutritional challenges related to nutrient timing and quality. Incorporating strategies to consume efficacious micronutrients and ingredients is necessary to support athlete recovery in season.

Perspectives on Exertional Rhabdomyolysis.

Exertional (exercise-induced) rhabdomyolysis is a potentially life threatening condition that has been the subject of research, intense discussion, and media attention. The causes of rhabdomyolysis are numerous and can include direct muscle injury, unaccustomed exercise, ischemia, extreme temperatures, electrolyte abnormalities, endocrinologic conditions, genetic disorders, autoimmune disorders, infections, drugs, toxins, and venoms. The objective of this article is to review the literature on exertional rhabdomyolysis, identify precipitating factors, and examine the role of the dietary supplement creatine monohydrate. PubMed and SPORTDiscus databases were searched using the terms rhabdomyolysis, muscle damage, creatine, creatine supplementation, creatine monohydrate, and phosphocreatine. Additionally, the references of papers identified through this search were examined for relevant studies. A meta-analysis was not performed. Although the prevalence of rhabdomyolysis is low, instances still occur where exercise is improperly prescribed or used as punishment, or incomplete medical history is taken, and exertional rhabdomyolysis occurs. Creatine monohydrate does not appear to be a precipitating factor for exertional rhabdomyolysis. Healthcare professionals should be able to recognize the basic signs of exertional rhabdomyolysis so prompt treatment can be administered. For the risk of rhabdomyolysis to remain low, exercise testing and prescription must be properly conducted based on professional standards.

Creatine supplementation in the aging population: effects on skeletal muscle, bone and brain.

This narrative review aims to summarize the recent findings on the adjuvant application of creatine supplementation in the management of age-related deficits in skeletal muscle, bone and brain metabolism in older individuals. Most studies suggest that creatine supplementation can improve lean mass and muscle function in older populations. Importantly, creatine in conjunction with resistance training can result in greater adaptations in skeletal muscle than training alone. The beneficial effect of creatine upon lean mass and muscle function appears to be applicable to older individuals regardless of sex, fitness or health status, although studies with very old (>90 years old) and severely frail individuals remain scarce. Furthermore, there is evidence that creatine may affect the bone remodeling process; however, the effects of creatine on bone accretion are inconsistent. Additional human clinical trials are needed using larger sample sizes, longer durations of resistance training (>52 weeks), and further evaluation of bone mineral, bone geometry and microarchitecture properties. Finally, a number of studies suggest that creatine supplementation improves cognitive processing under resting and various stressed conditions. However, few data are available on older adults, and the findings are discordant. Future studies should focus on older adults and possibly frail elders or those who have already experienced an age-associated cognitive decline.

Effect of exercise intensity on percent body fat determined by leg-to-leg and segmental bioelectrical impedance analyses in adults.

PURPOSE: We examined the impact that cycle ergometry exercise had on percent body fat (% BF) estimates when assessed using either leg-to-leg or segmental bioelectrical impedance analysis (LBIA; SBIA) and whether the intensity of the exercise bout impacts the %BF magnitude of change. METHOD: Seventy-four college-aged adults participated in this study. Participants visited the laboratory on three separate occasions. Testing included two 30-min exercise sessions (70% HR(max) and 85% HR(max)) and a 30-min no-exercise session, which served as the control. RESULTS: Following exercise, significant (p < .05) reductions in mean %BF were observed when using LBIA (70% HR(max) = 0.3%; 85% HR(max) = 0.5%) and SBIA (70% HR(max) = 0.8%; 85% HR(max) = 1.4%). The mean %BF reductions were significantly (p < .04) greater following exercise at the higher intensity for both analyzers. CONCLUSIONS: Our findings indicate that cycle exercise performed before LBIA and SBIA body composition assessment reduces mean %BF estimates. In addition, the %BF reductions were found to be larger at the higher end of the American College of Sports Medicine/American Heart Association recommended intensity range (85% HR(max)) and when the SBIA analyzer was used to conduct the assessment.

Estimation of resistance exercise energy expenditure using triaxial accelerometry.

Recently, it was demonstrated that a uniaxial accelerometer worn at the hip could estimate resistance exercise energy expenditure. As resistance exercise takes place in more than 1 plane, the use of a triaxial accelerometer may be more effective in estimating resistance exercise energy expenditure. The aims of this study were to estimate the energy cost of resistance exercise using triaxial accelerometry and to determine the optimal location for wearing triaxial accelerometers during resistance exercise. Thirty subjects (15 men and 15 women; age = 21.7 ± 1.0 years) performed a resistance exercise protocol consisting of 2 sets of 8 exercises (10RM loads). During the resistance exercise protocol, subjects wore triaxial accelerometers on the wrist, waist, and ankle; a heart rate monitor; and a portable metabolic system. Net energy expenditure was significantly correlated with vertical (r = 0.67, p < 0.001), horizontal (r = 0.43, p = 0.02), third axis (r = 0.36, p = 0.048), and sum of 3 axes (r = 0.50, p = 0.005) counts at the waist, and horizontal counts at the wrist (r = -0.40, p = 0.03). Regression analysis using fat-free mass, sex, and the sum of accelerometer counts at the waist as variables was used to develop an equation that explained 73% of the variance of resistance exercise energy expenditure. A triaxial accelerometer worn at the waist can be used to estimate resistance exercise energy expenditure but appears to offer no benefit over uniaxial accelerometry. The use of accelerometers in estimating resistance exercise energy expenditure may prove useful for individuals and athletes who participate in resistance training and are focused on maintaining a tightly regulated energy balance.

In sickness and in health: the widespread application of creatine supplementation.

There is an extensive and still growing body of the literature supporting the efficacy of creatine (Cr) supplementation. In sports, creatine has been recognized as the most effective nutritional supplement in enhancing exercise tolerance, muscle strength and lean body mass. From a clinical perspective, the application of Cr supplementation is indeed exciting. Evidences of benefits from this supplement have been reported in a broad range of diseases, including myopathies, neurodegenerative disorders, cancer, rheumatic diseases, and type 2 diabetes. In addition, after hundreds of published studies and millions of exposures creatine supplementation maintains an excellent safety profile. Thus, we contend that the widespread application of this supplement may benefit athletes, elderly people and various patient populations. In this narrative review, we aimed to summarize both the ergogenic and therapeutic effects of Cr supplementation. Furthermore, we reviewed the impact of Cr supplementation on kidney function.

Use of creatine in the elderly and evidence for effects on cognitive function in young and old.

The ingestion of the dietary supplement creatine (about 20 g/day for 5 days or about 2 g/day for 30 days) results in increased skeletal muscle creatine and phosphocreatine. Subsequently, the performance of high-intensity exercise tasks, which rely heavily on the creatine-phosphocreatine energy system, is enhanced. The well documented benefits of creatine supplementation in young adults, including increased lean body mass, increased strength, and enhanced fatigue resistance are particularly important to older adults. With aging and reduced physical activity, there are decreases in muscle creatine, muscle mass, bone density, and strength. However, there is evidence that creatine ingestion may reverse these changes, and subsequently improve activities of daily living. Several groups have demonstrated that in older adults, short-term high-dose creatine supplementation, independent of exercise training, increases body mass, enhances fatigue resistance, increases muscle strength, and improves the performance of activities of daily living. Similarly, in older adults, concurrent creatine supplementation and resistance training increase lean body mass, enhance fatigue resistance, increase muscle strength, and improve performance of activities of daily living to a greater extent than resistance training alone. Additionally, creatine supplementation plus resistance training results in a greater increase in bone mineral density than resistance training alone. Higher brain creatine is associated with improved neuropsychological performance, and recently, creatine supplementation has been shown to increase brain creatine and phosphocreatine. Subsequent studies have demonstrated that cognitive processing, that is either experimentally (following sleep deprivation) or naturally (due to aging) impaired, can be improved with creatine supplementation. Creatine is an inexpensive and safe dietary supplement that has both peripheral and central effects. The benefits afforded to older adults through creatine ingestion are substantial, can improve quality of life, and ultimately may reduce the disease burden associated with sarcopenia and cognitive dysfunction.