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.     

Benefits and drawbacks of guanidinoacetic acid as a possible treatment to replenish cerebral creatine in AGAT deficiency

Arginine–glycine amidinotransferase (AGAT) deficiency is a rare inherited metabolic disorder that severely affects brain bioenergetics. Characterized by mental retardation, language impairment, and behavioral disorders, AGAT deficiency is a treatable condition, where long-term creatine supplementation usually restores brain creatine levels and improves its clinical features. In some cases of AGAT deficiency, creatine treatment might be somewhat limited due to possible shortcomings in performance and transport of creatine to the brain. Guanidinoacetic acid (GAA), a direct metabolic precursor of creatine, has recently been suggested as a possible alternative to creatine to tackle brain creatine levels in experimental medicine. AGAT patients might benefit from oral GAA due to upgraded bioavailability and convenient utilization of the compound, while possible drawbacks (e.g. brain methylation issues, neurotoxicity, and hyperhomocysteinemia) should be accounted as well.     

Anti-Inflammatory and Anti-Catabolic Effects of Creatine Supplementation: A Brief Review

It is well established that creatine supplementation, primarily when combined with resistance training, significantly increases measures of muscle mass and performance (primarily strength). Emerging research also indicates that creatine supplementation may have favorable effects on measures of bone biology. These anabolic adaptations may be related to creatine influencing cellular hydration status, high-energy phosphate metabolism, growth factors, muscle protein kinetics, and the bone remodeling process. Accumulating research also suggests that creatine supplementation has anti-inflammatory and anti-catabolic properties, which may help create a favorable environment for muscle and bone accretion and recovery from exercise. Creatine supplementation has the ability to decrease markers of inflammation and possibly attenuate cancerous tumor growth progression. From a musculoskeletal perspective, there is some evidence to show that creatine supplementation reduces measures of muscle protein catabolism (primarily in males) and bone resorption when combined with resistance training. The purpose of this brief review is to summarize the current body of literature examining the potential anti-inflammatory and anti-catabolic effects of creatine supplementation across various research populations.     

Safety of Dietary Guanidinoacetic Acid: A Villain of a Good Guy?

Guanidinoacetic acid (GAA) is a natural amino acid derivative that is well-recognized for its central role in the biosynthesis of creatine, an essential compound involved in cellular energy metabolism. GAA (also known as glycocyamine or betacyamine) has been investigated as an energy-boosting dietary supplement in humans for more than 70 years. GAA is suggested to effectively increase low levels of tissue creatine and improve clinical features of cardiometabolic and neurological diseases, with GAA often outcompeting traditional bioenergetics agents in maintaining ATP status during stress. This perhaps happens due to a favorable delivery of GAA through specific membrane transporters (such as SLC6A6 and SLC6A13), previously dismissed as un-targetable carriers by other therapeutics, including creatine. The promising effects of dietary GAA might be countered by side-effects and possible toxicity. Animal studies reported neurotoxic and pro-oxidant effects of GAA accumulation, with exogenous GAA also appearing to increase methylation demand and circulating homocysteine, implying a possible metabolic burden of GAA intervention. This mini-review summarizes GAA toxicity evidence in human nutrition and outlines functional GAA safety through benefit-risk assessment and multi-criteria decision analysis.     

Creatine Metabolism in Female Reproduction,Pregnancy and Newborn Health

Creatine metabolism is an important component of cellular energy homeostasis. Via the creatine kinase circuit, creatine derived from our diet or synthesized endogenously provides spatial and temporal maintenance of intracellular adenosine triphosphate (ATP) production; this is particularly important for cells with high or fluctuating energy demands. The use of this circuit by tissues within the female reproductive system, as well as the placenta and the developing fetus during pregnancy is apparent throughout the literature, with some studies linking perturbations in creatine metabolism to reduced fertility and poor pregnancy outcomes. Maternal dietary creatine supplementation during pregnancy as a safeguard against hypoxia-induced perinatal injury, particularly that of the brain, has also been widely studied in pre-clinical in vitro and small animal models. However, there is still no consensus on whether creatine is essential for successful reproduction. This review consolidates the available literature on creatine metabolism in female reproduction, pregnancy and the early neonatal period. Creatine metabolism is discussed in relation to cellular bioenergetics and de novo synthesis, as well as the potential to use dietary creatine in a reproductive setting. We highlight the apparent knowledge gaps and the research “road forward” to understand, and then utilize, creatine to improve reproductive health and perinatal outcomes.     

The role of gangliosides in brain development and the potential benefits of perinatal supplementation

The maternal diet provides critical nutrients that can influence fetal and infant brain development and function. This review highlights the potential benefits of maternal dietary ganglioside supplementation on fetal and infant brain development. English-language systematic reviews, preclinical studies, and clinical studies were obtained through searches on PubMed. Reports were selected if they included benefits and harms of maternal ganglioside supplementation during pregnancy or ganglioside-supplemented formula after pregnancy. The potential benefits of ganglioside supplementation were explored by investigating the following: (1) their role in neural development, (2) their therapeutic use in neural injury and disease, (3) their presence in human breast milk, and (4) their use as a dietary supplement during or after pregnancy. Preclinical studies indicate that ganglioside supplementation at high doses (1% of total dietary intake) can significantly increase cognitive development and body weight when given prenatally. However, lower ganglioside supplementation doses have no beneficial cognitive effects, even when given throughout pregnancy and lactation. In human clinical trials, infants given formula supplemented with gangliosides showed increased cognitive development and an increase in ganglioside content. Ganglioside supplementation may promote brain development and function in offspring when administered at the optimum dosage. We propose that prenatal maternal dietary supplementation with gangliosides throughout pregnancy may promote greater long-term effects on brain development and function. Before this concept can be encouraged in preconception clinics, future research and clinical trials are needed to confirm the ability of dietary gangliosides to improve cognitive development, but available results already encourage this area of research.     

重型颅脑外伤局灶低温与全身低温疗效的对比研究

目的：探究重型颅脑外伤局灶低温治疗与全身低温治疗的治疗效果。方法：采用Feeney自由落体改良模型（free fall improved model）,分别设定全身低温组（A组）、假颅脑外伤模型组（B组）、局灶低温组（C组）以及颅脑外伤模型组（D组）。对伤灶处以及与其相邻部位的脑组织进行检测,分别测定H2O、钠离子、钾离子的含量,观察比较各组间病理改变。结果：经检测发现,假颅脑外伤模型组受损神经元数为（2.2±0.4）个、全身低温组受损神经元数为（9.1±0.5）个、局灶低温组受损神经元数为（6.3±0.3）个、颅脑外伤模型组受损神经元数为（12.1±1.1）个;全身低温组和颅脑外伤模型组受损神经元数明显多于局灶低温组,差异具有统计学意义（P〈0.01）。全身低温组和颅脑外伤模型组H2O、钠离子的含量显著高于局灶低温组,差异具有统计学意义（P〈0.05）,而钾离子的含量明显低于局灶低温组,差异具有统计学意义（P〈0.01）。结论：局灶低温疗法相比较全身低温疗法在减少神经元损伤以及缓解脑水肿等方面具有明显优势,治疗效果显著,值得临床借鉴使用。     

Creatine Supplementation in Women’s Health: A Lifespan Perspective

Despite extensive research on creatine, evidence for use among females is understudied. Creatine characteristics vary between males and females, with females exhibiting 70–80% lower endogenous creatine stores compared to males. Understanding creatine metabolism pre- and post-menopause yields important implications for creatine supplementation for performance and health among females. Due to the hormone-related changes to creatine kinetics and phosphocreatine resynthesis, supplementation may be particularly important during menses, pregnancy, post-partum, during and post-menopause. Creatine supplementation among pre-menopausal females appears to be effective for improving strength and exercise performance. Post-menopausal females may also experience benefits in skeletal muscle size and function when consuming high doses of creatine (0.3 g·kg⁻¹·d⁻¹); and favorable effects on bone when combined with resistance training. Pre-clinical and clinical evidence indicates positive effects from creatine supplementation on mood and cognition, possibly by restoring brain energy levels and homeostasis. Creatine supplementation may be even more effective for females by supporting a pro-energetic environment in the brain. The purpose of this review was to highlight the use of creatine in females across the lifespan with particular emphasis on performance, body composition, mood, and dosing strategies.     

Creatine in Health and Disease

Although creatine has been mostly studied as an ergogenic aid for exercise, training, and sport, several health and potential therapeutic benefits have been reported. This is because 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 creatine’s role in promoting general health as we age and how creatine supplementation has been used as a nutritional strategy to help individuals recover from injury and/or manage chronic disease. Additionally, it provides reasonable conclusions about the role of creatine on health and disease based on current scientific evidence. Based on this analysis, it can be concluded that creatine supplementation has several health and therapeutic benefits throughout the lifespan.     

Moderate zinc deficiency increases cell death after brain injury in the rat

Zinc supplementation has been used clinically to reduce Zn losses and protein turnover in patients suffering from traumatic brain injury. Despite the known role of zinc in cell survival and integrity, the influence of zinc status on central nervous system wound healing in the weeks and months after brain injury has not been addressed. In this investigation, we examined cell death after unilateral cortical stab wounds in adult rats (n = 5 per group) that were provided diets containing adequate zinc (30 mg Zn/kg diet), supplemental zinc (180 mg/kg), or moderately deficient zinc (5 mg/kg). Four weeks following the brain injury there was a 1.82-2.65-fold increase in terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick-end labeling (TUNEL)-positive cells with DNA fragmentation at the site of injury in animals receiving a moderately zinc deficient diet compared to animals receiving a zinc-adequate or supplemented diet (p0.05). Examination of the nuclear morphology of these cells suggested the presence of both apoptosis and necrosis. Immunohistochemistry showed that the TUNEL-positive cells expressed both ED-1 and OX-42, identifying them as microglia/macrophages. Thus it appears that adequate zinc status may be necessary to minimize the amount of neuroimmune cell death after brain injury.     

Effects of creatine on thermoregulatory responses while exercising in the heat

OBJECTIVE: We hypothesized that creatine supplementation would interfere with normal body fluid shifts that occur during exercise in a hot environment due to its osmotic effect intracellularly. This study examined the effects of acute creatine loading (20 g/d for 5 d) on the thermoregulatory response of the body during a bout of exercise at 39 degrees C. METHODS: Subjects (15 men and 1 woman) performed a cycle test of maximum oxygen consumption to determine the proper work rate for the heat-stress test (40 min at 55% maximum oxygen consumption at 39 degrees C) and were assigned to a creatine group (n = 8) or a placebo group (n = 8) in a double-blind fashion. Each group performed the heat-stress test on two separate occasions: before supplementation and after supplementation (20 g/d of creatine with Gatorade or Solka-floc plus Gatorade). Dependent variables included rectal temperature, mean skin temperature, mean body temperature, and perceived thermal sensation. RESULTS: Repeated measure analysis of variance showed a significant (P < or = 0.05) increase in body weight in the group supplemented with Gatorade. Core temperature was significantly lower after supplementation for both groups combined (before supplementation at 37.85 degrees C and after supplementation at 37.7 degrees C), with no difference between groups. A significant three-way interaction (group x trial x time) was also found for rectal temperature, with both groups having significantly lower rectal temperature after supplementation. Mean body and mean skin temperatures showed no differences. CONCLUSIONS: Short-term creatine supplementation (20 g/d for 5 d) did not have a negative effect on thermoregulatory responses during exercise at 39 degrees C.     

The Dietary Supplement Creatyl-l-Leucine Does Not Bioaccumulate in Muscle,Brain or Plasma and Is Not a Significant Bioavailable Source of Creatine

Creatine is an important energy metabolite that is concentrated in tissues such as the muscles and brain. Creatine is reversibly converted to creatine phosphate through a reaction with ATP or ADP, which is catalyzed by the enzyme creatine kinase. Dietary supplementation with relatively large amounts of creatine monohydrate has been proven as an effective sports supplement that can enhances athletic performance during acute high-energy demand physical activity. Some side effects have been reported with creatine monohydrate supplementation, which have stimulated research into new potential molecules that could be used as supplements to potentially provide bioavailable creatine. Recently, a popular supplement, creatyl-l-leucine, has been proposed as a potential dietary ingredient that may potentially provide bioavailable creatine. This study tests whether creatyl-l-leucine is a bioavailable compound and determines whether it can furnish creatine as a dietary supplement. Rats were deprived of dietary creatine for a period of two weeks and then given one of three treatments: a control AIN-93G creatine-free diet, AIN-93G supplemented with creatine monohydrate or AIN-93G with an equimolar amount of creatyl-l-leucine supplement in the diet for one week. When compared to the control and the creatine monohydrate-supplemented diet, creatyl-l-leucine supplementation resulted in no bioaccumulation of either creatyl-l-leucine or creatine in tissue.     

Timing of Creatine Supplementation around Exercise: A Real Concern?

Creatine has been considered an effective ergogenic aid for several decades; it can help athletes engaged in a variety of sports and obtain performance gains. Creatine supplementation increases muscle creatine stores; several factors have been identified that may modify the intramuscular increase and subsequent performance benefits, including baseline muscle Cr content, type II muscle fibre content and size, habitual dietary intake of Cr, aging, and exercise. Timing of creatine supplementation in relation to exercise has recently been proposed as an important consideration to optimise muscle loading and performance gains, although current consensus is lacking regarding the ideal ingestion time. Research has shifted towards comparing creatine supplementation strategies pre-, during-, or post-exercise. Emerging evidence suggests greater benefits when creatine is consumed after exercise compared to pre-exercise, although methodological limitations currently preclude solid conclusions. Furthermore, physiological and mechanistic data are lacking, in regard to claims that the timing of creatine supplementation around exercise moderates gains in muscle creatine and exercise performance. This review discusses novel scientific evidence on the timing of creatine intake, the possible mechanisms that may be involved, and whether the timing of creatine supplementation around exercise is truly a real concern.     

Youth Soccer Parents' Attitudes and Perceptions About Concussions

PurposeParents are important figures in properly managing youth sport concussions. Although media attention has predominantly centered on concussions in contact/collision sports, evidence suggests that the concussion rate in soccer is comparable to those found in contact/collision sports. Given the high rate of concussions in youth soccer, this study aimed to examine parents of youth soccer athletes' attitudes and perceptions about concussions and associated factors.MethodsA cross-sectional study was conducted by surveying parents of youth soccer athletes from the five largest organized youth soccer programs across the U.S. The researchers developed a questionnaire after an extensive literature review and by modifying previously used instruments.ResultsOverall, 419 parents completed the survey. The vast majority (85%) agreed that a concussion is a serious injury, but only 27.9% believed that their child could suffer a concussion during the next season. Parents were most concerned about permanent brain damage when their child suffers a concussion. The vast majority (4.37 ± .89) perceived concussion reporting as an important injury prevention strategy. Greater appreciation and perceived risk about concussions was found particularly among parents who received concussion education and those who had witnessed or heard about a concussive incidence(s).ConclusionsFindings suggest that youth soccer parents have high appreciation and perceived risk about concussions. However, the need for more targeted education was noted, as improvements to better manage and reduce concussions can be made. Future research should continue examining youth sport parents' belief and understanding about concussions as well as factors affecting them.     

Potential of Creatine in Glucose Management and Diabetes

Creatine is one of the most popular supplements worldwide, and it is frequently used by both athletic and non-athletic populations to improve power, strength, muscle mass and performance. A growing body of evidence has been identified potential therapeutic effects of creatine in a wide variety of clinical conditions, such as cancer, muscle dystrophy and neurodegenerative disorders. Evidence has suggested that creatine supplementation alone, and mainly in combination with exercise training, may improve glucose metabolism in health individuals and insulin-resistant individuals, such as in those with type 2 diabetes mellitus. Creatine itself may stimulate insulin secretion in vitro, improve muscle glycogen stores and ameliorate hyperglycemia in animals. In addition, exercise induces numerous metabolic benefits, including increases in insulin-independent muscle glucose uptake and insulin sensitivity. It has been speculated that creatine supplementation combined with exercise training could result in additional improvements in glucose metabolism when compared with each intervention separately. The possible mechanism underlying the effects of combined exercise and creatine supplementation is an enhanced glucose transport into muscle cell by type 4 glucose transporter (GLUT-4) translocation to sarcolemma. Although preliminary findings from small-scale trials involving patients with type 2 diabetes mellitus are promising, the efficacy of creatine for improving glycemic control is yet to be confirmed. In this review, we aim to explore the possible therapeutic role of creatine supplementation on glucose management and as a potential anti-diabetic intervention, summarizing the current knowledge and highlighting the research gaps.     

Scientific basis and practical aspects of creatine supplementation for athletes

A large number of studies have been published on creatine supplementation over the last decade. Many studies show that creatine supplementation in conjunction with resistance training augments gains in muscle strength and size. The underlying physiological mechanism(s) to explain this ergogenic effect remain unclear. Increases in muscle fiber hypertrophy and myosin heavy chain expression have been observed with creatine supplementation. Creatine supplementation increases acute weightlifting performance and training volume, which may allow for greater overload and adaptations to training. Creatine supplementation may also induce a cellular swelling in muscle cells, which in turn may affect carbohydrate and protein metabolism. Several studies point to the conclusion that elevated intramuscular creatine can enhance glycogen levels but an effect on protein synthesis/degradation has not been consistently detected. As expected there is a distribution of responses to creatine supplementation that can be largely explained by the degree of creatine uptake into muscle. Thus, there is wide interest in methods to maximize muscle creatine levels. A carbohydrate or carbohydrate/protein-induced insulin response appears to benefit creatine uptake. In summary, the predominance of research indicates that creatine supplementation represents a safe, effective, and legal method to enhance muscle size and strength responses to resistance training.     

Experimental Concussion: (Section of Neurology)

The various hypotheses of the mechanism of coma resulting from cerebral trauma are discussed. Experimental evidence shows that there are two kinds of transient abolition of cerebral function by trauma—acceleration concussion, and compression concussion. The former is a passing paralysis which occurs in all brain-stem mechanisms examined and is brought about at and beyond a threshold value of change in velocity. A lesser degree of change causes momentary depression of function, a greater degree prolongs the phase of paralysis before recovery occurs. Movement of the head is necessary for the usual kind of concussion to occur, as also for contre-coup injury. Compression concussion has much more selective incidence on the respiratory centre, and appears to require an extreme crushing injury or penetration of the skull by a relatively large object. Acceleration concussion is that accompanying closed head injury and is not accompanied by any significant change in C.S.F. pressure. The cerebral blood flow is verv greatly increased in this variety owing to stimulation of the vagoglossopharyngeal nerves at the foramen magnum. With more severe blows subpial or intramedullary lesions may occur in this situation, indicating that distortion at the foramen magnum occurs. No evidence of vascular spasm or paralysis is found. An immediate brief rise of blood-pressure is due to stimulation of the vasomotor centre. Vagal effects may not appear until the traumatic paralysis of all centres begins to pass off. A delayed fall in blood-pressure lasting many minutes may follow severe vagal effects, and appears comparable to acute surgical shock as produced by intense stimulation of any other visceral nerve. Death occurs from failure of blood-pressure, an intensification of shock with shallow respiration and intense constriction of viscera.It is concluded that sudden failure of what has been called the veno-pressor system is important in death shortly following experimental concussion. No macroscopical lesions are found, and histological examination shows no change with ordinary tissue stains. The unconsciousness of coma is believed to be related to direct traumatic paralysis of the cortical neurones and if their sensitivity to physical violence is similar to that of anæsthetics, prolonged impairment of function from this cause alone is possible. Clinical observations were related in support of these conclusions.     

No effect of heavy resistance training and creatine supplementation on blood lipids

In order to examine the effects of heavy resistance training and the influence of creatine supplementation on nonperformance measures of health status, 19 healthy resistance-trained men were matched and then randomly assigned in a double-blind fashion to either a creatine (n = 10) or placebo (n = 9) group. Periodized heavy resistance training was performed 3-4 times per week for 12 weeks. During the first week of training, creatine subjects consumed 25 g creatine monohydrate per day, while the placebo group ingested an equal number of placebo capsules. Five grams of supplement per day was consumed for the remainder of the study. Body composition, fasting serum creatinine, lipoproteins and triglycerides, and reported changes in body function were determined prior to and after 12 weeks of training and supplementation. After training, significant increases in body mass and fat-free mass were greater in creatine (5.2 and 4.3 kg, respectively) than placebo (3.0 and 2.1 kg, respectively) subjects. There was no change in percent body fat. Dietary energy and macronutrient distribution was not significantly different during Weeks 1 and 12. Serum creatinine was significantly elevated in creatine subjects after 1 (11.6%) and 12 weeks (13.8%); however, values were within normal limits for healthy men. There were no effects of training or supplementation on serum total cholesterol, HDL-cholesterol, LDL-cholesterol, or triglycerides. In healthy men, a 12-week heavy resistance training program, with or without creatine supplementation, did not significantly influence serum lipid profiles, subjective reports of body functioning, or serum creatinine concentrations.     

Moderate Zinc Deficiency Increases Cell Death After Brain Injury in the Rat

Abstract

Zinc supplementation has been used clinically to reduce Zn losses and protein turnover in patients suffering from traumatic brain injury. Despite the known role of zinc in cell survival and integrity, the influence of zinc status on central nervous system wound healing in the weeks and months after brain injury has not been addressed. In this investigation, we examined cell death after unilateral cortical stab wounds in adult rats (n=5 per group) that were provided diets containing adequate zinc (30 mg Zn/kg diet), supplemental zinc (180 mg/kg), or moderately deficient zinc (5 mg/kg). Four weeks following the brain injury there was a 1.82-2.65-fold increase in terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick-end labeling (TUNEL)-positive cells with DNA fragmentation at the site of injury in animals receiving a moderately zinc deficient diet compared to animals receiving a zinc-adequate or supplemented diet (p#0.05). Examination of the nuclear morphology of these cells suggested the presence of both apoptosis and necrosis. Immunohistochemistry showed that the TUNEL-positive cells expressed both ED-1 and OX-42, identifying them as microglia/macrophages. Thus it appears that adequate zinc status may be necessary to minimize the amount of neuroimmune cell death after brain injury.     

Brain damage and paraphilia: Treated with medroxyprogesterone acetate

Brain damage, due to cortical atrophy, brain tumor, epileptic foci, temporal lobectomy, or concussion, is most frequently associated with hyposexuality in males. Sometimes, hypersexuality and atypical sexual interests may be present, as exemplified in a case of a man who developed a paraphilia for his stepdaughter's breasts following traumatic frontal brain injury. Treatment with medroxyprogesterone acetate (Depo-Provera ®) was successful in ameliorating symptoms over a followup period of two years. Prior treatment with anticonvulsant medication, cognitive and behavioral retraining, individual and family psychotherapy had been unsuccessful.The author would like to thank Dr. John Money of The Johns Hopkins Hospital, and Drs. Andree Allen, HB Lehrman and Walter Mastek of the Veterans Administration Hospitals, for their assistance.