Dietary Creatine Supplementation Research Articles

Genetic Depletion of Adipocyte Creatine Metabolism Inhibits Diet-Induced Thermogenesis and Drives Obesity

Diet-induced thermogenesis is an important homeostatic mechanism that limits weight gain in response to caloric excess and contributes to the relative stability of body weight in most individuals. We previously demonstrated that creatine enhances energy expenditure through stimulation of mitochondrial ATP turnover, but the physiological role and importance of creatine energetics in adipose tissue have not been explored. Here, we have inactivated the first and rate-limiting enzyme of creatine biosynthesis, glycine amidinotransferase (GATM), selectively in fat (Adipo-Gatm KO). Adipo-Gatm KO mice are prone to diet-induced obesity due to the suppression of elevated energy expenditure that occurs in response to high-calorie feeding. This is paralleled by a blunted capacity for β3-adrenergic activation of metabolic rate, which is rescued by dietary creatine supplementation. These results provide strong invivo genetic support for a role of GATM and creatine metabolism in energy expenditure, diet-induced thermogenesis, and defense against diet-induced obesity.

Understanding the Full Spectrum of Organ Injury Following Intrapartum Asphyxia.

Birth asphyxia is a significant global health problem, responsible for ~1.2 million neonatal deaths each year worldwide. Those who survive often suffer from a range of health issues including brain damage—manifesting as cerebral palsy (CP)—respiratory insufficiency, cardiovascular collapse, and renal dysfunction, to name a few. Although the majority of research is directed toward reducing the brain injury that results from intrapartum birth asphyxia, the multi-organ injury observed in surviving neonates is of equal importance. Despite the advent of hypothermia therapy for the treatment of hypoxic–ischemic encephalopathy (HIE), treatment options following asphyxia at birth remain limited, particularly in low-resource settings where the incidence of birth asphyxia is highest. Furthermore, although cooling of the neonate results in improved neurological outcomes for a small proportion of treated infants, it does not provide any benefit to the other organ systems affected by asphyxia at birth. The aim of this review is to summarize the current knowledge of the multi-organ effects of intrapartum asphyxia, with particular reference to the findings from our laboratory using the precocial spiny mouse to model birth asphyxia. Furthermore, we reviewed the current treatments available for neonates who have undergone intrapartum asphyxia, and highlight the emergence of maternal dietary creatine supplementation as a preventative therapy, which has been shown to provide multi-organ protection from birth asphyxia-induced injury in our preclinical studies. This cheap and effective nutritional supplement may be the key to reducing birth asphyxia-induced death and disability, particularly in low-resource settings where current treatments are unavailable.

Creatine kinase in ischemic and inflammatory disorders.

The creatine/phosphocreatine pathway plays a conserved and central role in energy metabolism. Compartmentalization of specific creatine kinase enzymes permits buffering of local high energy phosphates in a thermodynamically favorable manner, enabling both rapid energy storage and energy transfer within the cell. Augmentation of this metabolic pathway by nutritional creatine supplementation has been shown to elicit beneficial effects in a number of diverse pathologies, particularly those that incur tissue ischemia, hypoxia or oxidative stress. In these settings, creatine and phosphocreatine prevent depletion of intracellular ATP and internal acidification, enhance post-ischemic recovery of protein synthesis and promote free radical scavenging and stabilization of cellular membranes. The creatine kinase energy system is itself further regulated by hypoxic signaling, highlighting the existence of endogenous mechanisms in mammals that can enhance creatine metabolism during oxygen deprivation to promote tissue resolution and homeostasis. Here, we review recent insights into the creatine kinase pathway, and provide rationale for dietary creatine supplementation in human ischemic and inflammatory pathologies.

Dietary Creatine Supplementation Reduced the Proportion of Dietary Arginine Directed toward Guanidinoacetic Acid (GAA) Synthesis and Reduced the Demand for Methionine‐Derived Methyl Groups, but Did Not Enhance Whole Body Protein Synthesis in Neonatal Piglets

Our previous work demonstrated that dietary arginine (Arg) intake influenced tissue creatine concentrations in neonatal piglets fed creatine‐free diets. Both Arg and methionine (Met) are required for creatine biosynthesis, as L‐arginine:glycine amidinotransferase (AGAT) converts Arg to guanidinoacetic acid (GAA),which is subsequently methylated by guanidinoacetate methyltransferase (GAMT) to form creatine, with Met as the methyl donor. In this study, we manipulated dietary Arg, Met, GAA and creatine supply to quantify the partitioning of amino acids towards GAA and creatine synthesis. Piglets (9 – 11 d old, N =35) were fed one of five elemental diets: 1) low Arg and low Met (Low Arg&Met), 2) low Arg and Met plus GAA, 3) low Arg and Met plus creatine 4) high Arg and high Met (High Arg&Met) or 5) low Arg with high Met plus GAA.On d 6, piglets underwent a primed, constant infusion of stable isotope tracers of Arg, GAA and creatine to measure Arg partitioning, and tracers of phenylalanine and tyrosine to measure whole body protein synthesis. On d 7, a second infusion of 3H‐methyl‐methionine was conducted to trace the partitioning of methyl groups to creatine synthesis. GAA synthesis was limited by Arg and/or Met since piglets fed the Low Arg&Met diet had less Arg conversion to GAA compared to the High Arg&Met group (P<0.001). Renal AGAT activity in the Low Arg&Met was significantly higher than all other groups (P<0.01), suggesting that the lower conversion rate was due to inadequate substrate availability and not due to lack of enzyme activity. The inclusion of GAA with low Arg and Met resulted in significantly lower Arg partitioning to GAA (P<0.01) and to creatine (P<0.001). Liver GAMT activity was similar across diet groups, except when GAA was supplied with high Met (P<0.01), suggesting GAMT was induced to accommodate creatine synthesis only when Met was abundant. The addition of creatine to the Low Arg&Met diet resulted in higher kidney, liver and plasma creatine concentrations (P < 0.001), but these values were not different from those concentrations in the piglets fed High Arg&Met. The addition of creatine also resulted in a smaller proportion of dietary Arg directed towards GAA synthesis (63 versus 91%, respectively, P<0.001), and a lower incorporation of methionine‐derived methyl groups into creatine (P<0.05) compared to all other diet groups. Although supplementing GAA or creatine appeared to spare Arg and Met, whole body protein synthesis or breakdown were not different. When Arg and Met availabilities were limited, creatine supplementation led to a reduction in the demand for these amino acids to satisfy GAA and creatine synthesis. Consideration of dietary creatine availability is essential when determining Arg and Met requirements of the neonate.Support or Funding Information(NSERC and Evonik)

Dietary creatine supplementation during pregnancy: a study on the effects of creatine supplementation on creatine homeostasis and renal excretory function in spiny mice.

Recent evidence obtained from a rodent model of birth asphyxia shows that supplementation of the maternal diet with creatine during pregnancy protects the neonate from multi-organ damage. However, the effect of increasing creatine intake on creatine homeostasis and biosynthesis in females, particularly during pregnancy, is unknown. This study assessed the impact of creatine supplementation on creatine homeostasis, body composition, capacity for de novo creatine synthesis and renal excretory function in non-pregnant and pregnant spiny mice. Mid-gestation pregnant and virgin spiny mice were fed normal chow or chow supplemented with 5% w/w creatine for 18days. Weight gain, urinary creatine and electrolyte excretion were assessed during supplementation. At post mortem, body composition was assessed by Dual-energy X-ray absorptiometry, or tissues were collected to assess creatine content and mRNA expression of the creatine synthesising enzymes arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT) and the creatine transporter (CrT1). Protein expression of AGAT and GAMT was also assessed by Western blot. Key findings of this study include no changes in body weight or composition with creatine supplementation; increased urinary creatine excretion in supplemented spiny mice, with increased sodium (P<0.001) and chloride (P<0.05) excretion in pregnant dams after 3days of supplementation; lowered renal AGAT mRNA (P<0.001) and protein (P<0.001) expressions, and lowered CrT1 mRNA expression in the kidney (P<0.01) and brain (P<0.001). Creatine supplementation had minimal impact on creatine homeostasis in either non-pregnant or pregnant spiny mice. Increasing maternal dietary creatine consumption could be a useful treatment for birth asphyxia.

Augmentation of Creatine in the Heart.

Creatine is a principle component of the creatine kinase (CK) phosphagen system common to all vertebrates. It is found in excitable cells, such as cardiomyocytes, where it plays an important role in the buffering and transport of chemical energy to ensure that supply meets the dynamic demands of the heart. Multiple components of the CK system, including intracellular creatine levels, are reduced in heart failure, while ischaemia and hypoxia represent acute crises of energy provision. Elevation of myocardial creatine levels has therefore been suggested as potentially beneficial, however, achieving this goal is not trivial. This mini-review outlines the evidence in support of creatine elevation and critically examines the pharmacological approaches that are currently available. In particular, dietary creatine-supplementation does not sufficiently elevate creatine levels in the heart due to subsequent down-regulation of the plasma membrane creatine transporter (CrT). Attempts to increase passive diffusion and bypass the CrT, e.g. via creatine esters, have yet to be tested in the heart. However, studies in mice with genetic overexpression of the CrT demonstrate proof-of-principle that elevated creatine protects the heart from ischaemia-reperfusion injury. This suggests activation of the CrT as a major unmet pharmacological target. However, translation of this finding to the clinic will require a greater understanding of CrT regulation in health and disease and the development of small molecule activators.

Effects of long-term low-dose dietary creatine supplementation in older women

ObjectiveWe aimed to investigate the effects of a one-year low-dose creatine supplementation trial on bone health, lean mass, and muscle function in older postmenopausal women. MethodsA double-blind, randomized, parallel-group, placebo controlled trial was conducted between November 2011 and November 2013 in Sao Paulo, Brazil. Postmenopausal osteopenic women were randomly allocated (1:1) into creatine (n=56; 1g/d) or placebo group (n=53; dextrose at same dose). At baseline and after one year of intervention, we assessed parameters of bone health, body composition, and muscle function. Blood parameters were also assessed before and after the intervention and adverse events were recorded throughout the trial. Possible differences in dietary intake were assessed by three 24-h dietary recalls. ResultsBone mineral density at lumbar spine, femoral neck, total femur, and whole body did not differ within- or between-groups. No significant changes in body weight, BMI, absolute and relative body fat, and body lean mass were observed. Muscle function, as assessed by timed-up-and-go and timed-stands tests, were not significantly changed within- or between-groups. Safety laboratory parameters remained unaltered. ConclusionA one-year low-dose creatine supplementation (1g/d) was free of adverse effects, but did not affect bone health parameters, lean mass, or muscle function in older women. Further studies with longer follow-up periods and higher doses of creatine supplementation are warranted. (Registered at clinicaltrials.gov as NCT01472393).

Creatine supplementation enhances corticomotor excitability and cognitive performance during oxygen deprivation.

Impairment or interruption of oxygen supply compromises brain function and plays a role in neurological and neurodegenerative conditions. Creatine is a naturally occurring compound involved in the buffering, transport, and regulation of cellular energy, with the potential to replenish cellular adenosine triphosphate without oxygen. Creatine is also neuroprotective in vitro against anoxic/hypoxic damage. Dietary creatine supplementation has been associated with improved symptoms in neurological disorders defined by impaired neural energy provision. Here we investigate, for the first time in humans, the utility of creatine as a dietary supplement to protect against energetic insult. The aim of this study was to assess the influence of oral creatine supplementation on the neurophysiological and neuropsychological function of healthy young adults during acute oxygen deprivation. Fifteen healthy adults were supplemented with creatine and placebo treatments for 7 d, which increased brain creatine on average by 9.2%. A hypoxic gas mixture (10% oxygen) was administered for 90 min, causing global oxygen deficit and impairing a range of neuropsychological processes. Hypoxia-induced decrements in cognitive performance, specifically attentional capacity, were restored when participants were creatine supplemented, and corticomotor excitability increased. A neuromodulatory effect of creatine via increased energy availability is presumed to be a contributing factor of the restoration, perhaps by supporting the maintenance of appropriate neuronal membrane potentials. Dietary creatine monohydrate supplementation augments neural creatine, increases corticomotor excitability, and prevents the decline in attention that occurs during severe oxygen deficit. This is the first demonstration of creatine's utility as a neuroprotective supplement when cellular energy provision is compromised.

Effects of dietary creatine supplementation for 8 weeks on neuromuscular coordination and learning in male albino mouse following neonatal hypoxic ischemic insult.

Creatine monohydrate (Cr) is a dietary supplement known to improve cognitive functions and has positive therapeutic results under various clinical conditions. The aim of this study was to determine the effect of 2 % Cr supplementation on learning, memory formation, neuromuscular coordination, exploratory and locomotory in male albino mice following hypoxic ischemic insult. At postnatal day, 10 male albino mice pups were subjected to right common carotid artery ligation followed by 8 % hypoxia for 25 min. On postnatal day 20, male mice were separated from the litter and divided into two groups on the basis of special diet supplementation. One group was supplemented with 2 % Cr in diet while the other group was raised on ordinary rodent chow for 8 weeks. Behavioral observations were made during rota rod, open field and Morris water maze test for both treatments. It was observed that supplementation with 2 % Cr for 8 weeks following neonatal brain damage resulted in enhanced muscular strength, neuromuscular coordination and improved body weight. In Morris water maze test, it was observed that Cr supplementation significantly improved mean swimming speed and mice on 2 % Cr diet covered more distance but the spatial memory was not improved significantly following hypoxia ischemia encephalopathy (HIE). Open field parameters and percentage of infarct volume remained unaffected following Cr supplementation. We concluded that 2 % dietary Cr supplementation has a potential to improve the muscle strength and body weight in male albino mice following (HIE) and should be considered for the treatment of neurological ailments.

Effects of dietary creatine supplementation on systemic microvascular density and reactivity in healthy young adults

BackgroundDietary creatine supplementation (CrS) is a practice commonly adopted by physically active individuals. However, the effects of CrS on systemic microvascular reactivity and density have never been reported. Additionally, CrS is able to influence blood levels of homocysteine, resulting in presumed effects on vascular endothelial function. Thus, we investigated the effects of CrS on the systemic microcirculation and on homocysteine levels in healthy young individuals.MethodsThis open-label study was performed on a group of 40 healthy male, moderately physically active subjects aged 27.7 ± 13.4 years who received one week of CrS at a dose of 20 g/day of commercially available micronized creatine monohydrate. Laser speckle contrast imaging was used in the evaluation of cutaneous microvascular reactivity, and intra-vital video microscopy was used to evaluate skin capillary density and reactivity, before and after CrS.ResultsCrS did not alter plasma levels of homocysteine, although CrS increased creatinine (p = 0.0001) and decreased uric acid (p = 0.0004) plasma levels. Significant changes in total cholesterol (p = 0.0486) and LDL-cholesterol (p = 0.0027) were also observed along with a reduction in plasma levels of T3 (p = 0.0074) and an increase in T4 levels (p = 0.0003). Skin functional capillary density (p = 0.0496) and capillary recruitment during post-occlusive reactive hyperemia (p = 0.0043) increased after CrS. Increases in cutaneous microvascular vasodilation induced by post-occlusive reactive hyperemia (p = 0.0078) were also observed.ConclusionsOral supplementation with creatine in healthy, moderately physically active young adults improves systemic endothelial-dependent microvascular reactivity and increases skin capillary density and recruitment. These effects are not concurrent with changes in plasma homocysteine levels.

LOSS OF HOMOARGININE IS RESPONSIBLE FOR CARDIAC DYSFUNCTION IN CREATINE-DEFICIENT ARGININE:GLYCINE AMIDINOTRANSFERASE (AGAT) KNOCKOUT MICE

RationaleCreatine is an intrinsic component of cardiac energy metabolism. We therefore hypothesised that genetic deletion of the creatine biosynthetic enzyme, arginine:glycine amidinotransferase (AGAT KO), would result in impaired cardiac function...

A review of creatine supplementation in age-related diseases: more than a supplement for athletes.

Creatine is an endogenous compound synthesized from arginine, glycine and methionine. This dietary supplement can be acquired from food sources such as meat and fish, along with athlete supplement powders. Since the majority of creatine is stored in skeletal muscle, dietary creatine supplementation has traditionally been important for athletes and bodybuilders to increase the power, strength, and mass of the skeletal muscle. However, new uses for creatine have emerged suggesting that it may be important in preventing or delaying the onset of neurodegenerative diseases associated with aging. On average, 30% of muscle mass is lost by age 80, while muscular weakness remains a vital cause for loss of independence in the elderly population. In light of these new roles of creatine, the dietary supplement's usage has been studied to determine its efficacy in treating congestive heart failure, gyrate atrophy, insulin insensitivity, cancer, and high cholesterol. In relation to the brain, creatine has been shown to have antioxidant properties, reduce mental fatigue, protect the brain from neurotoxicity, and improve facets/components of neurological disorders like depression and bipolar disorder. The combination of these benefits has made creatine a leading candidate in the fight against age-related diseases, such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, long-term memory impairments associated with the progression of Alzheimer's disease, and stroke. In this review, we explore the normal mechanisms by which creatine is produced and its necessary physiology, while paying special attention to the importance of creatine supplementation in improving diseases and disorders associated with brain aging and outlining the clinical trials involving creatine to treat these diseases.

The Effect of Dietary Creatine and Leucine Supplementation on Protein Synthesis and Functional Properties of Skeletal Muscle During 8 Weeks of Resistance Exercise

The Effect of Dietary Creatine and Leucine Supplementation on Protein Synthesis and Functional Properties of Skeletal Muscle During 8 Weeks of Resistance Exercise

Control of creatine metabolism by HIF is an endogenous mechanism of barrier regulation in colitis

Mucosal surfaces of the lower gastrointestinal tract are subject to frequent, pronounced fluctuations in oxygen tension, particularly during inflammation. Adaptive responses to hypoxia are orchestrated largely by the hypoxia-inducible transcription factors (HIFs). As HIF-1α and HIF-2α are coexpressed in mucosal epithelia that constitute the barrier between the lumen and the underlying immune milieu, we sought to define the discrete contribution of HIF-1 and HIF-2 transactivation pathways to intestinal epithelial cell homeostasis. The present study identifies creatine kinases (CKs), key metabolic enzymes for rapid ATP generation via the phosphocreatine-creatine kinase (PCr/CK) system, as a unique gene family that is coordinately regulated by HIF. Cytosolic CKs are expressed in a HIF-2-dependent manner in vitro and localize to apical intestinal epithelial cell adherens junctions, where they are critical for junction assembly and epithelial integrity. Supplementation with dietary creatine markedly ameliorated both disease severity and inflammatory responses in colitis models. Further, enzymes of the PCr/CK metabolic shuttle demonstrate dysregulated mucosal expression in a subset of ulcerative colitis and Crohn disease patients. These findings establish a role for HIF-regulated CK in epithelial homeostasis and reveal a fundamental link between cellular bioenergetics and mucosal barrier.

Muscle metabolism and fatigue – in memory of Eric Hultman (10 October 1925–9 March 2011)

With the opening day of the 15th International Biochemistry of Exercise Congress in Stockholm, June 2012, it was appropriate that the scientific organizing committee welcomed delegates to a symposium dedicated to the memory of Professor Eric Hultman, who spent the whole of his scientific career at the Karolinska Institute, Stockholm. The symposium, entitled ‘Muscle Metabolism and Fatigue’, highlighted the outstanding research contributions of Professor Hultman over a career spanning more than 4 decades, and also emphasized new research findings stemming from his original research contributions. This edition of the Journal of Physiology includes review articles from two of the speakers from the symposium, Niels Ortenblad and Arend Bonen, which focus on muscle glycogen availability and fatigue (Ortenblad et al. 2013), and the regulation of muscle fatty acid oxidation during exercise and training (Yoshida et al. 2013). Eric Hultman was born on 10 October 1925 in Kristinehamn, Sweden. Following completion of his secondary schooling at Kristinehamn Laroverket, Eric entered the Royal Pharmaceutical Institute, Stockholm in 1944 and was awarded the degree of Bachelor of Pharmacy in 1946. In 1948 he entered the Karolinska Institute, and was made a Bachelor of Medicine in 1955, and a Doctor of Medicine in 1956. On completion of his medical studies, Eric was employed as a junior associate in the Central Laboratory at St Eriks Hospital, and already by 1959 had published three papers on methods to determine glucose in blood, the last describing a procedure based on the colour reaction of σ-toluidine with glucose. By 1962, Eric had published 11 further papers; the last two being co-authored by his close friend and colleague Jonas Bergstrom, a PhD student at that time at St Eriks Hospital, who was notable in introducing the percutaneous muscle biopsy technique. Bringing together his earlier studies on the σ-toluidine method, with muscle biopsy sampling, Eric began a PhD in 1962 focusing on changes in muscle glycogen with exercise and diet. In 1967, Eric obtained a PhD for his thesis entitled ‘Studies on muscle metabolism of glycogen and active phosphate in man with special reference to exercise and diet’. This period marked the start of a prolific clinical scientific career at the Karolinska Institute that was to last a lifetime. This period also heralds a milestone in studies of human exercise metabolism as Eric, together with Jonas Bergstrom, undertook the first ever studies in humans concerned directly with muscle glycogen utilization during exercise, and the importance of dietary composition and timing of food intake to post-exercise glycogen restoration. From these early studies the central role of dietary carbohydrate intake to post-exercise recovery of muscle glycogen was established leading to dietary procedures employed by athletes worldwide. Eric and Lars Nilsson extended this work in the 1970s by undertaking pioneering human studies documenting liver glycogen depletion and restoration during dietary manipulation, exercise and recovery, which provided further important practical insight for athletes. In 1967 Eric, together with others, published an additional major scientific breakthrough by documenting the degradation and resynthesis of ATP in human muscle during exercise, and highlighting the role of muscle phosphocreatine in maintaining ATP turnover. This was followed 15 years later by a further pivotal paper showing muscle creatine and phosphocreatine could be increased by dietary creatine supplementation, which was subsequently shown to increase work output during high-intensity exercise. Today dietary creatine supplementation is regularly undertaken by athletes to increase exercise performance and muscle adaptation during training. In reality, these highlights do not do justice to a career of immense scientific impact. In all Eric published 310 peer-reviewed papers, 45 of these after he had ‘retired’ in 1991. Six of his papers have been cited more than 500 times. Eric, whose career involved positions at several Stockholm hospitals, including Huddinge University Hospital Karolinska Institute, was made Professor Emeritus at the Karolinska Institute in 1991. He was the recipient of an award from the Swedish Medical Society in 1966, the Mclauglin Fellowship from McMaster University in 1990, the honorary award for Biochemistry and Exercise (2000), and doctorates from the Universities of Waterloo (2001) and Guelph (2005). In addition he was made honorary Professor of Physiology at Nottingham University in 2000. Eric, in addition to being a clinical scientist, was also passionate about art and Swedish history. Eric Hultman was one of several giants in muscle biochemistry and physiology to emerge from Scandinavia during the 1960s. Athletes, coaches and exercise scientists throughout the world acknowledge these visionaries who gave birth to a new chapter in exercise science. However, arguably none has had a greater impact on this field, particularly in the area of human exercise metabolism and performance, than Eric Hultman. Revered by former friends and colleagues, he died on the 9 March 2011 in his beloved Stockholm.

Maternal Dietary Creatine Supplementation Does Not Alter the Capacity for Creatine Synthesis in the Newborn Spiny Mouse

We have previously reported that maternal creatine supplementation protects the neonate from hypoxic injury. Here, we investigated whether maternal creatine supplementation altered expression of the creatine synthesis enzymes (arginine:glycine amidinotransferase [AGAT], guanidinoaceteate methyltransferase [GAMT]) and the creatine transporter (solute carrier family 6 [neurotransmitter transporter, creatine] member 8: SLC6A8) in the term offspring. Pregnant spiny mice were fed a 5% creatine monohydrate diet from midgestation (day 20) to term (39 days). Placentas and neonatal kidney, liver, heart, and brain collected at 24 hours of age underwent quantitative polymerase chain reaction and Western blot analysis. Maternal creatine had no effect on the expression of AGAT and GAMT in neonatal kidney and liver, but mRNA expression of AGAT in brain tissues was significantly decreased in both male and female neonates born to mothers who were fed the creatine diet. SLC6A8 expression was not affected by maternal dietary creatine loading in any tissues. Maternal dietary creatine supplementation from midgestation in the spiny mouse did not alter the capacity for creatine synthesis or transport.

Creatine Supplementation may prevent NAFLD by stimulating fatty acid oxidation

Creatine is a naturally occurring metabolite responsible for maintaining ATP levels in tissues with high and rapidly fluctuating energy demands. Recently, we reported the novel and surprising finding that dietary creatine supplementation prevents hepatic steatosis in rats fed a high‐fat diet. The primary goal of this project is to investigate the mechanism by which creatine influences hepatic lipid metabolism. To accomplish this goal we incubated McArdle RH‐7777 hepatoma cells with oleic acid (OA) and creatine. We found that creatine reduces cellular TG levels by 50% (P&lt;0.05). Incorporation of 3H‐oleate into TG was reduced by creatine by 40% (P&lt;0.05). Creatine supplementation resulted in a 2‐fold increase (P&lt;0.05) in 14CO2 production from 14C‐oleate, and a 20% increase (P&lt;0.05) in levels of the ketone body, â‐hydroxybutyrate. To determine whether dietary creatine supplementation can improve liver function in mice susceptible to NAFLD, we fed the liver‐specific CTP:phosphocholine cytidylyltransferase‐α knockout (LCTαKO) and control mice a HFD with or without 1% creatine. After 3 weeks of feeding, creatine supplementation prevented the 3‐fold increase (P&lt;0.05) in hepatic TG in the LCTαKO mice. The data suggests that creatine may be a potential and novel therapy for Non‐Alcoholic Fatty Liver Disease in humans.

Attenuation of hepatic steatosis in Zucker rats by dietary creatine supplementation

We have previously shown that supplementation with creatine prevents hepatic steatosis caused by feeding a high‐fat diet in rats (J. Nutr. 141: 1799–1804, 2011). The present study examines whether creatine supplementation could prevent hepatic fat accumulation in genetically obese Zucker rats fed a moderate‐fat diet. Seven‐week‐old male lean (Fa/?) and obese (fa/fa) rats were sacrificed at the start of the study to obtain baseline data. Baseline liver histology showed some hepatic fat accumulation in fa/fa compared to Fa/? rats. An additional group of fa/fa rats were fed either Purina 5008 (7% fat w/w) non‐supplemented diet or the same diet supplemented with 1% w/w creatine monohydrate for 6 weeks. Creatine supplementation reduced total hepatic fat by 55% and hepatic triglcyeride content by 66%. This was confirmed by Oil‐Red‐O staining. There was also a trend towards decreased hepatic cholesterol in the creatine‐supplemented rats. These data extend the reach of creatine's effect in decreasing liver fat to genetically obese rats fed a moderate‐fat diet. Supported by CIHR, NSERC and Memorial University of Newfoundland.

Creatine pretreatment prevents birth asphyxia–induced injury of the newborn spiny mouse kidney

Acute kidney injury (AKI) is a major complication for infants following an asphyxic insult at birth. We aimed to determine if kidney structure and function were affected in an animal model of birth asphyxia and if maternal dietary creatine supplementation could provide an energy reserve to the fetal kidney, maintaining cellular respiration during asphyxia and preventing AKI. Pregnant spiny mice were maintained on normal chow or chow supplemented with creatine from day 20 gestation. On day 38 (term ~39 d), pups were delivered by cesarean section (c-section) or subjected to intrauterine asphyxia. Twenty-four hours after insult, kidneys were collected for histological or molecular analysis. Urine and plasma were also collected for biochemical analysis. AKI was evident at 24 h after birth asphyxia, with a higher incidence of shrunken glomeruli (P < 0.02), disturbance to tubular arrangement, tubular dilatation, a twofold increase (P < 0.02) in expression of Ngal (early marker of kidney injury), and decreased expression of the podocyte differentiation marker nephrin. Maternal creatine supplementation prevented the glomerular and tubular abnormalities observed in the kidney at 24 h and the increased expression of Ngal. Maternal creatine supplementation may prove useful in ameliorating kidney injury associated with birth asphyxia.

Nutritional targets to enhance exercise performance in chronic obstructive pulmonary disease

This review presents current knowledge regarding the rationale and efficacy of nutrition as an ergogenic aid to enhance the effects of exercise and training in chronic obstructive pulmonary disease (COPD). Altered body composition and skeletal muscle dysfunction in COPD suggest that exercise capacity can be targeted via several metabolic routes. Muscle metabolic alterations in COPD include a reduced oxidative metabolism and enhanced susceptibility for oxidative stress. Muscle wasting may be associated with deficiencies of vitamin D and low branched-chain amino acid levels. Exercise training is of established benefit in COPD but clear-cut clinical trial evidence to support the performance enhancing effect of nutritional intervention is lacking. One randomized controlled trial suggested that augmentation of training with polyunsaturated fatty acids may improve exercise capacity. Conflicting results are reported on dietary creatine supplementation in patients with COPD receiving pulmonary rehabilitation and results from acute intervention studies do not directly imply long-term effects of glutamate or glutamine supplementation as an ergogenic aid in COPD. Recent data indicate that not only muscle but also visceral fat may be an important additional target for combined nutrition and exercise intervention in COPD to improve physical performance and decrease cardiometabolic risk. There is a clear need for adequately powered and controlled intervention and maintenance trials to establish the role of nutritional supplementation in the enhancement of exercise performance and training and the wider management of the systemic features of the disease.