ArticleLiterature Review

Health implications of creatine: Can oral creatine supplementation protect against neurological and atherosclerotic disease?

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Abstract

Major achievements made over the last several years have highlighted the important roles of creatine and the creatine kinase reaction in health and disease. Inborn errors of metabolism have been identified in the three main steps involved in creatine metabolism: arginine:glycine amidinotransferase (AGAT), S-adenosyl-L-methionine:N-guanidinoacetate methyltransferase (GAMT), and the creatine transporter. All these diseases are characterized by a lack of creatine and phosphorylcreatine in the brain, and by (severe) mental retardation. Similarly, knockout mice lacking the brain cytosolic and mitochondrial isoenzymes of creatine kinase displayed a slightly increased creatine concentration, but no phosphorylcreatine in the brain. These mice revealed decreased weight gain and reduced life expectancy, disturbed fat metabolism, behavioral abnormalities and impaired learning capacity.

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... is converted into creatinine per day by a non-enzymatic mechanism (spontaneously dehydrating and cyclization) [4]. Creatinine then passively diffuses out of the cell and is eliminated in urine. ...
... Creatinine then passively diffuses out of the cell and is eliminated in urine. Creatine is an energy reserve molecule for different organs but also seems to play a role in central nervous system (CNS) on neuroprotection, as an antioxidant [4] and on GABA neurotransmission [4,5]. CNS expresses AGAT, GAMT and CRTR [6,7]. ...
... Creatinine then passively diffuses out of the cell and is eliminated in urine. Creatine is an energy reserve molecule for different organs but also seems to play a role in central nervous system (CNS) on neuroprotection, as an antioxidant [4] and on GABA neurotransmission [4,5]. CNS expresses AGAT, GAMT and CRTR [6,7]. ...
... is converted into creatinine per day by a non-enzymatic mechanism (spontaneously dehydrating and cyclization) [4]. Creatinine then passively diffuses out of the cell and is eliminated in urine. ...
... Creatinine then passively diffuses out of the cell and is eliminated in urine. Creatine is an energy reserve molecule for different organs but also seems to play a role in central nervous system (CNS) on neuroprotection, as an antioxidant [4] and on GABA neurotransmission [4,5]. CNS expresses AGAT, GAMT and CRTR [6,7]. ...
... Creatinine then passively diffuses out of the cell and is eliminated in urine. Creatine is an energy reserve molecule for different organs but also seems to play a role in central nervous system (CNS) on neuroprotection, as an antioxidant [4] and on GABA neurotransmission [4,5]. CNS expresses AGAT, GAMT and CRTR [6,7]. ...
... Elevated levels of Hcy have been associated with an increased risk for a variety of CVDs [149]. For example, a 5 µM increment in plasma Hcy has been associated with a 60% and 80% increase in the risk of coronary heart disease in both men and women, respectively [150]. Although increased plasma Hcy levels have been established as a potent independent risk factor for CVD development, the underlining mechanism in still largely unknown. ...
... In summary, throughout this review we have highlighted studies that have not only shown potential benefit of using creatine to improve vasculature function, but have also elucidated the potential of creatine to alleviate the various factors that contribute to the development of CVD ( Figure 2). For example, creatine has shown potential to: (1) help decrease Hcy levels in those with dysfunctional Hcy homeostasis [12,154], (2) increase EC-specific creatine stores [17,27], (3) quench damaging free radicals such as superoxide and peroxynitrite, which have long been associated with CVD [10,18,138], (4) manage the inflammatory response [17,173,181], (5) improve EC membrane stability and decrease EC leakiness [17,150], (6) preserve the integrity and efficiency of mitochondria and reduce mtROS production [32], (7) reduce hemodynamic and inflammatory responses to exercise [16,108,178], and (8) increase microvasculature density, recruitment, and vasotone [12,112]. Therefore, it is clear that further disorder-specific randomized control trials must be conducted, using populations who are at risk of vascular deterioration and complications, to determine the full therapeutic potential of creatine supplementation in the fight for vascular health. ...
... Therefore, it is clear that further disorder-specific randomized control trials must be conducted, using populations who are at risk of vascular deterioration and complications, to determine the full therapeutic potential of creatine supplementation in the fight for vascular health. stability and decrease EC leakiness [17,150], (6) preserve the integrity and efficiency of mitochondria and reduce mtROS production [32], (7) reduce hemodynamic and inflammatory responses to exercise [16,108,178], and (8) increase microvasculature density, recruitment, and vasotone [12,112]. Therefore, it is clear that further disorder-specific randomized control trials must be conducted, using populations who are at risk of vascular deterioration and complications, to determine the full therapeutic potential of creatine supplementation in the fight for vascular health. ...
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Creatine is a naturally occurring compound, functioning in conjunction with creatine kinase to play a quintessential role in both cellular energy provision and intracellular energy shuttling. An extensive body of literature solidifies the plethora of ergogenic benefits gained following dietary creatine supplementation; however, recent findings have further indicated a potential therapeutic role for creatine in several pathologies such as myopathies, neurodegenerative disorders, metabolic disturbances, chronic kidney disease and inflammatory diseases. Furthermore, creatine has been found to exhibit non-energy-related properties, such as serving as a potential antioxidant and anti-inflammatory. Despite the therapeutic success of creatine supplementation in varying clinical populations, there is scarce information regarding the potential application of creatine for combatting the current leading cause of mortality, cardiovascular disease (CVD). Taking into consideration the broad ergogenic and non-energy-related actions of creatine, we hypothesize that creatine supplementation may be a potential therapeutic strategy for improving vascular health in at-risk populations such as older adults or those with CVD. With an extensive literature search, we have found only four clinical studies that have investigated the direct effect of creatine on vascular health and function. In this review, we aim to give a short background on the pleiotropic applications of creatine, and to then summarize the current literature surrounding creatine and vascular health. Furthermore, we discuss the varying mechanisms by which creatine could benefit vascular health and function, such as the impact of creatine supplementation upon inflammation and oxidative stress.
... In any case, the effect of a covariate on the results is proportional to the strength of its relation with the dependent variable. Since it has been reported that PCr+Cre plays a key role in brain energy homeostasis, increasing PCr+Cre levels may boost brain performance, as suggested by previous investigations in neurological (31) and healthy (32) conditions. Indeed, in these studies, PCr+Cre was found to have significant neuroprotective effects (31), and its biochemical levels have been shown to be involved during mental training (32). ...
... Since it has been reported that PCr+Cre plays a key role in brain energy homeostasis, increasing PCr+Cre levels may boost brain performance, as suggested by previous investigations in neurological (31) and healthy (32) conditions. Indeed, in these studies, PCr+Cre was found to have significant neuroprotective effects (31), and its biochemical levels have been shown to be involved during mental training (32). Additionally, oral Cre supplementation has been reported to have significant effects during calculation, in particular reducing mental fatigue and oxygen demand during the task (33) as well as to have positive effects on working memory and intelligence (34), further supporting its role in dynamically modulating brain energy capacity during cognitive performance. ...
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Despite various advances in the study of the neurobiological underpinnings of personality traits, the specific neural correlates associated with character and temperament traits are not yet fully understood. Therefore, this study aims to fill this gap by exploring the biochemical basis of personality, which is explored with the temperament and character inventory (TCI), during brain development in a sample of adolescents. Twenty-six healthy adolescents (aged between 13 and 21 years; 9 males and 18 females) with behavioral and emotional problems underwent a TCI evaluation and a 3T single-voxel proton magnetic resonance spectroscopy (1H MRS) acquisition of the anterior cingulate cortex (ACC). Absolute metabolite levels were estimated using LCModel: significant correlations between metabolite levels and selective TCI scales were identified. Specifically, phosphocreatine plus creatine (PCr+Cre) significantly correlated with self-directedness, positively, and with a self-transcendence (ST), negatively, while glycerophosphocholine plus phosphocholine (GPC+PC) and myo-inositol negatively correlated with ST. To the best of our knowledge, this is the first study reporting associations of brain metabolites with personality traits in adolescents. Therefore, our results represent a step forward for personality neuroscience within the study of biochemical systems and brain structures.
... Thus, rats consumed approximately equimolar quantity of creatine and CLL during the feeding period. [15][16][17][18][19][20][21]. Open circles represent the average daily food intake for rats fed creatine-free AIN-93G diet for the entire 21 days; open triangles represent average daily food intake for rats fed creatine-free diet for 14 days and then switched to AIN-93G diet supplemented with 0.4% (w/w) creatine monohydrate for days 15-21; black circles represent average daily food intake for rats fed creatine-free diet for 14 days and then switched to AIN-93G diet supplemented with 0.656% (w/w) creatyl-L-leucine (CLL) for days 15-21. ...
... CrM remains one of the most widely used dietary supplements that provides significant ergogenic benefit during sport [5]. CrM supplements are also used as a therapy to treat several muscular and neurodegenerative disorders [13][14][15]. CrM is a stable powder that is soluble in water but is somewhat unstable in solution, depending on temperature and pH [1]. Scientific consensus is that CrM as a supplement is safe and the only adverse effect reported was gastrointestinal discomfort [1,16]. ...
Article
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.
... Additionally, the PCr peak area percentage was decreased in the left frontal lobe of the patients during the depressive state, as well as in the right frontal lobe during manic/euthymic states. Long-term abnormalities in PCr levels generally reflect much larger modifications in cellular metabolism and, in particular, an insufficient supply of the ATP needed for normal cellular function (Wyss and Schulze, 2002). A sustained decrease of PCr levels is therefore suggestive of regional hypometabolism. ...
... Creatine is a non-essential dietary element endogenously synthesized by the liver and kidneys and usually present in meat and fish (Juhn and Tarnopolsky, 1998;Terjung et al., 2000). The primary physiological function of creatine is to buffer energy concentrations in tissues with significant and fluctuating energy demands, especially in muscles and the brain (Wyss and Schulze, 2002). This buffering is coupled to the reversible creatine kinase reaction that transfers a high-energy phosphate moiety from ATP to creatine to generate PCr or draws on PCr to produce ATP. ...
Article
Bipolar disorder (BD) is a chronic psychiatric illness characterized by severe and biphasic changes in mood. Several pathophysiological mechanisms have been hypothesized to underpin the neurobiology of BD, including the presence of mitochondrial dysfunction. A confluence of evidence points to an underlying dysfunction of mitochondria, including decreases in mitochondrial respiration, high-energy phosphates and pH; changes in mitochondrial morphology; increases in mitochondrial DNA polymorphisms; and downregulation of nuclear mRNA molecules and proteins involved in mitochondrial respiration. Mitochondria play a pivotal role in neuronal cell survival or death as regulators of both energy metabolism and cell survival and death pathways. Thus, in this review, we discuss the genetic and physiological components of mitochondria and the evidence for mitochondrial abnormalities in BD. The final part of this review discusses mitochondria as a potential target of therapeutic interventions in BD.
... Increasing the cellular pool of creatine/ phosphocreatine (PCr) through dietary supplementation or subcutaneous injection has been shown to ameliorate the progress of CNS deterioration in several animal models of neurodegenerative disorders (Adcock et al., 2002a, Berger et al., 2004b. Creatine has also been shown to decrease the severity of damage in models of acquired brain injury (Wyss and Schulze, 2002). Clinical trials of dietary creatine supplementation in several of these conditions have yielded positive results (Ohtsuki et al., 2002, Schulze, 2003. ...
... One of the primary mechanisms of injury arising from severe hypoxia at birth, particularly for the brain, includes mitochondrial dysfunction, leading to impaired energy metabolism and oxidative stress (Calvert andZhang, 2005, Wyss andSchulze, 2002). As outlined below, it is now clear that perinatal hypoxia arising: (i) during pregnancy and resulting in fetal growth retardation; (ii) at birth due to problems with placental or umbilical cord perfusion; or (iii) immediately after birth due to problems with the initiation of breathing by the neonate -can result in compromise of several organ systems including the brain, kidney, heart, and musculo-skeletal systems. ...
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... After non-enzymatic dehydration and cyclization of creatine, creatinine is produced and it freely diffuses to the bloodstream where it will be eliminated in urine. Creatinine is frequently used as a marker of the renal function (Wyss and Schulze 2002). In order to compensate this loss, creatine synthesis must be regulated physiologically, being that the major regulator is the activity of AGAT, which is the biosynthesisinitiating and rate-limiting step of creatine formation. ...
... Regarding the CNS, creatine supplementation may increase cell hydration and membrane stabilization in mice (Wyss and Schulze 2002), both essential features for neuronal function and signal transduction. Moreover, researchers proposed that exocytotic creatine release would be electrically evoked in an action potential-dependent process, being dependent from Ca 2+ , inhibited by the Na + -channel blocker tetrodotoxin and enhanced by the K + -channel blocker 4-amino-pyridine, consistent with neurotransmitter behavior (Almeida et al. 2006). ...
Article
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Creatine is a nitrogenous organic acid that plays a central role as an energy buffer in high energy demanding systems, including the muscular and the central nervous system. It can be acquired from diet or synthesized endogenously, and its main destination is the system creatine/phosphocreatine that strengthens cellular energetics via a temporal and spatial energy buffer that can restore cellular ATP without a reliance on oxygen. This compound has been proposed to possess secondary roles, such as direct and indirect antioxidant, immunomodulatory agent, and possible neuromodulator. However, these effects may be associated with its bioenergetic role in the mitochondria. Given the fundamental roles that creatine plays in the CNS, several preclinical and clinical studies have tested the potential that creatine has to treat degenerative disorders. However, although in vitro and in vivo animal models are highly encouraging, most clinical trials fail to reproduce positive results suggesting that the prophylactic use for neuroprotection in at-risk populations or patients is the most promising field. Nonetheless, the only clearly positive data of the creatine supplementation in human beings are related to the (rare) creatine deficiency syndromes. It seems critical that future studies must establish the best dosage regime to increase brain creatine in a way that can relate to animal studies, provide new ways for creatine to reach the brain, and seek larger experimental groups with biomarkers for prediction of efficacy.
... Moreover, specific mechanisms of creatine supplementation have been identified in improving athletic performance [3,4]; there are ambiguities about its effects on oxidative stress and its mechanism of action. The antioxidant effects of creatine may be due to various functional mechanisms, such as indirect mechanisms involved in the cell membrane stabilization and improvement of cellular energy capacity [5] and its direct antioxidant properties [6]. Oxidative stress reduces strength and performance [7]; mechanically, reactive oxygen ...
... Young et al. reported the capacity of creatine exposure to promote the thiol redox system, of which the GSH and thioredoxin pathways are important components (indirect antioxidant effect) [54]. In addition, studies have shown other indirect antioxidant mechanisms such as hydration and membrane stabilization [5] and increased or normalized cell energy status [107,108]. In contrast, the findings of Kingsley et al. showed that shortterm creatine consumption had no effect on the antioxidant defense or protection against lipid peroxidation caused by the exhaustive cycling among healthy men [109]. ...
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Oxidative stress is the result of an imbalance between the generation of reactive oxygen species (ROS) and their elimination by antioxidant mechanisms. ROS degrade biogenic substances such as deoxyribonucleic acid, lipids, and proteins, which in turn may lead to oxidative tissue damage. One of the physiological conditions currently associated with enhanced oxidative stress is exercise. Although a period of intense training may cause oxidative damage to muscle fibers, regular exercise helps increase the cells’ ability to reduce the ROS over-accumulation. Regular moderate-intensity exercise has been shown to increase antioxidant defense. Endogenous antioxidants cannot completely prevent oxidative damage under the physiological and pathological conditions (intense exercise and exercise at altitude). These conditions may disturb the endogenous antioxidant balance and increase oxidative stress. In this case, the use of antioxidant supplements such as creatine can have positive effects on the antioxidant system. Creatine is made up of two essential amino acids, arginine and methionine, and one non-essential amino acid, glycine. The exact action mechanism of creatine as an antioxidant is not known. However, it has been shown to increase the activity of antioxidant enzymes and the capability to eliminate ROS and reactive nitrogen species (RNS). It seems that the antioxidant effects of creatine may be due to various mechanisms such as its indirect (i.e., increased or normalized cell energy status) and direct (i.e., maintaining mitochondrial integrity) mechanisms. Creatine supplement consumption may have a synergistic effect with training, but the intensity and duration of training can play an important role in the antioxidant activity. In this study, the researchers attempted to review the literature on the effects of creatine supplementation and physical exercise on oxidative stress.
... In the past decade, the use of Cr for therapeutic purposes has received increasing attention (13). Creatine supplementation has been beneficial in a large number of muscular, neurological, and cardiovascular diseases (12,(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25); however less documented are the effects of Cr on Dox-induced skeletal muscle dysfunction. ...
Article
The purpose of this study was to investigate the effects of in vivo creatine monohydrate (Cr) supplementation on doxorubicin (Dox)-induced muscle dysfunction. Male rats were fed a diet supplemented with 3% Cr or a standard chow for 2 wk. After 2 wk of feeding, animals received Dox or saline as a placebo. Five days post-injection, grip strength was measured, and muscle fatigue was analyzed ex vivo. When compared with controls, a significantly lower grip strength was observed with Dox treatment, but no significant handgrip difference was observed with Cr feeding prior to Dox treatment when compared to controls. In the isolated muscle fatigue experiments, solei (primarily type I muscle) from controls produced significantly less force than baseline at 60 s and solei from Dox treated rats produced significantly less force than baseline at 30 s; however, Cr feeding prior to Dox produced significantly less force than baseline at 60 s. In the primarily type II EDL, a decline in force production from baseline was observed at 50 s in controls and Cr + Dox and at 20 s in standard chow + Dox. Cr attenuated the increase in fatigue that accompanies Dox treatment suggesting that Cr supplementation may have use in managing Dox myotoxicity.
... Creatine provides a physiological buffer in tissues with large and shifting energy demands, such as muscle and brain [72]. In the brain, creatine serves as energy shuttle and regulator of energy homeostasis [73,74]. ...
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Determinants of lifetime health are complex and emphasize the need for robust predictors of disease risk. Allostatic load (AL) has become a clinical framework to estimate the cumulative biological burden associated with chronic stress. To assist knowledge translation in the developmental origins of health and disease field, clinically valid methods for reliable AL assessment in experimental models are urgently needed. Here, we introduce the rat cumulative allostatic load measure (rCALM), as a new preclinical knowledge translation tool to assess the burden of chronic stress. First, we identified an array of stress-associated physiological markers that are particularly sensitive to hypothalamic–pituitary–adrenal axis dysregulation by ancestral prenatal stress. Second, we determined which of these markers are susceptible to an intervention by environmental enrichment (EE) to mitigate AL. The markers most responsive to stress and EE therapy were assembled to become operationalized in the rCALM. Third, the new rCALM was validated for the ability to indicate future disease risks. The results show that the rCALM estimates the burden of chronic stress and serves as a proxy to estimate stress resilience and vulnerability to disease. Using the rCALM we showed that enrichment therapy can offset the adverse health outcomes linked to a high AL. Thus, the rCALM provides a model for the development of new test strategies that facilitate knowledge translation in preclinical animal models.
... For this reason, the CK/PCr-system is assumed to play a critical function in neuronal ATP metabolism [71,86]. In line with this notion, several reports have demonstrated that the CK/PCr-circuit plays a key role in the energy metabolism of the brain and spinal cord [39,45,86,195,206]. Consequently, Cr depletion in brain is associated with disruption of neuronal functions, e.g., loss of hippocampal mossy fiber connection [92], and changes in mitochondrial structure, showing intramitochondrial uMt-CK-rich inclusion bodies [208] that are typical for several clinical pathological conditions, such as encephalomyopathies and mitochondrial myopathies (for review see [201]). ...
... Creatinine is produced spontaneously from creatine and phosphocreatine metabolism in muscle and other tissues. 3 Creatinine levels are frequently used to assess kidney function in normalizing the levels of various excreted compounds, which is efficiently achieved by glomerular ltration in the kidneys prior to excretion in urine. 4,5 Since the creatinine excretion rate is relatively constant, the decrease of its concentration in urine indicates deterioration of kidney function. ...
Article
Determination of residual creatinine and metformin in the urine is essential in estimating the creatinine clearance and monitoring the therapeutic effect of metformin, respectively, in type 2 diabetes mellitus (T2DM) patients. This report describes the validation of the quantitative spectral deconvolution of 1H NMR method (qsd-NMR) and its application in simultaneous determination of the creatinine and metformin concentrations in the human urine. Two different approaches, namely, the single-individual and the mixture of standards, were successfully developed and validated against the referenced concentrations. The method was subsequently tested for the determination of the two analytes in the healthy human urine spiked with metformin. The results showed that the method was selective with high linearity, accuracy, and precision. The method based on the single-individual standard approach was more suitable for creatinine, while that based on the mixture of standards was more suitable for metformin quantitative determinations. The results suggested that the method is potentially useful in the determination of creatinine, and metformin concentration monitoring of the urine in T2DM patient undergoing metformin treatment.
... This enzyme catalyzes the reversible transfer of phosphate between ATP and creatine, generating phosphocreatine (Hemmer and Wallimann, 1994). Creatine is taken up by neurons and oligodendrocytes by creatine transporters and the circuit of converting creatine to phosphocreatine by creatine kinase acts as a bioenergetic sensor that rapidly reloads ATP in the area to maintain stable levels when there are significant energy demands (Wyss and Schulze, 2002;Allen, 2012). There have been reports of decreased brain phosphocreatine levels in BPD patients in the depressed state, as compared with normal controls (Manji et al., 2012). ...
Article
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Psychiatric disorders represent a great medical and social challenge and people suffering from these conditions face many impairments regarding personal and professional life. In addition, a mental disorder will manifest itself in approximately one quarter of the world's population at some period of their life. Dysfunction in energy metabolism is one of the most consistent scientific findings associated with these disorders. With this is mind, this review compiled data on disturbances in energy metabolism found by proteomic analyses of postmortem brains collected from patients affected by the most prevalent psychiatric disorders: schizophrenia (SCZ), bipolar disorder (BPD), and major depressive disorder (MDD). We searched in the PubMed database to gather the studies and compiled all the differentially expressed proteins reported in each work. SCZ studies revealed 92 differentially expressed proteins related to energy metabolism, while 95 proteins were discovered in BPD, and 41 proteins in MDD. With the compiled data, it was possible to determine which proteins related to energy metabolism were found to be altered in all the disorders as well as which ones were altered exclusively in one of them. In conclusion, the information gathered in this work could contribute to a better understanding of the impaired metabolic mechanisms and hopefully bring insights into the underlying neuropathology of psychiatric disorders.
... There are studies showing that creatine contributes to the improvement of energy homeostasis in several tissues (Kolling and Wyse 2010;Kolling et al. 2012Kolling et al. , 2014Kolling et al. , 2015 and prevents behavioral alterations in open field tasks (Vasques et al. 2006). These findings pinpoint to a close correlation between the functional capacity of the creatine kinase/phosphocreatine/creatine system and the proper brain function (Wyss and Schulze 2002). On this, we can highlight that creatine biosynthesis contributes to Hcy fluctuating concentrations in the plasma. ...
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In the present study, we investigate the effect of severe hyperhomocysteinemia on biochemical (creatine kinase activity), behavioral (memory tests), and histological assessments (hippocampal volume). A possible neuroprotective role of creatine on hyperhomocysteinemia effects was also evaluated. Severe hyperhomocysteinemia was induced in neonate rats (starting at 6 days of age) by treatment with homocysteine (0.3-0.6 μmol/g body weight) for 23 days. Creatine (50 mg/kg body weight) was administered concomitantly with homocysteine. Controls received saline in the same volumes. Twelve hours after the last injection, the rats were submitted to behavioral tests [(recognition task (NOR)] and inhibitory avoidance (IA)]. Following behavioral assessment, the animals were perfused and decapitated, the brain removed for subsequent morphological analysis of the hippocampus. Another group of animals was used to test creatine kinase activity in hippocampus. The results showed that rats treated with homocysteine decreased (44%) the exploration of the novel object in NOR. In the IA task, homocysteine-treated animals presented decreased latencies to step down the platform in short- (32%) and long-term (18%) testings (3 h and 7 days, respectively), evidencing aversive memory impairment. Hippocampal volume was not altered by homocysteine administration. Hyperhomocysteinemia decreased (45%) creatine kinase activity, and creatine was able to prevent such effect probably by creatine kinase/phosphocreatine/creatine homeostasis, which serves as energy circuit within of the cell. This finding may be associated, at least in part, with memory improvement, suggesting that creatine might represent an effective adjuvant to protect against the effects of high homocysteine plasma levels.
... Existing drugs such as levodopa, dopamine agonists, monoamine oxidase inhibitors (MAO-B inhibitors), and catechol-O-methyltransferase inhibitors (COMT inhibitors) are not completely effective in PD patients. Therefore, neuroprotective agents such as creatine have increasingly been considered for their potential efficacy [5][6][7][8][9]. ...
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Background The effectiveness of creatine in treating Parkinson’s disease (PD) has not been conclusively determined. Therefore, we performed a meta-analysis to address this issue. Methods The Cochrane Central Register of Controlled Trials, PUBMED, EMBASE, and other databases were searched, and outcomes measured by the Total Unified Parkinson’s Disease Rating Scale (UPDRS) and the Schwab & England Scale were analyzed. Results Five randomized controlled trials (RCTs) were selected, and 1339 participants were included in the analysis. There were no significant differences between the control and treatment groups in the total, mental, activities of daily living (ADL), or motor UPDRS scores, but an improvement in Schwab & England Scale scores was observed. Conclusions Creatine has no observed benefit in PD patients, although more correlated studies are still needed.
... Thus, Cr supplementation may be envisaged as a potentially new approach for fatty liver diseases [150] also for CKD patients. Since hypercholesterolemia and inflammation in atherogenesis are two sides of the same coin [155], and since, as shown above, Cr supplementation favorably affects both of these pathologies, Cr supplementation should be an attractive therapeutic strategy for reducing atherogenesis in high-risk individuals, including patients with CKD [156]. ...
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The CK/PCr-system, with creatine (Cr) as an energy precursor, plays a crucial role in cellular physiology. In the kidney, as in other organs and cells with high and fluctuating energy requirements, energy-charged phospho-creatine (PCr) acts as an immediate high-energy source and energy buffer, and as an intracellular energy transport vehicle. A maximally filled total Cr (Cr plus PCr) pool is a prerequisite for optimal functioning of the body and its organs, and health. Skeletal- and cardiac muscles of dialysis patients with chronic kidney disease (CKD) are depleted of Cr in parallel with the duration of dialysis. The accompanying accumulation of cellular damage seen in CKD patients lead to a deterioration of musculo-skeletal and neurological functioning and poor quality of life (QOL). Therefore, to counteract Cr depletion, it is proposed to supplement CKD patients with Cr. The anticipated benefits include previously documented improvements in the musculo-skeletal system, brain and peripheral nervous system, as well as improvements in the common comorbidities of CKD patients (see below). Thus, with a relatively simple, safe and inexpensive Cr supplementation marked improvements in quality of life (QOL) and life span are likely reached. To avoid Cr and fluid overload by oral Cr administration, we propose intradialytic Cr supplementation, whereby a relatively small amount of Cr is added to the large volume of dialysis solution to a final concentration of 1-10mM. From there, Cr enters the patient’s circulation by back diffusion during dialysis. Because of the high affinity of the Cr transporter (CRT) for Cr affinity for Cr (Vmax of CRT for Cr = 20-40 μM Cr), Cr is actively transported from the blood stream into the target cells and organs, including skeletal and cardiac muscle, brain, proximal tubules of kidney epithelial cells, neurons, and leukocytes and erythrocytes, which all express CRT and depend on the CK/PCr system. By this intradialytic strategy, only as much Cr is taken up by the body as is needed to fill the tissue Cr pools and no excess Cr has to be excreted, as is the case with oral Cr. Because aqueous solutions of Cr are not very stable, Cr must be added immediately before dialysis either as solid Cr powder or from a frozen Cr stock solution to the dialysate, or alternatively, Cr could become an additional component of a novel dry dialysate mixture in a cartridge device.
... Significant concentrations of creatine are also in glial cells [Brand et al., 1993;Urenjak et al., 1993], thus increased Cre in the lesioned cortex may be due to increased Cre in cells that have a role in supporting neuronal function particularly in perilesional cortex, rather than neuronal function itself. Regardless of the cellular location of the measured Cre, higher creatine levels have been suggested to be neuroprotective and associated with enhanced cognitive functioning in some populations [Wyss and Schulze, 2002]. Given these general associations with better neurological function and the relative specificity we observed of correlations between Cre in the lesioned hemisphere (and not the contralesional tissue) and motor function, it is possible that creatine compounds reflect different elements of regional brain metabolism and health in our patient population. ...
Article
Perinatal stroke causes hemiparetic cerebral palsy and lifelong motor disability. Bilateral motor cortices are key hubs within the motor network and their neurophysiology determines clinical function. Establishing biomarkers of motor cortex function is imperative for developing and evaluating restorative interventional strategies. Proton magnetic resonance spectroscopy (MRS) quantifies metabolite concentrations indicative of underlying neuronal health and metabolism in vivo. We used functional magnetic resonance imaging (MRI)-guided MRS to investigate motor cortex metabolism in children with perinatal stroke. Children aged 6-18 years with MRI-confirmed perinatal stroke and hemiparetic cerebral palsy were recruited from a population-based cohort. Metabolite concentrations were assessed using a PRESS sequence (3T, TE=30 ms, voxel=4 cc). Voxel location was guided by functional MRI activations during finger tapping tasks. Spectra were analysed using LCModel. Metabolites were quantified, cerebral spinal fluid corrected and compared between groups (ANCOVA) controlling for age. Associations with clinical motor performance (Assisting Hand, Melbourne, Box-and-Blocks) were assessed. Fifty-two participants were studied (19 arterial, 14 venous, 19 control). Stroke participants demonstrated differences between lesioned and nonlesioned motor cortex N-acetyl-aspartate [NAA mean concentration=10.8±1.9 vs. 12.0±1.2, P<0.01], creatine [Cre 8.0±0.9 vs. 7.4±0.9, P<0.05] and myo-Inositol [Ins 6.5±0.84 vs. 5.8±1.1, P<0.01]. Lesioned motor cortex NAA and creatine were strongly correlated with motor performance in children with arterial but not venous strokes. Interrogation of motor cortex by fMRI-guided MRS is feasible in children with perinatal stroke. Metabolite differences between hemispheres, stroke types and correlations with motor performance support functional relevance. MRS may be valuable in understanding the neurophysiology of developmental neuroplasticity in cerebral palsy.
... One of the most important physiological functions of creatine relates to the energy levels in muscle and brain tissue. 22 Creatine, synthesized adenosine triphosphate (ATP), is a major source of energy, and has been primarily known as a supplement for muscle power and to improve sports performance. 23 Creatine intake produces phosphocreatine (PC), which is attached to a phosphate molecule, and partially forms the ATP-PC energy system and free creatine, and increases the body's stores of creatine in the muscle to provide more immediate energy. ...
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[Purpose] The effects of creatine and exercise on chronic stress-induced depression are unclear. In the present study, we identified the effects of 4-week supplementation of creatine monohydrate and/or exercise on antidepressant behavior and raphe 5-HT expression in a chronic mild stress-induced depressed mouse model. [Methods] Seven-week-old male C57BL/6 mice (n=48) were divided randomly into 5 groups: (1) non-stress control (CON, n=10), (2) stress control (ST-CON, n=10), (3) stress and creatine intake (ST-Cr, n=10), (4) stress and exercise (ST-Ex, n=9), and (5) combined stress, exercise, and creatine intake (ST-Cr+Ex, n=9). After five weeks’ treatment, we investigated using both anti-behavior tests (the Tail Suspension Test (TST) and the Forced Swimming Test (FST)), and 5-HT expression in the raphe nuclei (the dorsal raphe (DR) and median raphe (MnR)). [Results] Stress for 4 weeks significantly increased depressive behaviors in the mice. Treatment with creatine supplementation combined with exercise significantly decreased depressive behaviors as compared with the CON-ST group in both the TST and FST tests. With stress, 5-HT expression in the raphe nuclei decreased significantly. With combined creatine and exercise, 5-HT positive cells increased significantly and had a synergic effect on both DR and MnR. [Conclusion] The present study found that even a single treatment of creatine or exercise has partial effects as an antidepressant in mice with chronic mild stress-induced depression. Furthermore, combined creatine and exercise has synergic effects and is a more effective prescription than a single treatment.
... One study reported that fatigue ratings in an American Cup sailing team were significantly and inversely associated with CPK levels (Hadala et al., 2010). CPK catalyses the conversion of creatine to phosphocreatine, which functions as a stored energy reservoir that may quickly regenerate ATP, especially in cells with high energy requirements, including skeletal muscles and brain cells (Andres et al., 2008;Wyss and Schulze, 2002). As such, CPK is important for avoiding muscle fatigue at the onset of high-intensity stimulation, although during more prolonged stimulation, CPK may contribute to fatigue by increasing myoplasmic concentration of inorganic phosphate (Dahlstedt et al., 2001). ...
Preprint
Chronic fatigue and fibromyalgia symptoms frequently occur in major depressive disorder (MDD). The pathophysiology of these symptoms may in part, be ascribed to activated immune pathways, although it is unclear whether muscular factors play a role in their onset. The aim of the present study is to examine the role of muscle proteins in major depression in association with symptoms of chronic fatigue and fibromyalgia. We measured serum levels of agrin, talin-2, titin, and creatine phosphokinase (CPK) as well as the FibroFatigue (FF), the Hamilton Depression Rating Scale (HAM-D) and the Beck Depression Inventory (BDI-II) in 60 MDD patients and 30 healthy controls. The results show a significant increase in agrin and talin-2 in MDD patients as compared with controls. There were highly significant correlations between agrin and HAM-D, BDI-II and FF scores. Agrin, but not talin or titin, was significantly and positively associated with all 12 items of the FF scale. We found that a large part of the variance in HAM-D (47.4%), BDI-II (43.4%) and FF (43.5%) scores was explained by the regression on agrin, smoking, female sex (positively associated) and education (inversely associated). CPK was significantly and inversely associated with the total FF score and with muscle and gastro-intestinal symptoms, fatigue, a flu-like malaise, headache and memory, autonomic and sleep disturbances. These results suggest that aberrations in neuromuscular (NMJs) and myotendinous junctions may play a role in MDD and that the aberrations in NMJs coupled with lowered CPK may play a role in symptoms of chronic fatigue and fibromyalgia in MDD. Moreover, the increase of agrin in MDD probably functions as part of the compensatory immune-regulatory system (CIRS).
... One study reported that fatigue ratings in an American Cup sailing team were significantly and inversely associated with CPK levels (Hadala et al., 2010). CPK catalyses the conversion of creatine to phosphocreatine, which functions as a stored energy reservoir that may quickly regenerate ATP, especially in cells with high energy requirements, including skeletal muscles and brain cells (Andres et al., 2008;Wyss and Schulze, 2002). As such, CPK is important for avoiding muscle fatigue at the onset of high-intensity stimulation, although during more prolonged stimulation, CPK may contribute to fatigue by increasing myoplasmic concentration of inorganic phosphate (Dahlstedt et al., 2001). ...
Preprint
Full-text available
Chronic fatigue and fibromyalgia symptoms frequently occur in major depressive disorder (MDD). The pathophysiology of these symptoms may in part, be ascribed to activated immune pathways, although it is unclear whether muscular factors play a role in their onset. The aim of the present study is to examine the role of muscle proteins in major depression in association with symptoms of chronic fatigue and fibromyalgia. We measured serum levels of agrin, talin-2, titin, and creatine phosphokinase (CPK) as well as the FibroFatigue (FF), the Hamilton Depression Rating Scale (HAM-D) and the Beck Depression Inventory (BDI-II) in 60 MDD patients and 30 healthy controls. The results show a significant increase in agrin and talin-2 in MDD patients as compared with controls. There were highly significant correlations between agrin and HAM-D, BDI-II and FF scores. Agrin, but not talin or titin, was significantly and positively associated with all 12 items of the FF scale. We found that a large part of the variance in HAM-D (47.4%), BDI-II (43.4%) and FF (43.5%) scores was explained by the regression on agrin, smoking, female sex (positively associated) and education (inversely associated). CPK was significantly and inversely associated with the total FF score and with muscle and gastro-intestinal symptoms, fatigue, a flu-like malaise, headache and memory, autonomic and sleep disturbances. These results suggest that aberrations in neuromuscular (NMJs) and myotendinous junctions may play a role in MDD and that the aberrations in NMJs coupled with lowered CPK may play a role in symptoms of chronic fatigue and fibromyalgia in MDD. Moreover, the increase of agrin in MDD probably functions as part of the compensatory immune-regulatory system (CIRS).
... The average Cr turnover rate, assessed in male muscles, was 2.1 ± 0.7 %/day. The linear uptake rates of Cr were variable between muscles, although not 1 3 (Wyss and Schulze 2002;Gualano et al. 2012;Kley et al. 2013). ...
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Creatine (Cr) supplementation to enhance muscle performance shows variable responses among individuals and different muscles. Direct monitoring of the supplied Cr in muscles would address these differences. In this feasibility study, we introduce in vivo 3D (13)C MR spectroscopic imaging (MRSI) of the leg with oral ingestion of (13)C4-creatine to observe simultaneously Cr and phosphocreatine (PCr) for assessing Cr uptake, turnover, and the ratio PCr over total Cr (TCr) in individual muscles. (13)C MRSI was performed of five muscles in the posterior thigh in seven subjects (two males and two females of ~20 years, one 82-year-old male, and two neuromuscular patients) with a (1)H/(13)C coil in a 3T MR system before, during and after intake of 15 % (13)C4-enriched Cr. Subjects ingested 20 g Cr/day for 4 days in four 5 g doses at equal time intervals. The PCr/TCr did not vary significantly during supplementation and was similar for all subjects and investigated muscles (average 0.71 ± 0.07), except for the adductor magnus (0.64 ± 0.03). The average Cr turnover rate, assessed in male muscles, was 2.1 ± 0.7 %/day. The linear uptake rates of Cr were variable between muscles, although not significantly different. This assessment was possible in all investigated muscles of young male volunteers, but less so in muscles of the other subjects due to lower signal-to-noise ratio. Improvements for future studies are discussed. In vivo (13)C MRSI after (13)C-Cr ingestion is demonstrated for longitudinal studies of Cr uptake, turnover, and PCr/TCr ratios of individual muscles in one exam.
... With respect to this, the observed Cr/PCr concentrations in the brain of treated GAMT-D patients, measured by proton magnetic resonance spectroscopy, reaching ~80% of controls, might reflect Cr enrichment in interstitial compartments of the brain rather than Cr enrichment in the Cr requiring brain cells. 26 Cr replenishment in brain incomplete, WM ~ GM Effect of the substrate deprivation approach by an arginine restrictive diet combined with supplementation of ornithine and sodium benzoate has been proven effective in both patients as well as in a third one (Ensenauer et al., submitted for publication). This treatment achieves an approximately 50% reduction of GAA in body fluids. ...
... Therefore, it was assumed that creatine supplementation could improve clinical outcome in cases of mitochondrial dysfunction. Creatine is able to buffer lactate accumulation by reducing the need for glycolysis [126], reducing ROS [127] and restoring calcium homeostasis. Table 2 presents an overview of the level of evidence for creatine supplementation for chronic, atraumatic mitochondrial dysfunction. ...
Article
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Creatine monohydrate (CrM) is one of the most widely used nutritional supplements among active individuals and athletes to improve high-intensity exercise performance and training adaptations. However, research suggests that CrM supplementation may also serve as a therapeutic tool in the management of some chronic and traumatic diseases. Creatine supplementation has been reported to improve high-energy phosphate availability as well as have antioxidative, neuroprotective, anti-lactatic, and calcium-homoeostatic effects. These characteristics may have a direct impact on mitochondrion’s survival and health particularly during stressful conditions such as ischemia and injury. This narrative review discusses current scientific evidence for use or supplemental CrM as a therapeutic agent during conditions associated with mitochondrial dysfunction. Based on this analysis, it appears that CrM supplementation may have a role in improving cellular bioenergetics in several mitochondrial dysfunction-related diseases, ischemic conditions, and injury pathology and thereby could provide therapeutic benefit in the management of these conditions. However, larger clinical trials are needed to explore these potential therapeutic applications before definitive conclusions can be drawn.
... -ATPase a1 subunit in the amygdala. Wyss and Schulze (2002) suggested that the antioxidant effect of creatine can be attributed to the improved energy capacity of the cells that receive this substance, as well as to indirect antioxidant mechanisms such as an increase in membrane stability. While several studies suggest that creatine may provide a protection against oxidative damage (Cunha et al. 2014;Deminice and Jordao 2015;de Andrade et al. 2015). ...
Article
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Severe hyperhomocysteinemia is caused by increased plasma levels of homocysteine (Hcy), a methionine derivative, and is associated with cerebral disorders. Creatine supplementation has emerged as an adjuvant to protect against neurodegenerative diseases, due to its potential antioxidant role. Here, we examined the effects of severe hyperhomocysteinemia on brain metabolism, and evaluated a possible neuroprotective role of creatine in hyperhomocysteinemia, by concomitant treatment with Hcy and creatine (50 mg/Kg body weight). Hyperhomocysteinemia was induced in young rats (6-day-old) by treatment with homocysteine (0.3-0.6 µmol/g body weight) for 23 days, and then the following parameters of rat amygdala were evaluated: (1) the activity of the respiratory chain complexes succinate dehydrogenase, complex II and cytochrome c oxidase; (2) mitochondrial mass and membrane potential; (3) the levels of necrosis and apoptosis; and (4) the activity and immunocontent of Na(+),K(+)-ATPase. Hcy treatment decreased the activities of succinate dehydrogenase and cytochrome c oxidase, but did not alter complex II activity. Hcy treatment also increased the number of cells with high mitochondrial mass, high mitochondrial membrane potential, and in late apoptosis. Importantly, creatine administration prevented some of the key effects of Hcy administration on the amygdala. We also observed a decrease in the activity and immunocontent of the α1 subunit of the Na(+),K(+)-ATPase in amygdala after Hcy- treatment. Our findings support the notion that Hcy modulates mitochondrial function and bioenergetics in the brain, as well as Na(+),K(+)-ATPase activity, and suggest that creatine might represent an effective adjuvant to protect against the effects of high Hcy plasma levels.
... g/kg/day) vs. placebo, the CRMH group showed a significant increase of 8.1-9.3% in brain total creatine levels and a marginal increase (3.4%) in PCR levels vs. controls [33]. These studies confirm the potential of using CRMH treatment to improve brain energetics in people with disorders linked to brain hypometabolism, such as MDD [33,34,62]. ...
Article
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Background: Rates of major depressive disorder (MDD) increase with living at altitude. In our model, rats housed at moderate altitude (in hypobaric hypoxia) exhibit increased depression-like behavior, altered brain serotonin and a lack of antidepressant response to most selective serotonin reuptake inhibitors (SSRIs). A forebrain deficit in the bioenergetic marker creatine is noted in people living at altitude or with MDD. Methods: Rats housed at 4500 ft were given dietary creatine monohydrate (CRMH, 4% w/w, 5 weeks) vs. un-supplemented diet, and impact on depression-like behavior, brain bioenergetics, serotonin and SSRI efficacy assessed. Results: CRMH significantly improved brain creatine in a sex-based manner. At altitude, CRMH increased serotonin levels in the female prefrontal cortex and striatum but reduced male striatal and hippocampal serotonin. Dietary CRMH was antidepressant in the forced swim test and anti-anhedonic in the sucrose preference test in only females at altitude, with motor behavior unchanged. CRMH improved fluoxetine efficacy (20 mg/kg) in only males at altitude: CRMH + SSRI significantly improved male striatal creatine and serotonin vs. CRMH alone. Conclusions: Dietary CRMH exhibits sex-based efficacy in resolving altitude-related deficits in brain biomarkers, depression-like behavior and SSRI efficacy, and may be effective clinically for SSRI-resistant depression at altitude. This is the first study to link CRMH treatment to improving brain serotonin.
... PCr is a high-energy product behaving both as short-term energy reserve and as an energy shuttle within the cell through the creatine kinase/PCr/creatine system [36]. Creatine is secreted by the mammary gland during lactation and has been shown to be essential for normal brain development and brain function [37]. Differences in milk PCr concentrations among mammalians have been correlated to the mammary gland metabolic activity and to specific neonate requirements during the suckling period [38]. ...
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A fast and reliable method for the identification of milk from different mammalians was developed by using ³¹P NMR metabolite profile of milk serum coupled to multivariate analysis (PCA and classification models UNEQ, SIMCA and K-NN). Ten milk samples from six different mammalians, relevant to human nutrition (human, cow, donkey, mare, goat, sheep), were analyzed and eight monophosphorylated components were identified and quantified: phosphocreatine (PCr), glycerophosphorylcholine (GPC), glycerophosphorylethanolamine (GPE), N-acetylglucosamine-1-phosphate (NAcGlu-1P), lactose-1-phosphate (Lac-1P), galactose-1-phosphate (Gal-1P), phosphorylcholine (PC), glucose-6-phosphate (Glu-6P). PCA showed interesting clustering based on the animal genus. K-NN can be successfully used to discriminate between donkey and cow samples while UNEQ class-modeling resulted more suitable for compliance verification. Results confirm the natural variability of milk samples among different species. These data highlight the great potentials of NMR/multivariate analysis combined method in the rapid analysis of phosphorylated milk serum metabolites for milk origin assessment and milk adulteration detection.
... Several authors have provided a rationale for why creatine supplementation would be a viable treatment option for individuals diagnosed with ALS [128,129]. Plausible explanations for why creatine might enhance various aspects of quality of life in patients with ALS include protection against neuron loss in the substantia nigra and motor cortex [130], as well as decreased oxidative stress [131] and mitochondrial dysfunction [132] commonly observed with this condition. Despite this initial enthusiasm and encouraging animal work [133], clinical trials in humans have reported disappointing results. ...
Article
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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.
... Literature data have suggested a potential role for creatine supplementation in mitochondrial encephalomyopathies, cerebral ischemia and stroke, and traumatic injuries of CNS, AD, PD, ALS, and HD [101,102]. Most importantly, creatine supplementation may have no benefit in patients with creatine transporter defects [103]. Creatine kinase is highly sensitive to oxidative stress due to the presence of cysteine residues, which can be easily modified by reactive oxygen species. ...
Article
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Mitochondrial dysfunction results in a series of defective cellular events, including decreased adenosine triphosphate (ATP) production, enhanced reactive oxygen species (ROS) output, and altered proteastasis and cellular quality control. An enhanced output of ROS may damage mitochondrial components, such as mitochondrial DNA and elements of the electron transport chain, resulting in the loss of proper electrochemical gradient across the mitochondrial inner membrane and an ensuing shutdown of mitochondrial energy production. Neurons have an increased demand for ATP and oxygen, and thus are more prone to damage induced by mitochondrial dysfunction. Mitochondrial dysfunction, damaged electron transport chains, altered membrane permeability and Ca2+ homeostasis, and impaired mitochondrial defense systems induced by oxidative stress, are pathological changes involved in neurodegenerative disorders. A growing body of evidence suggests that the use of antioxidants could stabilize mitochondria and thus may be suitable for preventing neuronal loss. Numerous natural products exhibit the potential to counter oxidative stress and mitochondrial dysfunction; however, science is still looking for a breakthrough in the treatment of neurodegenerative disorders. β-caryophyllene is a bicyclic sesquiterpene, and an active principle of essential oils derived from a large number of spices and food plants. As a selective cannabinoid receptor 2 (CB2) agonist, several studies have reported it as possessing numerous pharmacological activities such as antibacterial (e.g., Helicobacter pylori), antioxidant, anti-inflammatory, analgesic (e.g., neuropathic pain), anti-neurodegenerative and anticancer properties. The present review mainly focuses on the potential of β-caryophyllene in reducing oxidative stress and mitochondrial dysfunction, and its possible links with neuroprotection.
... This molecule is frequently used as a marker of the renal function. 13 Creatine synthesis is regulated physiologically in kidney by downregulation of AGAT and in developing brain cells by retroregulation of AGAT by creatine levels. 14 Creatine transporter (SLC6A8) is regulated by creatine levels in the bloodstream and is inhibited by high levels of GAA. 1 Furthermore, the ingestion of creatine supplement has been shown to decrease the rate of endogenous synthesis. ...
Article
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Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessively inherited disorder of the metabolism of creatine that leads to depleted levels of creatine and excessive concentrations of guanidinoacetate (GAA). Patients affected develop neurological symptoms during childhood, such as muscular hypotonia, involuntary extrapyramidal movements, convulsions, slurred speech, and even autism. Although the pathophysiology of GAMT deficiency is unclear, neurological dysfunction is commonly found in this disease, and it has been mainly attributed to a reduction in creatine or/and an increase in GAA levels. Reports from literature suggest that GAA may interfere with neuronal γ-aminobutyric acid (GABA) receptors type A and cause epilepsy in human. Preclinical studies show that GAA increases free radical formation and decreases brain antioxidant defenses, inducing alteration in oxidative status. Guanidinoacetate also impairs energy metabolism in brain. The discussion of this review focuses on various and latest studies addressing GAMT deficiency and creatine metabolism, as well as addresses the question of neurotoxicity GAA.
... One study reported that fatigue ratings in an American Cup sailing team were significantly and inversely associated with CPK levels (Hadala et al. 2010). CPK catalyzes the conversion of creatine to phosphocreatine, which functions as a stored energy reservoir that may quickly regenerate ATP, especially in cells with high energy requirements, including skeletal muscles and brain cells (Andres et al. 2008;Wyss and Schulze 2002). As such, CPK is important for avoiding muscle fatigue at the onset of high-intensity stimulation, although during more prolonged stimulation, CPK may contribute to fatigue by increasing myoplasmic concentration of inorganic phosphate (Dahlstedt and Westerblad 2001). ...
Article
Full-text available
Chronic fatigue and fibromyalgia symptoms frequently occur in major depressive disorder (MDD). The pathophysiology of these symptoms may in part, be ascribed to activated immune pathways, although it is unclear whether muscular factors play a role in their onset. The aim of the present study is to examine the role of muscle proteins in major depression in association with symptoms of chronic fatigue and fibromyalgia. We measured serum levels of agrin, talin-2, titin, and creatine phosphokinase (CPK) as well as the FibroFatigue (FF), the Hamilton Depression Rating Scale (HAM-D) and the Beck Depression Inventory (BDI-II) scores in 60 MDD patients and 30 healthy controls. The results show a significant increase in agrin and talin-2 in MDD patients as compared with controls. There were highly significant correlations between agrin and HAM-D, BDI-II and FF scores. Agrin, but not talin or titin, was significantly and positively associated with all 12 items of the FF scale. We found that a large part of the variance in HAM-D (47.4%), BDI-II (43.4%) and FF (43.5%) scores was explained by the regression on agrin, smoking, female sex (positively associated) and education (inversely associated). CPK was significantly and inversely associated with the total FF score and with muscle and gastro-intestinal symptoms, fatigue, a flu-like malaise, headache and memory, autonomic and sleep disturbances. These results suggest that aberrations in neuromuscular (NMJs) and myotendinous junctions play a role in MDD and that the aberrations in NMJs coupled with lowered CPK may play a role in chronic fatigue and fibromyalgia symptoms in MDD. Moreover, the increase of agrin in MDD probably functions as part of the compensatory immune-regulatory system (CIRS).
... The guanidine-like compound creatine has been used for several decades as an ergogenic aid to improve exercise performance in humans (Cooper et al., 2012). Of note, it has been proposed as a useful nutraceutical agent to ameliorate excitotoxicity-mediated diseases (Andres et al., 2008;Cunha et al., 2015;Persky and Brazeau, 2001;Wyss and Schulze, 2002). For example, inborn or acquired diseases characterized by progressive loss of nervoussystem cells such as Alzheimer's, Huntington's, Charcot-Marie-Tooth's and Parkinson's disease and amyotrophic lateral sclerosis could be potentially treated by creatine administration (Gualano et al., 2012;Rae and Br€ oer, 2015). ...
Article
Creatine has been reported to exert beneficial effects in several neurodegenerative diseases in which glutamatergic excitotoxicity and oxidative stress play an etiological role. The purpose of this study was to investigate the protective effects of creatine, as compared to the N-Methyl-D-Aspartate (NMDA) receptor antagonist dizocilpine (MK-801), against glutamate or hydrogen peroxide (H2O2)-induced injury in human neuroblastoma SH-SY5Y cells. Exposure of cells to glutamate (60-80 mM) or H2O2 (200-300 μM) for 24 h decreased cellular viability and increased dichlorofluorescein (DCF) fluorescence (indicative of increased reactive oxygen species, ROS) and nitric oxide (NO) production (assessed by mono-nitrogen oxides, NOx, levels). Creatine (1–10 mM) or MK-801 (0.1-10 μM) reduced glutamate- and H2O2-induced toxicity. The protective effect of creatine against glutamate-induced toxicity involves its antioxidant effect, since creatine, similar to MK-801, prevented the increase on DCF fluorescence induced by glutamate or H2O2. Furthermore, creatine or MK-801 blocked glutamate- and H2O2-induced increases in NOx levels. In another set of experiments, the repeated, but not acute, administration of creatine (300 mg/kg, po) in mice prevented the decreases on cellular viability and mitochondrial membrane potential (assessed by tetramethylrhodamine ethyl ester, TMRE, probe) of hippocampal slices incubated with glutamate (10 mM). Creatine concentration-dependent decreased the amount of nitrite formed in the reaction of oxygen with NO produced from sodium nitroprusside solution, suggesting that its protective effect against glutamate or H2O2-induced toxicity might be due to its scavenger activity. Overall, the results suggest that creatine may be useful as adjuvant therapy for neurodegenerative disease treatments.
... These adverse outcomes included renal dysfunction [107][108][109][110][111][112][113][114][115], increased lower leg compartment syndrome [104,116], rhabdomyolysis [116][117][118], ischaemic stroke [119], haemorrhagic stroke [120], liver injury [121,122], atrial fibrillation [123], acute cholestatic liver injury [124] and toxic hepatitis [122]. These events are not replicated in placebo controlled clinical trials [125][126][127][128][129]. Compartment syndrome has been reported in the literature often associated with exertional rhabdomyolysis in males undertaking intensive exercise, and supplementing with creatine, [104,116] but there is no evidence supporting a causal link between these symptoms and creatine supplements [87,130]. ...
Article
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Creatine Monohydrate (CrM) is a dietary supplement routinely used as an ergogenic aid for sport and training, and as a potential therapeutic aid to augment different disease processes. Despite its increased use in recent years, studies reporting potential adverse outcomes of CrM have been mostly derived from male or mixed sex populations. A systematic search was conducted, which included female participants on CrM, where adverse outcomes were reported, with meta-analysis performed where appropriate. Six hundred and fifty-six studies were identified where creatine supplementation was the primary intervention; fifty-eight were female only studies (9%). Twenty-nine studies monitored for adverse outcomes, with 951 participants. There were no deaths or serious adverse outcomes reported. There were no significant differences in total adverse events, (risk ratio (RR) 1.24 (95% CI 0.51, 2.98)), gastrointestinal events, (RR 1.09 (95% CI 0.53, 2.24)), or weight gain, (mean difference (MD) 1.24 kg pre-intervention, (95% CI −0.34, 2.82)) to 1.37 kg post-intervention (95% CI −0.50, 3.23)), in CrM supplemented females, when stratified by dosing regimen and subject to meta-analysis. No statistically significant difference was reported in measures of renal or hepatic function. In conclusion, mortality and serious adverse events are not associated with CrM supplementation in females. Nor does the use of creatine supplementation increase the risk of total adverse outcomes, weight gain or renal and hepatic complications in females. However, all future studies of creatine supplementation in females should consider surveillance and comprehensive reporting of adverse outcomes to better inform participants and health professionals involved in future trials.
... Arg and GAA have only 'apparent' repressor activity. They exert no effect on AGAT expression by themselves but are readily converted to Cr, which then acts as the true repressor (Wyss and Schulze, 2002). On the opposite, a low nutritional supply in Cr is associated with a sustained increase in AGAT activity contributing to Cr homeostasis (Wyss and Kaddurah-Daouk, 2000). ...
... 123 Additionally, the PCr peak area percentage was observed to be decreased in the left frontal lobe of patients during the depressive state, as well as in the right frontal lobe during manic/euthymic states. 124,125 Moreover, previous studies have shown that patients with BD present lower levels of N-acetyl-aspartate (NAA), which is thought to represent a surrogate marker for impaired mitochondria, along with a negative correlation between NAA/creatine + PCr or NAA levels and illness duration. [126][127][128][129] Taken together, these studies provide indirect evidence that mitochondrial dysfunction may play a role in illness progression. ...
Article
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Bipolar disorder (BD) is a chronic mental illness characterized by changes in mood that alternate between mania and hypomania or between depression and mixed states, often associated with functional impairment. Although effective pharmacological and non-pharmacological treatments are available, several patients with BD remain symptomatic. The advance in the understanding of the neurobiology underlying BD could help in the identification of new therapeutic targets as well as biomarkers for early detection, prognosis, and response to treatment in BD. In this review, we discuss genetic, epigenetic, molecular, physiological and neuroimaging findings associated with the neurobiology of BD. Despite the advances in the pathophysiological knowledge of BD, the diagnosis and management of the disease are still essentially clinical. Given the complexity of the brain and the close relationship between environmental exposure and brain function, initiatives that incorporate genetic, epigenetic, molecular, physiological, clinical, environmental data, and brain imaging are necessary to produce information that can be translated into prevention and better outcomes for patients with BD.
... By delaying the depletion of ATP during oxygen deprivation and reducing the availability of ROS (Balestrino et al. 1999), pretreatment with creatine can reduce the cardiac and neurological damages induced by ischemia or anoxia and that such treatment can also be useful even after the onset of stroke or myocardial infarction (Balestrino et al. 2002;Lensman et al. 2006;Osbakken et al. 1992;Perasso et al. 2013;Prass et al. 2007;Scheer et al. 2016;Shen and Goldberg 2012;Whittingham and Lipton 1981;Wilken et al. 1998;Zapara et al. 2004). Of note, creatine has been safely and beneficially administered to patients affected by age-related neurological diseases, including Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, long-term memory deficits, Alzheimer's disease, and stroke (Adhihetty and Beal 2008; Smith et al. 2014), as well as patients with pathophysiological conditions, such as gyrate atrophy, post-stroke depression, congestive heart failure, chronic musculoskeletal pain disorders, atherosclerotic diseases, and cisplatin-induced renal damage (Genc et al. 2014;Hummer et al. 2019;Persky and Brazeau 2001;Wyss and Schulze 2002). Through increasing the availability of arginine for the generation of nitric oxide (a killer of pathogenic bacteria, fungi, parasites, and viruses), dietary supplementation with creatine plays an important role in protecting humans from infectious diseases (Ren et al. 2018). ...
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Taurine (a sulfur-containing β-amino acid), creatine (a metabolite of arginine, glycine and methionine), carnosine (a dipeptide; β-alanyl-l-histidine), and 4-hydroxyproline (an imino acid; also often referred to as an amino acid) were discovered in cattle, and the discovery of anserine (a methylated product of carnosine; β-alanyl-1-methyl-l-histidine) also originated with cattle. These five nutrients are highly abundant in beef, and have important physiological roles in anti-oxidative and anti-inflammatory reactions, as well as neurological, muscular, retinal, immunological and cardiovascular function. Of particular note, taurine, carnosine, anserine, and creatine are absent from plants, and hydroxyproline is negligible in many plant-source foods. Consumption of 30 g dry beef can fully meet daily physiological needs of the healthy 70-kg adult human for taurine and carnosine, and can also provide large amounts of creatine, anserine and 4-hydroxyproline to improve human nutrition and health, including metabolic, retinal, immunological, muscular, cartilage, neurological, and cardiovascular health. The present review provides the public with the much-needed knowledge of nutritionally and physiologically significant amino acids, dipeptides and creatine in animal-source foods (including beef). Dietary taurine, creatine, carnosine, anserine and 4-hydroxyproline are beneficial for preventing and treating obesity, cardiovascular dysfunction, and ageing-related disorders, as well as inhibiting tumorigenesis, improving skin and bone health, ameliorating neurological abnormalities, and promoting well being in infants, children and adults. Furthermore, these nutrients may promote the immunological defense of humans against infections by bacteria, fungi, parasites, and viruses (including coronavirus) through enhancing the metabolism and functions of monocytes, macrophages, and other cells of the immune system. Red meat (including beef) is a functional food for optimizing human growth, development and health.
Chapter
Few supplement combinations that are marketed to athletes are supported by scientific evidence of their effectiveness. Under the rigor of scientific investigation, we often see that the patented combination fails to provide any greater benefit when compared to an active (generic) ingredient. The focus of this chapter is supplement combinations and dosing strategies that are effective at promoting an acute physiological response that may improve/enhance exercise performance and/or influence chronic adaptations desired from training. In recent years, there has been a particular focus on two nutrition ergogenic aids—creatine monohydrate and protein/amino acids—in combination with specific nutrients in an effort to augment or add to their already established independent ergogenic effects. These combinations and others are discussed in this chapter.
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The purpose of this study was to assess the efficacy of the thermoplastic filling techniques, Touch’n Heat®, TC® System and Tagger’s Hybrid Technique, in oval-shaped canals at the apical third.Thirty-three human uniradicular lower pre-molar teeth were treated by the reciprocating movement technique and were subsequently split into 3 groups, according to the filling technique performed:Touch’n Heat (TH), TC System (TC) and the Tagger’s Hybrid Technique (TG).In the sequence, the teeth were sectioned at 2mm and 4mm from the foramen and images were taken to measure the percentage of canal area filled with the obturation materials as well as void spaces.Data were submitted for Kruskal- Wallis statistical analysis. Irrespective of levels, data showed that the TC System delivered the best results.(p<0,001).At 2mm and 4mm levels, there was no difference between the TG technique and the TH technique (p<0,001).With all the techniques and at all levels, no differences were observed regarding the void area variable.(p>0,001).The techniques evaluated showed an adequate filling with obturation materials and the TC has reached the highest filling with the guta-percha material. Key words: Endodontics; root canal therapy; dental materials.
Chapter
Research concerning the physiological and biobehavioral effects of supplements commonly used in sport or exercise settings has multiplied rapidly over the last decade. However, less attention has been directed to understanding the motivational pathways leading to sport and exercise supplement use. This chapter summarizes known usage rates for sport/fitness supplements and describes motivational theories and constructs which may be of use for understanding individuals’ use of these substances. In this respect, we contend that researchers should consider behavioral approaches, the theory of planned behavior, balance theory, achievement goal theory, social physique anxiety, and muscle dysmorphia as useful for developing an understanding of the psychological influences on supplement use. For some of the latter theories/constructs, research has already shown support for their explanatory abilities, whereas research is scant and the utility for understanding sport/exercise supplement use is yet to be determined for many of the theories. In addition to describing the motivation behind supplement use, this chapter summarizes the biobehavioral effects of a select group of supplements commonly used to improve performance, fitness, or health. Specifically, we consider psychobiological effects of caffeine, creatine, Ginkgo biloba, St. John’s wort, and omega-3 fatty acids related to enhanced arousal, improved memory and cognition, enhanced brain function and protection, and reduced depression. There is promising initial evidence for the efficacy of these compounds in producing favorable psychological outcomes, though certain shortcomings of many studies on these compounds must be taken into account before reaching definitive conclusions.
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Previous studies demonstrated levels of serum CK (sCK) in the majority of patients undergoing acute psychosis. Records of 1054 patients hospitalized in Geha Mental Health Center during the study period were analysed. Of them, 743 have been diagnosed with schizophrenia (Sz), 170 with schizoaffective disorder (SzA), and 158 with bipolar disorder (BP-I). Baseline sCK and PANSS values were obtained from each patient upon admission. Our results show that LnsCK is higher in patients with BP-I in comparison with patients with SZ, but not significantly different compared to patients with SzA. A multivariate analysis using linear regression model in which LnsCK was predicted by factors such as PANSS-total and sub-scores, IM injection, BMI, gender, and age among patients at each admission, revealed that PANSS-depression was inversely associated with LnsCK level in SzA and BP-I and not in SZ. A positive association was found between PANSS-total and sCK in SzA and BP-I; however, PANSS-positive scores correlated with sCK only in SzA. After controlling for confounders, it seems that sCK level is associated with the both affective and psychotic components. Serum CK may serve as a biomarker for affective exacerbation rather than psychosis.
Thesis
L’insuffisance rénale aigue (IRA), définie comme une altération brutale de la fonction de filtration rénale, est un véritable problème de santé publique par sa fréquence et son importante morbi-mortalité. La physiopathologie de ce syndrome est encore incomplètement comprise mais elle implique une adaptation métabolique insuffisante de l’épithélium tubulaire rénal dont les mécanismes régulateurs ne sont pas complètement connus. Ce déficit d’adaptation est à l’origine d’une souffrance cellulaire expliquant en partie les lésions tissulaires. De plus, ce syndrome est souvent ignoré ou identifié trop tardivement, en raison de critères diagnostiques imparfaits. Ces lacunes expliquent qu’il n’existe à l’heure actuelle aucun traitement spécifique efficace. Mon travail de thèse s’est organisé autour de ces trois problématiques : physiopathologique, thérapeutique et diagnostique.Le premier axe de mon travail, physiopathologique, a évalué le rôle du facteur de transcription Hepatocyte Nuclear Factor 1 β (HNF-1β) dans la régulation du métabolisme, notamment énergétique, au sein de l’épithélium tubulaire rénal. Nous avons démontré que l’invalidation de ce facteur de transcription dans une lignée tubulaire proximale murine, induit une réorientation du métabolisme énergétique en conditions basales, avec réduction du métabolisme oxydatif mitochondrial et augmentation de la glycolyse, sans d’autre explication que la modulation de PGC-1α. Ces anomalies, proches de celles induites par l’hypoxie dans les cellules sauvages, ne permettent pas d’adaptation supplémentaire des cellules invalidées à un stress. L’invalidation d’Hnf1b induit également des modifications métaboliques au-delà de la production énergétique à l’image de la synthèse des phospholipides, potentiellement en lien avec un régulation directe de la choline kinase-α. Ce travail confirme un rôle d’Hnf1b dans le métabolisme cellulaire énergétique, pouvant expliquer une partie du phénotype des patients souffrant d’une mutation de ce facteur mais le plaçant aussi comme un régulateur de la réponse à l’agression en situation générale Le deuxième axe, thérapeutique, s’est intéressé aux anomalies de la voie de biosynthèse de novo du Nicotinamide Adénine Dinucléotide (NAD) à partir du tryptophane en contexte d’IRA. En comparant, par approche métabolomique ciblée, la composition des urines de patients développant ou non une IRA, après chirurgie cardiaque, nous avons pu confirmer dans un nombre plus important de patients, certaines anomalies observés dans des études antérieures. Néanmoins, à l’inverse d’observations publiées, une supplémentation en nicotinamide, précurseur alternatif de la biosynthèse du NAD, ne permet pas de restaurer le stock intra-rénal de NAD ni d’améliorer les conséquences rénales d’une ischémie-reperfusion chez la souris. Ces résultats incitent à la prudence quant à l’efficacité attendue de ce traitement, en cours d’essai thérapeutique. Le troisième axe, diagnostique, s’est intéressé à l’identification de biomarqueurs urinaires permettant le diagnostic d’une IRA. Nous avons identifié, par approche peptidomique sur des urines prélevées précocement après chirurgie cardiaque, de nombreux peptides différentiellement présents en cas d’IRA. Leur combinaison en une signature permet un diagnostic précoce de l’AKI avec de bonnes performances (AUC = 0.79) dans divers contextes. La poursuite de ces analyses, avec utilisation de nouvelles approches (métabolomique) ou de combinaisons d’approches (multiomics, scores clinico-biologiques), donnent déjà de bons résultats accroissant encore ce bénéfice diagnostique avec même un potentiel prédictif. Bien que préliminaire et difficilement transposable en l’état à la pratique, ce type d’approche offre des perspectives intéressantes dans le diagnostic et la prédiction de cette affection. Ce travail de thèse, a permis de mettre en évidence de nouveaux éléments utiles concernant la physiopathologie, le traitement et le diagnostic de l’IRA.
Chapter
Reliable measurement of creatinine is necessary to assess kidney function, and also to quantitate drug levels and diagnostic compounds in urine samples. The most commonly used methods are based on the Jaffe principal of alkaline creatinine-picric acid complex color formation. However, other compounds commonly found in serum and urine may interfere with Jaffe creatinine measurements. Therefore, many laboratories have made modifications to the basic method to remove or account for these interfering substances. This appendix will summarize the basic Jaffe method, as well as a modified, automated version. Also described is a high performance liquid chromatography (HPLC) method that separates creatinine from contaminants prior to direct quantification by UV absorption. Lastly, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method is described that uses stable isotope dilution to reliably quantify creatinine in any sample. This last approach has been recommended by experts in the field as a means to standardize all quantitative creatinine methods against an accepted reference.
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Creatine (Cr) plays an important role in storage and transmission of phosphate-bound energy. Cerebral creatine deficiency syndromes comprise three inherited defects in Cr biosynthesis and transport. The aim of this study was to investigate whether Cr and Guanidinoacetate (GAA) can be detected in saliva of healthy subjects and to establish the relationship between salivary and plasma levels of these molecules. An adapted gas chromatography (GC) method is described for the quantification of Cr and GAA biomarkers in saliva. Reference values were established for GAA and Cr in saliva. These values were age dependent (p= 0.001). No difference between genders was observed. We detected a difference between GAA and Cr concentrations in saliva and in plasma. The GC method for simultaneous determination of GAA and Cr in human saliva is fast, reliable, sensitive, non-invasive and precise to use as a biochemical approach in early detection of cerebral creatine deficiency syndromes. Sociedad Argentina de Investigación Odontológica.
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Background The objective of this study was to evaluate creatine as an anti-nociceptive compound in an animal model of thermal and inflammatory pain. Creatine has the structural potential to interact with acid-sensing ion channels (ASIC), which have been involved in pain sensation modulation. The hypothesis evaluated in this study was that creatine will interact with ASICs leading to decreased nociception. Methods Male and female C57BL/6J mice were fed with either a control diet or the control diet supplemented with creatine (6.25 g/kg diet). After one week on the diet, the mice were tested for thermal hyperalgesia and inflammatory pain response. Results The latency to withdraw the tail during the thermal hyperalgesia test was unaffected by sex or diet. During the formalin test, males and females responded differently to the stimulus, and the female mice supplemented with creatine seemed to recover faster than the controls. To determine whether ASICs mediate the action of creatine, GMQ, an ASIC3 agonist, was injected in one paw and pain response was quantified. Females responded more strongly to GMQ injections, and all mice fed creatine had a decreased response to GMQ. Conclusions These preliminary data suggest a potential effect of creatine on inflammation-based nociception that may be mediated via ASIC3. While preliminary, this study warrants further research on the potential of creatine as an analgesic and can serve as a stepping stone for the development of ASIC-based therapeutics.
Article
The dried stem bark of Berberids kansuensis C.K. Schneid. (Berberidaceae) was widely used to treat diabetes in traditional Tibetan medicine system. However, its anti‐diabetic mechanisms have not been elucidated. In this study, 1 H NMR‐based metabolomics combined with biochemistry assay was applied to investigate the anti‐diabetic activities as well as underlying mechanisms of B. kansuensis extract on type 2 diabetic rats. The results showed that after 30 days treatment with B. kansuensis extract, the levels of FBG, GSP, INS, TNF‐α, IL‐1β, and IL‐6 were significantly decreased in B. kansuensis group compared with the model group. Besides, a total of 28 metabolites were identified in rat serum by 1 H NMR‐based metabolomics method, 16 of which were significantly different in the normal group compared with the model group, and 8 of them were significantly reversed after B. kansuensis intervention. Further analysis of metabolic pathways indicated that therapeutic effect of B. kansuensis might be predominantly related to their ability to improve glycolysis and gluconeogenesis, citric acid cycle, lipid metabolism, amino acid metabolism, and choline metabolism. The results of both metabolomics and biochemical analysis indicated that B. kansuensis extract has a potential anti‐diabetic effect on type 2 diabetic rats. Its therapeutic effect may be based on the ability of anti‐inflammation, alleviating insulin resistance, and restoring several disturbed metabolic pathways.
Article
In 2001 we identified a new inborn error of metabolism caused by a defect in the X‐linked creatine transporter SLC6A8 gene mapped at Xq28 (SLC6A8 deficiency, McKusick 300352). An X‐linked creatine transporter defect was presumed because of (1) the absence of creatine in the brain as indicated by proton magnetic resonance spectroscopy (MRS); (2) the elevated creatine levels in urine and normal guanidinoacetate levels in plasma, ruling out a creatine biosynthesis defect; (3) the absence of an improvement on creatine supplementation; and (4) the fact that the pedigree suggested an X‐linked disease. Our hypothesis was proved by the presence of a hemizygous nonsense mutation in the male index patient and by the impaired creatine uptake by cultured fibroblasts. Currently, at least 7 unrelated families (13 male patients and 13 carriers) with a SLC6A8 deficiency have been identified. Four families come fromone metropolitan area. This suggests that SLC6A8 deficiency may have a relatively high incidence. The hallmarks of the disorder are X‐linked mental retardation, expressive speech and language delay, epilepsy, developmental delay and autistic behaviour. In approximately 50% of the female carriers, learning disabilities of varying degrees have been noted.
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The research was conducted to investigate the effect of supplementation of Creatine and Carnitine with their combination on some blood of Ross 308 broiler chicks. Atotal number of 450, one day old chicks were used in the research , those chicks were randomly alloted in to 9 equal treatments and each treatment included 2 equal replicates.Chicks were fed on diets supplemented with Creatine 100 and 200 mg/ kg and Carnintine 100 and 200 mg / kg with their combination by different doses. on the starter diet till 21 day, then transferred to the growing diet till 42 day. Results illustrated a highly significant (p<0.01) effect of Carnitine on PCV and highly significant improvement of H/L. Mean while supplementation of Creatine plus Carnitineled to highly significant effect on total protein with highly significant reduction of glucose , cholestral and triglyceride in the plasma. More over Carnitine caused a highly significant effect on Newcastle and and Infectious Bronchitis antibody titer with significant (p<0.05) improvement of antibody titer against Infectious Bursal Disease
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Objective: The aim of this study was to investigate the levels of homocysteine and lipid profiles in patients included in hemodialysis programs for chronic renal failure (CRF). Material and Methods: The patients were divided into 2 groups and each group consisted of 30 patients, leading to a total of 60 patients. On the other hand, 20 healthy people comprised the control group. The first group (nontreated CRF) included new patients without a previous history of dialysis or any medical treatment; the second group (treated CRF) included patients who have received medical treatment [vitamin B12 (1 mg/month) and folic acid (15 mg/week)] and dialysis for at least the last 5 years. Serum total homocysteine, vitamin B12, folic acid, creatinine, triglyceride, total cholesterol, HDL, LDL, VLDL, cholesterol levels were measured in all patients and the control group. Results: Levels of homocysteine were high in group 1 and group 2 patients (respectively p< 0.01, p< 0.05), whereas serum HDL cholesterol levels in group 2 were low compared to those in the control group (p< 0.01). In addition, a negative correlation was observed between homocysteine and folic acid levels in group 2 patients (r=-0.48, p< 0.01). Conclusion: The results of this study showed that homocysteine levels in CRF increased and this increase was lower in group 2 patients. Administration of folic acid reduced the levels of homocycstein. Thus, we suggest that folic acid may be a significant factor to prevent the progression of chronic renal failure.
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Creatine is a substance occurring naturally in the, human body. The major proportion of the total Creatine pool is found in skeletal muscle (circa 90 %), heart and brain. The total creatine content in a normal, healthy person of TO kg is approximately 120 g. Creatine and its phosphorylated form, phospho-creatine, play an important role for cellular energy storage, buffering, and transport. Due to these properties, Creatine supplementation has become very popular in sports among athletes to enhance muscle performance and muscle mass. For this purpose, Creatine is usually taken during a loading phase at 20 g per day for one week and during a maintenance phase at 5-10 g, per day during extended periods of training. According to numerous publications, such a supplementation scheme is well tolerated and does not lead to significant side effects. Occasionally slight gastrointestinal discomfort or muscle cramping were reported. in those reports where liver and kidney functions of healthy athletes were examined specifically, no indications for adverse effects of Creatine an these organs have been noticed. Systematic studies on the clinical toxicology of creatine, however, are not available at present. Since no reports about experimental toxicity studies have been published so far, a series of toxicological examinations was thus performed, the results of which are reported within the scope of this publication. Based on these new data, Creatine did not reveal acute nor subacute toxic effects. The substance is well tolerated locally, as well. Furthermore, Creatine does not act as a sensitizing agent. Finally, no mutagenic effects were observed with Creatine in standardized bacterial mutagenicity tests. Since a significant proportion of the Creatine, taken at the dose levels mentioned above, is immediately excreted via the kidneys and since there is no evidence that very high dosages of Creatine are more beneficial, a loading dosage of 10 g per day for the first 8 days, to fill-up endogenous creatine pools, and a maintenance dose of 4-5 g per day, during the time after, are thus recommended. In addition, as a precautionary measure, it is advisable, after a prolonged period of Creatine intake (e.g. during 3 months), to take a break for several weeks (e, g. 4 weeks which is the wash-out time to return to original Creatine levels).
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Since the first description of a creatine deficiency syndrome, the guanidinoacetate methyltransferase (GAMT) deficiency, in 1994, the two further suspected creatine deficiency syndromes--the creatine transporter (CrT1) defect and the arginine:glycine amidinotransferase (AGAT) deficiency were disclosed. GAMT and AGAT deficiency have autosomal-recessive traits, whereas the CrT1 defect is a X-linked disorder. All patients reveal developmental delay/regression, mental retardation, and severe disturbance of their expressive and cognitive speech. The common feature of all creatine deficiency syndromes is the severe depletion of creatine/phosphocreatine in the brain. Only the GAMT deficiency is in addition characterized by accumulation of guanidinoacetic acid in brain and body fluids. Guanidinoacetic acid seems to be responsible for intractable seizures and the movement disorder, both exclusively found in GAMT deficiency. Treatment with oral creatine supplementation is in part successful in GAMT and AGAT deficiency, whereas in CrT1 defect it is not able to replenish creatine in the brain. Treatment of combined arginine restriction and ornithine substitution in GAMT deficiency is capable to decrease guanidinoacetic acid permanently and improves the clinical outcome. The lack of the creatine/phosphocreatine signal in the patient's brain by means of in vivo proton magnetic resonance spectroscopy is the common finding and the diagnostic clue in all three diseases. In AGAT deficiency guanidinoacetic acid is decreased, whereas creatine in blood was found to be normal. On the other hand the CrT1 defect is characterized by an increased concentration of creatine in blood and urine whereas guanidinoacetic acid concentration is normal. The increasing number of patients detected very recently suffering from a creatine deficiency syndrome and the unfavorable outcome highlights the need of further attempts in early recognition of affected individuals and in optimizing its treatment. The study of creatine deficiency syndromes and their comparative consideration contributes to the better understanding of the pathophysiological role of creatine and other guanidino compounds in man
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Creatine and phosphocreatine were evaluated for their ability to prevent death of cultured striatal and hippocampal neurons exposed to either glutamate or 3-nitropropionic acid (3NP) and to inhibit the mitochondrial permeability transition in CNS mitochondria. Phosphocreatine (PCr), and to a lesser extent creatine (Cr), but not (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK801), dose-dependently ameliorated 3NP toxicity when applied simultaneously with the 3NP in Mg2+-free media. Pre-treatment of PCr for 2 or 5 days and Cr for 5 days protected against glutamate excitotoxicity equivalent to that achieved by MK801 post-treatment. The combination of PCr or Cr pre-treatment and MK801 post-treatment did not provide additional protection, indicating that both prevented the toxicity attributable to secondary glutamate release. To determine if Cr or PCr directly inhibited the permeability transition, mitochondrial swelling and depolarization were assayed in isolated, purified brain mitochondria. PCr reduced the amount of swelling induced by calcium by 20%. Cr decreased mitochondrial swelling when inhibitors of creatine kinase octamer–dimer transition were present. However, in brain mitochondria prepared from rats fed a diet supplemented with 2% creatine for 2 weeks, the extent of calcium-induced mitochondrial swelling was not altered. Thus, the neuroprotective properties of PCr and Cr may reflect enhancement of cytoplasmic high-energy phosphates but not permeability transition inhibition.
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The loss of ATP, which is needed for ionic homeostasis, is an early event in the neurotoxicity of glutamate and β-amyloid (Aβ). We hypothesize that cells supplemented with the precursor creatine make more phosphocreatine (PCr) and create large energy reserves with consequent neuroprotection against stressors. In serum-free cultures, glutamate at 0.5-1 mM was toxic to embryonic hippocampal neurons. Creatine at >0.1 mM greatly reduced glutamate toxicity. Creatine (1 mM) could be added as late as 2 h after glutamate to achieve protection at 24 h. In association with neurotoxic protection by creatine during the first 4 h, PCr levels remained constant, and PCr/ATP ratios increased. Morphologically, creatine protected against glutamate-induced dendritic pruning. Toxicity in embryonic neurons exposed to Aβ (25-35) for 48 h was partially prevented by creatine as well. During the first 6 h of treatment with Aβ plus creatine, the molar ratio of PCr/ATP in neurons increased from 15 to 60. Neurons from adult rats were also partially protected from a 24-h exposure to Aβ (25-35) by creatine, but protection was reduced in neurons from old animals. These results suggest that fortified energy reserves are able to protect neurons against important cytotoxic agents. The oral availability of creatine may benefit patients with neurodegenerative diseases.
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Energy utilization by the flagellum of motile sea urchin sperm is tightly coupled to the rate of energy production by the mitochondrion. This tight coupling depends upon the transport of high energy phosphate (P) from mitochondrion to axoneme, which we propose to be mediated by a phosphorylcreatine shuttle. The shuttle employs distinct mitochondrial and axonemal creatine kinase isozymes, the latter being a novel creatine kinase of 145 kd. To examine whether P is directed to the tail by such a shuttle, we inactivated creatine kinase specifically with fluorodinitrobenzene. Creatine kinase inactivation led to an inhibition of coupled, but not uncoupled, respiration and affected the pattern of sperm motility as predicted for the disruption of an obligatory link in P transport.
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In order to explain the insulin-like effect of exercise, it was proposed in 1951 that contracting muscle fibers liberate creatine, which acts to produce an acceptor effect--later called respiratory control--on the muscle mitochondria. The development of this notion paralleled the controversy between biochemists and physiologists over the delivery of energy for muscle contraction. With the demonstration of functional compartmentation of creatine kinase on the mitochondrion, it became clear that the actual form of energy transport in the muscle fiber is phosphorylcreatine. The finding of an isoenzyme of creatine phosphokinase attached to the M-line region of the myofibril revealed the peripheral receptor for the mitochondrially generated phosphorylcreatine. This established a molecular basis for a phosphorylcreatine-creatine shuttle for energy transport in heart and skeletal muscle and provided an explanation for the inability to demonstrate experimentally a direct relation between muscle activity and the concentrations of adenosine triphosphate and adenosine diphosphate.
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We previously suggested that an importance of adenylate kinase (AdK) in skeletal muscle is to function as a high energy phosphoryl transfer system regulating ATP generation in correspondence with its consumption by specific cellular processes. The present experiments are intended to define the ATP-generating system coupled to and regulated by AdK-catalyzed phosphotransfer in skeletal muscle and also to examine the relationship between AdK- and creatine kinase (CK)-catalyzed phosphotransfer. Rates of phosphoryl transfer catalyzed by AdK were assessed in intact, isolated rat diaphragm by determining rates of AMP phosphorylation with endogenously generated [gamma-18O]ATP under conditions of altered anaerobic and aerobic ATP production. AdK-catalyzed phosphoryl transfer rates accelerated incrementally up to 12-fold in direct proportion to stimulated contractile frequency in parallel with equivalent increases in rates of ATP generation by lactate producing glycolysis. Stoichiometric equivalent increases of AdK-catalyzed phosphotransfer and anaerobic ATP production also occurred up to more than 20-fold when oxidative phosphorylation was impaired by either O2 deprivation or treatment with KCN or p-(trifluoromethoxy)-phenylhydrazone. These enhanced rates of AMP phosphorylation were balanced by virtually identically increased rates of AdK-catalyzed generation of AMP. This AMP was traced to arise from AdK-catalyzed phosphotransfer involving ADP generated by a muscle ATPase. Increased AdK-catalyzed phosphotransfer paired with the apparent compensatory increase in ATP generation by anaerobic glycolysis in oxygen-deprived muscle occurred coincident with diminished rates of CK-catalyzed phosphoryl transfer indicative of a pairing between oxidatively produced ATP and CK-catalyzed phosphotransfer. A metabolic model consistent with these results and conforming to the Mitchell general principle of vectorial ligand conduction is suggested.
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In a patient with extrapyramidal movement disorder and extremely low creatinine concentrations in serum and urine, in vivo proton magnetic resonance spectroscopy disclosed a generalized depletion of creatinine in the brain. Oral substitution of arginine, a substrate for creatine synthesis, resulted in an increase of brain guanidinoacetate as the immediate precursor of creatine but did not elevate cerebral creatine levels. In contrast, oral substitution of creatine-monohydrate led to a significant increase of brain creatine, a decrease of brain guanidinoacetate, and a normalization of creatinine in serum and urine. Phosphorus magnetic resonance spectroscopy of the brain revealed no detectable creatine-phosphate before oral substitution of creatine and a significant increase afterward. Partial restoration of cerebral creatine concentrations was accompanied by improvement of the patient's neurologic symptoms. This is the first report of a patient with complete creatine deficiency in the brain. Magnetic resonance spectroscopy during arginine and creatine treatment point to an inborn error of creatine biosynthesis at the level of guanidinoacetete-methyltransferase.
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The kinetics of creatine kinase (CK) and adenylate kinase (AK) activities were monitored in intact diaphragm muscle by 18O phosphoryl oxygen exchange to assess whether these two phosphotransferases provide an interrelated function integral to high energy phosphoryl metabolism. This possibility was examined by quantitating the net rates of CK- and AK-catalyzed phosphoryl transfer in comparison to the total cellular ATP metabolic rate when CK activity in the intact diaphragm muscle was progressively inhibited by 2,4-dinitrofluorobenzene. In noncontracting muscle from untreated rats, net rates of CK- and AK-catalyzed phosphotransfer were equivalent to 88 and 7%, respectively, of the total ATP metabolic rate. These results were compared with reported 31P NMR analyses of total creatine phosphate flux to estimate that each creatine phosphate molecule produced undergoes about 50 unidirectional CK-catalyzed phosphotransfers in transit to an ATP consumption site in the intact muscles. Graded inhibition by 2,4-dinitrofluorobenzene of intracellular CK activity by up to 98% resulted in a progressive shift in phosphotransferase catalysis from the CK to the AK system; the sum of the net rates of phosphoryl transfer by combining the increasing AK and decreasing CK activities continued to approximate the total cellular ATP metabolic rate. These results indicate that in diaphragm muscle CK and AK operate as interrelated cellular high energy phosphoryl transfer systems through which the majority of newly generated ATP is processed prior to its utilization.
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Hepatic guanidinoacetate methyltransferase deficiency induces a deficiency of creatine/phosphocreatine in muscle and brain and an accumulation of guanidinoacetic acid (GAA), the precursor of creatine. We describe a patient with this defect, a 4-year-old girl with a dystonic-dyskinetic syndrome in addition to developmental delay and therapy-resistant epilepsy. Several methods were used in the diagnosis of the disease: (1) the creatinine excretion in 24-hour urine was significantly lowered, whereas the creatinine concentration in plasma and in randomly collected urine was not strikingly different from control values; (2) the Sakaguchi staining reaction of guanidino compounds in random urine samples indicated an enhanced GAA excretion; (3) GAA excretion measured quantitatively by guanidino compound analysis using an amino acid analyzer was markedly elevated in random urine samples; (4) in vivo 1H magnetic resonance spectroscopy (MRS) revealed a strong depletion of creatine and an accumulation of GAA in brain; (5) in vivo phosphorus 31 MRS showed a strong decrease of the phosphocreatine resonance and a resonance identified as guanidinoacetate phosphate; and (6) in vitro 1H MRS showed an absence of creatine and creatinine resonances in cerebrospinal fluid and the occurrence of GAA in urine. For early detection of this disease, we recommend the Sakaguchi staining reaction of urine from patients with dystonic-dyskinetic syndrome, seizures, and psychomotor retardation. Positive results should result in further investigations including quantitative guanidino compound analysis and both in vivo and in vitro MRS. Although epilepsy was not affected by orally administered creatine (400 to 500 mg/kg per day), this treatment resulted in clinical improvement and an increase of creatine in cerebrospinal fluid and brain tissue.
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Fatigue in patients with mitochondrial cytopathies is associated with decreased basal and postactivity muscle phosphocreatine (PCr). Creatine monohydrate supplementation has been shown to increase muscle PCr and high-intensity power output in healthy subjects. We studied the effects of creatine monohydrate administration (5 g PO b.i.d. x 14 days --> 2 g PO b.i.d. x 7 days) in 7 mitochondrial cytopathy patients using a randomized, crossover design. Measurements included: activities of daily living (visual analog scale); ischemic isometric handgrip strength (1 min); basal and postischemic exercise lactate; evoked and voluntary contraction strength of the dorsiflexors; nonischemic, isometric, dorsiflexion torque (NIDFT, 2 min); and aerobic cycle ergometry with pre- and post-lactate measurements. Creatine treatment resulted in significantly (P < 0.05) increased handgrip strength, NIDFT, and postexercise lactate, with no changes in the other measured variables. We concluded that creatine monohydrate increased the strength of high-intensity anaerobic and aerobic type activities in patients with mitochondrial cytopathies but had no apparent effects upon lower intensity aerobic activities.
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In gyrate atrophy of the choroid and retina with hyperornithinaemia (GA), a genetically determined deficiency of ornithine {3}d‐aminotransferase activity leads to high ornithine concentrations in body fluids. GA is characterized by centripetally progressing retinal and choroidal destruction and selective atrophy with tubular aggregates in type II skeletal muscle fibres. These findings have been suggested to be mediated by hyperornithinaemia‐induced deficiency of high‐energy creatine phosphate. As abnormal brain magnetic resonance images and electroencephalograms are found in another disorder of creatine metabolism, guanidinoacetate methyltransferase deficiency, we investigated the central nervous system involvement in GA, which seems to be associated with a milder degree of phosphocreatine deficiency. We compared 23 untreated GA patients with age‐matched healthy controls, and with 9 patients who had received creatine or creatine precursor supplementation daily for several years. The mean age of the patients (32±18 years) was similar to that of the controls (36±22 years). The MRI or EEG findings of the patients on creatine supplementation did not differ from those of the untreated group. Brain MRI revealed degenerative lesions in the white matter in 50% of the GA patients, and 70% of the patients had premature atrophic changes, with a striking increase in the number of Virchow's spaces. Of the patients whose EEG was recorded, 58% had abnormal slow background activity, focal lesions or high‐amplitude β rhythm (>50μV). The EEG findings were not associated with the MRI changes or with the age or the sex of the patients. Early degenerative and atrophic brain changes and abnormal EEG are thus features of GA, in addition to the well‐characterized eye and muscle manifestations.
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Objectives: To determine whether chronic treatment with coenzyme Q(10) or remacemide hydrochloride slows the functional decline of early Huntington's disease (HD). Methods: The authors conducted a multicenter, parallel group, double-blind, 2 X 2 factorial, randomized clinical trial. Research participants with early HD (n = 347) were randomized to receive coenzyme Q(10) 300 mg twice daily, remacemide hydrochloride 200 mg three times daily, both, or neither treatment, and were evaluated every 4 to 5 months for a total of 30 months on assigned treatment. The prespecified primary measure of efficacy was the change in total functional capacity (TFC) between baseline and 30 months. Safety measures included the frequency of clinical adverse events. Results: Neither intervention significantly altered the decline in TFC. Patients treated with coenzyme Q(10) showed a trend toward slowing in TFC decline (13%) over 30 months (2.40- versus 2.74-point decline, p = 0.15), as well as beneficial trends in some secondary measures. There was increased frequency of nausea, vomiting, and dizziness with remacemide and increased frequency of stomach upset with coenzyme Q(10). Conclusions: Neither remacemide nor coenzyme Q(10), at the dosages studied, produced significant slowing in functional decline in early HD.
Article
This article reviews the involvement of the mitochondrial permeability transition pore in necrotic and apoptotic cell death. The pore is formed from a complex of the voltage-dependent anion channel (VDAC), the adenine nucleotide translocase and cyclophilin-D (CyP-D) at contact sites between the mitochondrial outer and inner membranes. In vitro, under pseudopathological conditions of oxidative stress, relatively high Ca2+ and low ATP, the complex flickers into an open-pore state allowing free diffusion of low-Mr solutes across the inner membrane. These conditions correspond to those that unfold during tissue ischaemia and reperfusion, suggesting that pore opening may be an important factor in the pathogenesis of necrotic cell death following ischaemia/reperfusion. Evidence that the pore does open during ischaemia/reperfusion is discussed. There are also strong indications that the VDAC-adenine nucleotide translocase-CyP-D complex can recruit a number of other proteins, including Bax, and that the complex is utilized in some capacity during apoptosis. The apoptotic pathway is amplified by the release of apoptogenic proteins from the mitochondrial intermembrane space, including cytochrome c, apoptosis-inducing factor and some procaspases. Current evidence that the pore complex is involved in outer-membrane rupture and release of these proteins during programmed cell death is reviewed, along with indications that transient pore opening may provoke 'accidental' apoptosis.
Article
The cellular role of creatine (Cr) and Cr phosphate (CrP) has been studied extensively in neural, cardiac and skeletal muscle. Several studies have demonstrated that alterations in the cellular total Cr (Cr + CrP) concentration in these tissues can produce marked functional and/or structural change. The primary aim of this review was to critically evaluate the literature that has examined the regulation of cellular total Cr content. In particular, the review focuses on the regulation of the activity and gene expression of the Cr transporter (CreaT), which is primarily responsible for cellular Cr uptake. Two CreaT genes (CreaT1 and CreaT2) have been identified and their chromosomal location and DNA sequencing have been completed. From these data, putative structures of the CreaT proteins have been formulated. Transcription products of the CreaT2 gene are expressed exclusively in the testes, whereas CreaT1 transcripts are found in a variety of tissues. Recent research has measured the expression of the CreaT1 protein in several tissues including neural, cardiac and skeletal muscle. There is very little information available about the factors regulating CreaT gene expression. There is some evidence that suggests the intracellular Cr concentration may be involved in the regulatory process but there is much more to learn before this process is understood. The activity of the CreaT protein is controlled by many factors. These include substrate concentration, transmembrane Na^+ gradients, cellular location, and various hormones. It is also likely that transporter activity is influenced by its phosphorylation state and by its interaction with other plasma membrane proteins. The extent of CreaT protein glycosylation may vary within cells, the functional significance of which remains unclear.
Article
To describe the clinical, spectroscopic and neuropsychological features of the first family diagnosed with a defect in the creatine transporter.Proton Magnetic Resonance Spectroscopy (MRS) indicated an absence of creatine and phosphocreatine in the brain of a male patient characterized by developmental delay, mild epilepsy and severe expressive language impairment. Subsequent genetic testing revealed a defect in the X-linked creatine transporter (SLC6A8/CT1), with a hemizygous mutation in the patient and a heterozygous mutation for the female carriers.Magnetic resonance imaging and spectroscopy examinations were performed on a 1.5T clinical MR Scanner. Neuropsychological examinations were performed on the index patient and maternal relatives.Preliminary spectroscopy results indicate the disorder prevents transport of creatine and phosphocreatine in the brain of the affected male. However, the skeletal muscle demonstrates the presence of creatine and phosphocreatine which correlates clinically with normal structure and function. Female carriers demonstrated impairments in confrontational naming and verbal memory assessments.This new neurological syndrome is associated with developmental delay, mild epilepsy, severe language impairment. MR Spectroscopy is a non-invasive method for obtaining a preliminary diagnosis of this disorder. Muscle creatine uptake may be normal in this disorder.
Article
Fatigue in patients with mitochondrial cytopathies is associated with decreased basal and postactivity muscle phosphocreatine (PCr). Creatine monohydrate supplementation has been shown to increase muscle PCr and high-intensity power output in healthy subjects. We studied the effects of creatine monohydrate administration (5 g PO b.i.d. × 14 days → 2 g PO b.i.d. × 7 days) in 7 mitochondrial cytopathy patients using a randomized, crossover design. Measurements included: activities of daily living (visual analog scale); ischemic isometric handgrip strength (1 min); basal and postischemic exercise lactate; evoked and voluntary contraction strength of the dorsiflexors; nonischemic, isometric, dorsiflexion torque (NIDFT, 2 min); and aerobic cycle ergometry with pre- and post-lactate measurements. Creatine treatment resulted in significantly (P < 0.05) increased handgrip strength, NIDFT, and postexercise lactate, with no changes in the other measured variables. We concluded that creatine monohydrate increased the strength of high-intensity anaerobic and aerobic type activities in patients with mitochondrial cytopathies but had no apparent effects upon lower intensity aerobic activities. © 1997 John Wiley & Sons, Inc. Muscle Nerve20: 1502–1509, 1997
Article
Rapid exchange of high energy carrying molecules between intracellular compartments is essential in sustaining cellular energetic homeostasis. Adenylate kinase (AK)-catalyzed transfer of adenine nucleotide β- and γ-phosphoryls has been implicated in intracellular energy communication and nucleotide metabolism. To demonstrate the significance of this reaction in cardiac energetics, phosphotransfer dynamics were determined by [18O]phosphoryl oxygen analysis using31P NMR and mass spectrometry. In hearts with a null mutation of the AK1 gene, which encodes the major AK isoform, total AK activity and β-phosphoryl transfer was reduced by 94% and 36%, respectively. This was associated with up-regulation of phosphoryl flux through remaining minor AK isoforms and the glycolytic phosphotransfer enzyme, 3-phosphoglycerate kinase. In the absence of metabolic stress, deletion of AK1 did not translate into gross abnormalities in nucleotide levels, γ-ATP turnover rate or creatine kinase-catalyzed phosphotransfer. However, under hypoxia AK1-deficient hearts, compared with the wild type, had a blunted AK-catalyzed phosphotransfer response, lowered intracellular ATP levels, increased Pi/ATP ratio, and suppressed generation of adenosine. Thus, although lack of AK1 phosphotransfer can be compensated in the absence of metabolic challenge, under hypoxia AK1-knockout hearts display compromised energetics and impaired cardioprotective signaling. This study, therefore, provides first direct evidence that AK1 is essential in maintaining myocardial energetic homeostasis, in particular under metabolic stress.
Article
Purpose: Long-term safety of creatine supplementation has been questioned. This retrospective study was performed to examine markers related to health, the incidence of reported side effects and the perceived training benefits in athletes supplementing with creatine monohydrate. Methods: Twenty-six athletes (18 M and 8 F, 24.7 +/- 9.2 y; 82.4 +/- 20.0 kg; 176.5 +/- 8.8 cm) from various sports were used as subjects. Blood was collected between 7:00 and 8:30 a.m. after a 12-h fast. Standard clinical examination was performed for CBC and 27 blood chemistries. Testosterone, cortisol, and growth hormone were analyzed using an ELISA. Subjects answered a questionnaire on dietary habits, creatine supplementation, medical history, training history, and perceived effects of supplementation. Body mass was measured using a medical scale, body composition was estimated using skinfolds, and resting heart rate and blood pressure were recorded. Subjects were grouped by supplementation length or no use: Gp1 (control) = no use (N = 7; 3 F, 4 M); Gp2 = 0.8-1.0 yr (N = 9; 2 F, 7 M); and Gp3 = 1(+) (N = 10; 3 F, 7 M). Results: Creatine supplementation ranged from 0.8--4 yr. Mean loading dose for Gp2 and Gp3 was 13.7 +/- 10.0 and the maintenance dose was 9.7 +/- 5.7 g.d(-)1. Group differences were analyzed using one-way ANOVA. Conclusions: Expected gender differences were observed. Of the comparisons made among supplementation groups, only two differences for creatinine and total protein (P < 0.05) were noted. All group means fell within normal clinical ranges. There were no differences in the reported incidence of muscle injury, cramps, or other side effects. These data suggest that long-term creatine supplementation does not result in adverse health effects.
Article
Recently, 3 patients with a creatine synthesis defect have been described. They presented with developmental regression, extrapyramidal movement abnormalities, and intractable epilepsy, and they improved with treatment of creatine monohydrate. We report 2 unrelated boys with a creatine synthesis defect and nonspecific presenting signs of psychomotor retardation, behavioral problems, and, in 1, mild epilepsy. Metabolic urine screening revealed elevations in all metabolites, expressed as millimoles per mole of creatinine, which suggests decreased creatinine excretion. This finding led to the correct diagnosis. We propose to include the assessment of the overall concentrations of amino acids and organic acids relative to creatinine in routine metabolic urine screening. Ann Neurol 2000;47:540–543.
Article
1. We investigated the effect of oral creatine supplementation during leg immobilization and rehabilitation on muscle volume and function, and on myogenic transcription factor expression in human subjects. 2. A double-blind trial was performed in young healthy volunteers (n = 22). A cast was used to immobilize the right leg for 2 weeks. Thereafter the subjects participated in a knee-extension rehabilitation programme (3 sessions week _1 , 10 weeks). Half of the subjects received creatine monohydrate (CR; from 20 g down to 5 g daily), whilst the others ingested placebo (P; maltodextrin). 3. Before and after immobilization, and after 3 and 10 weeks of rehabilitation training, the cross- sectional area (CSA) of the quadriceps muscle was assessed by NMR imaging. In addition, an isokinetic dynamometer was used to measure maximal knee-extension power (W max), and needle biopsy samples taken from the vastus lateralis muscle were examined to asses expression of the myogenic transcription factors MyoD, myogenin, Myf5, and MRF4, and muscle fibre diameters. 4. Immobilization decreased quadriceps muscle CSA (~10 %) and W max (~25 %) by the same magnitude in both groups. During rehabilitation, CSA and Wmax recovered at a faster rate in CR than in P (P < 0.05 for both parameters). Immobilization changed myogenic factor protein expression in neither P nor CR. However, after rehabilitation myogenin protein expression was increased in P but not in CR (P < 0.05), whilst MRF4 protein expression was increased in CR but not in P (P < 0.05). In addition, the change in MRF4 expression was correlated with the change in mean muscle fibre diameter (r = 0.73, P < 0.05). 5. It is concluded that oral creatine supplementation stimulates muscle hypertrophy during rehabilitative strength training. This effect may be mediated by a creatine-induced change in MRF4 and myogenin expression.
Article
Recent reports highlight the utility of in vivo magnetic resonance spectroscopy (MRS) techniques to recognize creatine deficiency syndromes affecting the central nervous system (CNS). Reported cases demonstrate partial reversibility of neurologic symptoms upon restoration of CNS creatine levels with the administration of oral creatine. We describe a patient with a brain creatine deficiency syndrome detected by proton MRS that differs from published reports. Metabolic screening revealed elevated creatine in the serum and urine, with normal levels of guanidino acetic acid. Unlike the case with other reported creatine deficiency syndromes, treatment with oral creatine monohydrate demonstrated no observable increase in brain creatine with proton MRS and no improvement in clinical symptoms. In this study, we report a novel brain creatine deficiency syndrome most likely representing a creatine transporter defect. Ann Neurol 2001;49:401–404
Article
Creatine is synthesized from arginine by l-arginine:glycine amidinotransferase (AGAT) and S-adenosyl-l-methionine:N-guanidinoacetate methyltransferase (GAMT) and can be taken up by cells by creatine transporters (CRT). While creatine is mainly synthesized by the liver and the kidney, most of other tissues, including the brain, also express AGAT and GAMT. There is evidence that the permeability of the blood–brain barrier (BBB) for creatine is limited, suggesting that the brain is dependent on its own creatine synthesis. In order to better understand creatine synthesis and transport in the central nervous system (CNS), we studied the regional distribution of cells expressing AGAT, GAMT and the creatine transporter CRT1 in the adult rat brain by non-radioisotopic in situ hybridization. AGAT and GAMT presented an ubiquitous neuronal and glial expression, whereas CRT1 was present in neurons and oligodendrocytes throughout the brain, but not in astrocytes. This indicates that all cells in the CNS can synthesize creatine from arginine. The absence of expression of CRT1 in astrocytes and particularly in those contacting capillary endothelial cells (BBB) reinforces the idea that under normal conditions the creatine used by the brain is synthesized mainly in the CNS. Furthermore, the expression of CRT1 by neurons and oligodendrocytes indicates that creatine trafficking is possible in those brain areas of main creatine consumption.