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Creatine ( or ) is an organic compound with the nominal formula (H2N)(HN)CN(CH3)CH2CO2H. It exists in various tautomers in solutions (among which are neutral form and various zwitterionic forms). Creatine is found in vertebrates, where it facilitates recycling of adenosine triphosphate (ATP), primarily in muscle and brain tissue. Recycling is achieved by converting adenosine diphosphate (ADP) back to ATP via donation of phosphate groups. Creatine also acts as a buffer. |
Read full article at Wikipedia
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InChI=1S/C4H9N3O2/c1-7(4(5)6)2-3(8)9/h2H2,1H3,(H3,5,6)(H,8,9) |
CVSVTCORWBXHQV-UHFFFAOYSA-N |
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Mus musculus
(NCBI:txid10090)
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Source: BioModels - MODEL1507180067
See:
PubMed
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Homo sapiens
(NCBI:txid9606)
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See:
DOI
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Homo sapiens
(NCBI:txid9606)
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See:
PubMed
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Homo sapiens
(NCBI:txid9606)
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Found in
blood serum
(BTO:0000133).
See:
MetaboLights Study
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human metabolite
Any mammalian metabolite produced during a metabolic reaction in humans (Homo sapiens).
mouse metabolite
Any mammalian metabolite produced during a metabolic reaction in a mouse (Mus musculus).
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geroprotector
Any compound that supports healthy aging, slows the biological aging process, or extends lifespan.
neuroprotective agent
Any compound that can be used for the treatment of neurodegenerative disorders.
nutraceutical
A product in capsule, tablet or liquid form that provide essential nutrients, such as a vitamin, an essential mineral, a protein, an herb, or similar nutritional substance.
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View more via ChEBI Ontology
N-[amino(imino)methyl]-N-methylglycine
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((amino(imino)methyl)(methyl)amino)acetic acid
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HMDB
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(α-methylguanido)acetic acid
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HMDB
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(α-methylguanido)acetic acid
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NIST Chemistry WebBook
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(N-methylcarbamimidamido)acetic acid
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ChEBI
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alpha-Methylguanidino acetic acid
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KEGG COMPOUND
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Creatin
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ChemIDplus
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Creatine
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KEGG COMPOUND
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Kreatin
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ChemIDplus
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Methylglycocyamine
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KEGG COMPOUND
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N-(aminoiminomethyl)-N-methylglycine
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NIST Chemistry WebBook
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N-[(E)-AMINO(IMINO)METHYL]-N-METHYLGLYCINE
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PDBeChem
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N-amidinosarcosine
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ChemIDplus
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N-carbamimidoyl-N-methylglycine
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PDBeChem
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N-Methyl-N-guanylglycine
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HMDB
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N-methyl-N-guanylglycine
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ChemIDplus
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4661
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DrugCentral
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566
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ChemSpider
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C00300
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KEGG COMPOUND
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Creatine
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Wikipedia
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CREATINE
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MetaCyc
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CRN
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PDBeChem
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DB00148
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DrugBank
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HMDB0000064
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HMDB
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View more database links |
240513
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Gmelin Registry Number
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Gmelin
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57-00-1
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CAS Registry Number
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KEGG COMPOUND
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57-00-1
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CAS Registry Number
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ChemIDplus
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57-00-1
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CAS Registry Number
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NIST Chemistry WebBook
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907175
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Reaxys Registry Number
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Reaxys
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Dulinska J, Setkowicz Z, Janeczko K, Sandt C, Dumas P, Uram L, Gzielo-Jurek K, Chwiej J (2012) Synchrotron radiation Fourier-transform infrared and Raman microspectroscopy study showing an increased frequency of creatine inclusions in the rat hippocampal formation following pilocarpine-induced seizures. Analytical and bioanalytical chemistry 402, 2267-2274 [PubMed:22038587] [show Abstract] In the present work, synchrotron radiation Fourier-transform infrared (SRFTIR) and Raman microspectroscopies were used to evaluate a possible role of creatine in the pathogenesis and progress of pilocarpine-evoked seizures and seizure-induced neurodegenerative changes in the rat hippocampal tissue. The main goal of this study was to identify creatine deposits within the examined brain area, to analyze their frequency in epileptic animals and naive controls and to examine correlations between the number of inclusions in the hippocampal formation of epileptic rats and the quantitative parameters describing animal behavior during 6-h observation period after pilocarpine injection. The presence of creatine in the brain tissue was confirmed based on the vibrational bands specific for this compound in the infrared and Raman spectra. These were the bands occurring at the wavenumbers around 2800, 1621, 1398, and 1304 cm(-1) in IR spectra and around 1056, 908 and 834 cm(-1) in the Raman spectra. Creatine was detected in eight of ten analyzed epileptic samples and in only one of six controls under the study. The number of deposits in epileptic animals varied from 1 to 100 and a relative majority of inclusions were detected in the area of the Dentate Gyrus and in the multiform hippocampal layer. Moreover, the number of creatine inclusions was positively correlated with the total time of seizure activity. | Orsenigo MN, Porta C, Sironi C, Laforenza U, Meyer G, Tosco M (2012) Effects of creatine in a rat intestinal model of ischemia/reperfusion injury. European journal of nutrition 51, 375-384 [PubMed:21698493] [show Abstract]
PurposeCreatine belongs to a buffering system of cellular ATP level and has been reported to display direct antioxidant activity. Aim of this work was to investigate whether creatine treatment could ameliorate the antioxidant response of intestinal cells and limit the oxidative injury induced by anoxia and subsequent reoxygenation.MethodsJejunal and ileal tracts of rat intestine were everted and incubated in vitro under normoxic, anoxic and reoxygenation conditions in the absence and in the presence of 10 mM creatine. (Na+, K+)-ATPase, γ-GT and antioxidant enzymes activities were determined in mucosal homogenate, as well as malondialdehyde production and HSP70 expression.ResultsBoth in jejunum and ileum, creatine treatment increases (Na+, K+)-ATPase activity; γ-GT is unaffected in jejunum but stimulated in ileum. In both tissues, creatine does not alter the antioxidant activities or malondialdehyde level. HSP70 expression is increased only in jejunum. Anoxic conditions stimulate antioxidant activities to a greater extent in jejunum compared to ileum; reoxygenation does not evoke further effects, but enhances malondialdehyde production in both tracts. The protective action of creatine, in reoxygenation, is more marked in jejunum as for its stimulation of antioxidant activities; however, in jejunum, a prooxidant action of creatine is suggested, since malondialdehyde production is enhanced by its presence; on the contrary in ileum, where HSP70 is overexpressed in reoxygenation, peroxidation level is significantly reduced.ConclusionsThe presence of creatine seems to potentiate the defensive response of both tissues, in jejunum by means of cell antioxidant equipment, in ileum by the involvement of HSP70. | Stimpson SA, Turner SM, Clifton LG, Poole JC, Mohammed HA, Shearer TW, Waitt GM, Hagerty LL, Remlinger KS, Hellerstein MK, Evans WJ (2012) Total-body creatine pool size and skeletal muscle mass determination by creatine-(methyl-D3) dilution in rats. Journal of applied physiology (Bethesda, Md. : 1985) 112, 1940-1948 [PubMed:22422801] [show Abstract] There is currently no direct, facile method to determine total-body skeletal muscle mass for the diagnosis and treatment of skeletal muscle wasting conditions such as sarcopenia, cachexia, and disuse. We tested in rats the hypothesis that the enrichment of creatinine-(methyl-d(3)) (D(3)-creatinine) in urine after a defined oral tracer dose of D(3)-creatine can be used to determine creatine pool size and skeletal muscle mass. We determined 1) an oral tracer dose of D(3)-creatine that was completely bioavailable with minimal urinary spillage and sufficient enrichment in the body creatine pool for detection of D(3)-creatine in muscle and D(3)-creatinine in urine, and 2) the time to isotopic steady state. We used cross-sectional studies to compare total creatine pool size determined by the D(3)-creatine dilution method to lean body mass determined by independent methods. The tracer dose of D(3)-creatine (<1 mg/rat) was >99% bioavailable with 0.2-1.2% urinary spillage. Isotopic steady state was achieved within 24-48 h. Creatine pool size calculated from urinary D(3)-creatinine enrichment at 72 h significantly increased with muscle accrual in rat growth, significantly decreased with dexamethasone-induced skeletal muscle atrophy, was correlated with lean body mass (r = 0.9590; P < 0.0001), and corresponded to predicted total muscle mass. Total-body creatine pool size and skeletal muscle mass can thus be accurately and precisely determined by an orally delivered dose of D(3)-creatine followed by the measurement of D(3)-creatinine enrichment in a single urine sample and is promising as a noninvasive tool for the clinical determination of skeletal muscle mass. | Braissant O (2012) Creatine and guanidinoacetate transport at blood-brain and blood-cerebrospinal fluid barriers. Journal of inherited metabolic disease 35, 655-664 [PubMed:22252611] [show Abstract] While it was thought that most of cerebral creatine is of peripheral origin, AGAT and GAMT are well expressed in CNS where brain cells synthesize creatine. While the creatine transporter SLC6A8 is expressed by microcapillary endothelial cells (MCEC) at blood-brain barrier (BBB), it is absent from their surrounding astrocytes. This raised the concept that BBB has a limited permeability for peripheral creatine, and that the brain supplies a part of its creatine by endogenous synthesis. This review brings together the latest data on creatine and guanidinoacetate transport through BBB and blood-CSF barrier (BCSFB) with the clinical evidence of AGAT-, GAMT- and SLC6A8-deficient patients, in order to delineate a clearer view on the roles of BBB and BCSFB in the transport of creatine and guanidinoacetate between periphery and CNS, and on brain synthesis and transport of creatine. It shows that in physiological conditions, creatine is taken up by CNS from periphery through SLC6A8 at BBB, but in limited amounts, and that CNS also needs its own creatine synthesis. No uptake of guanidinoacetate from periphery occurs at BBB except under GAMT deficiency, but a net exit of guanidinoacetate seems to occur from CSF to blood at BCSFB, predominantly through the taurine transporter TauT. | Valayannopoulos V, Boddaert N, Chabli A, Barbier V, Desguerre I, Philippe A, Afenjar A, Mazzuca M, Cheillan D, Munnich A, de Keyzer Y, Jakobs C, Salomons GS, de Lonlay P (2012) Treatment by oral creatine, L-arginine and L-glycine in six severely affected patients with creatine transporter defect. Journal of inherited metabolic disease 35, 151-157 [PubMed:21660517] [show Abstract]
BackgroundX-linked cerebral creatine deficiency is caused by the deficiency of the creatine transporter (CTP) encoded by the SLC6A8 gene.Patients and methodsWe report here a series of six patients with severe CTP deficiency, four males and two females; clinical presentations include mild to severe mental retardation (6/6), associated with psychiatric symptoms (5/6: autistic behaviour, chronic hallucinatory psychosis), seizures (2/6) and muscular symptoms (2/4 males). Diagnosis was suspected upon elevated urinary creatine/creatinine (except in one of the female patients) and on a markedly decreased creatine peak on magnetic resonance spectroscopy (MRS). Diagnosis was confirmed by molecular analysis that identified four novel mutations not reported so far, including a mutation found twice in two male patients. All patients were treated successively and according to the same protocol by creatine alone then combined to its precursors, L-glycine and L-arginine for 42 months.Results and conclusionIn our patients, creatine supplementation alone or with its precursors L-glycine and L-arginine showed benefit only in the muscular symptoms of the disease and no improvement in the cognitive and psychiatric manifestations and did not modify brain creatine content on MRS of male and female CTP deficient patients. New treatment strategies are required including creatine derivatives transported independently from CTP or using alternative pathways and transporters. | van de Kamp JM, Pouwels PJ, Aarsen FK, ten Hoopen LW, Knol DL, de Klerk JB, de Coo IF, Huijmans JG, Jakobs C, van der Knaap MS, Salomons GS, Mancini GM (2012) Long-term follow-up and treatment in nine boys with X-linked creatine transporter defect. Journal of inherited metabolic disease 35, 141-149 [PubMed:21556832] [show Abstract] The creatine transporter (CRTR) defect is a recently discovered cause of X-linked intellectual disability for which treatment options have been explored. Creatine monotherapy has not proved effective, and the effect of treatment with L-arginine is still controversial. Nine boys between 8 months and 10 years old with molecularly confirmed CRTR defect were followed with repeated (1)H-MRS and neuropsychological assessments during 4-6 years of combination treatment with creatine monohydrate, L-arginine, and glycine. Treatment did not lead to a significant increase in cerebral creatine content as observed with H(1)-MRS. After an initial improvement in locomotor and personal-social IQ subscales, no lasting clinical improvement was recorded. Additionally, we noticed an age-related decline in IQ subscales in boys affected with the CRTR defect. | Berti SL, Nasi GM, Garcia C, Castro FL, Nunes ML, Rojas DB, Moraes TB, Dutra-Filho CS, Wannmacher CM (2012) Pyruvate and creatine prevent oxidative stress and behavioral alterations caused by phenylalanine administration into hippocampus of rats. Metabolic brain disease 27, 79-89 [PubMed:22101931] [show Abstract] Phenylketonuria is characterized by a variable degree of mental retardation and other neurological features whose mechanisms are not fully understood. In the present study we investigated the effect of intrahippocampal administration of phenylalanine, isolated or associated with pyruvate or creatine, on rat behavior and on oxidative stress. Sixty-day-old male Wistar rats were randomly divided into 6 groups: saline; phenylalanine; pyruvate; creatine; phenylalanine + pyruvate; phenylalanine + creatine. Phenylalanine was administered bilaterally in the hippocampus one hour before training; pyruvate, at the same doses, was administered in the hippocampus one hour before phenylalanine; creatine was administered intraperitoneally twice a day for 5 days before training; controls received saline solution at same volumes than the other substances. Parameters of exploratory behavior and of emotionality were assessed in both training and test sessions in the open field task. Rats receiving phenylalanine did not habituate to the open field along the sessions, indicating deficit of learning/memory, but parameters of emotionality were normal, not interfering in the habituation process. Pyruvate or creatine administration prevented the lack of habituation caused by phenylalanine. Pyruvate and creatine also prevented alterations provoked by phenylalanine on lipid peroxidation, total content of sulfhydryls, total radical-trapping antioxidant potential and total antioxidant reactivity. The results suggest that the behavioral alterations provoked by intra-hippocampal administration of phenylalanine may be caused, at least in part, by oxidative stress and/or energy deficit. If this also occurs in PKU, it is possible that pyruvate and creatine supplementation to the phenylalanine-restricted diet might be beneficial to phenylketonuric patients. | Ndika JD, Johnston K, Barkovich JA, Wirt MD, O'Neill P, Betsalel OT, Jakobs C, Salomons GS (2012) Developmental progress and creatine restoration upon long-term creatine supplementation of a patient with arginine:glycine amidinotransferase deficiency. Molecular genetics and metabolism 106, 48-54 [PubMed:22386973] [show Abstract]
BackgroundArginine:glycineamidinotransferase (AGAT/GATM) deficiency has been described in 9 patients across 4 families. Here we describe the clinical outcome and response to creatine supplementation in a patient of the second family affected with AGAT deficiency-a 9-year-old girl.Patient and methodsDelayed motor milestones were noticed from 4 months of age and at 14 months moderate hypotonia, developmental delay and failure to thrive. Laboratory studies revealed low plasma creatine as well as extremely low levels of guanidinoacetic acid in urine and plasma. Proton magnetic resonance spectroscopy (MRS) of the brain showed absence of creatine. DNA sequence analysis revealed a homozygous mutation (c.484+1G>T) in the AGAT/GATM gene. AGAT activity was not detectable in lymphoblasts and RNA analysis revealed a truncated mRNA (r.289_484del196) that is degraded via Nonsense Mediated Decay. At 16 months, Bayley's Infant Development Scale (BIDS) showed functioning at 43% of chronologic age. Oral creatine supplementation (up to 800 mg/kg/day) was begun.ResultsAt age 9 years she demonstrated advanced academic performance. Partial recovery of cerebral creatine levels was demonstrated on MRS at 25 months of age. Brain MRS at 40 months of age revealed a creatine/NAA ratio of about 80% of that in age-matched controls.Conclusions8 years post initiation of oral creatine supplementation, patient demonstrates superior nonverbal and academic abilities, with average verbal skills. We emphasize that early diagnosis combined with early treatment onset of AGAT deficiency may lead to improvement of developmental outcome. | Shen H, Goldberg MP (2012) Creatine pretreatment protects cortical axons from energy depletion in vitro. Neurobiology of disease 47, 184-193 [PubMed:22521466] [show Abstract] Creatine is a natural nitrogenous guanidino compound involved in bioenergy metabolism. Although creatine has been shown to protect neurons of the central nervous system (CNS) from experimental hypoxia/ischemia, it remains unclear if creatine may also protect CNS axons, and if the potential axonal protection depends on glial cells. To evaluate the direct impact of creatine on CNS axons, cortical axons were cultured in a separate compartment from their somas and proximal neurites using a modified two-compartment culture device. Axons in the axon compartment were subjected to acute energy depletion, an in vitro model of white matter ischemia, by exposure to 6mM sodium azide for 30 min in the absence of glucose and pyruvate. Energy depletion reduced axonal ATP by 65%, depolarized axonal resting potential, and damaged 75% of axons. Application of creatine (10 mM) to both compartments of the culture at 24h prior to energy depletion significantly reduced axonal damage by 50%. In line with the role of creatine in the bioenergy metabolism, this application also alleviated the axonal ATP loss and depolarization. Inhibition of axonal depolarization by blocking sodium influx with tetrodotoxin also effectively reduced the axonal damage caused by energy depletion. Further study revealed that the creatine effect was independent of glial cells, as axonal protection was sustained even when creatine was applied only to the axon compartment (free from somas and glial cells) for as little as 2h. In contrast, application of creatine after energy depletion did not protect axons. The data provide the first evidence that creatine pretreatment may directly protect CNS axons from energy deficiency. | Allen PJ (2012) Creatine metabolism and psychiatric disorders: Does creatine supplementation have therapeutic value? Neuroscience and biobehavioral reviews 36, 1442-1462 [PubMed:22465051] [show Abstract] Athletes, body builders, and military personnel use dietary creatine as an ergogenic aid to boost physical performance in sports involving short bursts of high-intensity muscle activity. Lesser known is the essential role creatine, a natural regulator of energy homeostasis, plays in brain function and development. Creatine supplementation has shown promise as a safe, effective, and tolerable adjunct to medication for the treatment of brain-related disorders linked with dysfunctional energy metabolism, such as Huntington's Disease and Parkinson's Disease. Impairments in creatine metabolism have also been implicated in the pathogenesis of psychiatric disorders, leaving clinicians, researchers and patients alike wondering if dietary creatine has therapeutic value for treating mental illness. The present review summarizes the neurobiology of the creatine-phosphocreatine circuit and its relation to psychological stress, schizophrenia, mood and anxiety disorders. While present knowledge of the role of creatine in cognitive and emotional processing is in its infancy, further research on this endogenous metabolite has the potential to advance our understanding of the biological bases of psychopathology and improve current therapeutic strategies. | Garcia P, Rodrigues F, Valongo C, Salomons GS, Diogo L (2012) Phenotypic variability in a portuguese family with x-linked creatine transport deficiency. Pediatric neurology 46, 39-41 [PubMed:22196490] [show Abstract] Cerebral creatine transporter deficiency, attributable to mutations in the SLC6A8 gene, causes X-linked mental retardation, language delay, epilepsy, and autistic features. In contrast with creatine synthesis defects, the vast majority of patients with SLC6A8 deficiency do not respond to treatment. We describe a Portuguese family with a mutation (c.456C>T; p.Gln486X) in the SL6CA8 gene: two adult monozygotic twin brothers, with psychomotor delay and severe speech impairment. The family also includes their maternal half-sister with psychomotor retardation, predominantly in language, and their mentally retarded mother. This family illustrates the remarkable phenotypic variability in this condition. Investigation of creatine metabolism is mandatory in patients with developmental delay of unknown etiology, to detect this condition. | Allen PJ, D'Anci KE, Kanarek RB, Renshaw PF (2012) Sex-specific antidepressant effects of dietary creatine with and without sub-acute fluoxetine in rats. Pharmacology, biochemistry, and behavior 101, 588-601 [PubMed:22429992] [show Abstract] The potential role of metabolic impairments in the pathophysiology of depression is motivating researchers to evaluate the treatment efficacy of creatine, a naturally occurring energetic and neuroprotective compound found in brain and muscle tissues. Growing evidence is demonstrating the benefit of oral creatine supplements for reducing depressive symptoms in humans and animals. A novel question is whether dietary creatine, when combined with antidepressant drug therapy, would be more effective than either compound alone. To answer this question, four studies were conducted to investigate the behavioral effects of combined creatine and low-dose fluoxetine treatment using the forced swim test in male and female rats. Sprague-Dawley rats were fed powdered rodent chow supplemented with 0%, 2% or 4% w/w creatine monohydrate for 5 weeks. Rats were injected with fluoxetine (5.0 or 10.0 mg/kg) or saline according to a sub-acute dosing schedule. Female rats maintained on a 4% creatine diet displayed antidepressant-like effects compared to non-supplemented females prior to fluoxetine treatment. In contrast, creatine did not alter behavior reliably in males. Following drug treatment and a second forced swim trial, the antidepressant-like profile of creatine remained significant only in females co-administered 5.0 mg/kg fluoxetine. Moreover, in females only, supplementation with 4% creatine produced a more robust antidepressant-like behavioral profile compared to either dose of fluoxetine alone. Estrous cycle data indicated that ovarian hormones influenced the antidepressant-like effects of creatine. Addressing the issue of sex differences in response to treatment may affect our understanding of creatine, its relationship with depressive behavior, and may lead to sex-specific therapeutic strategies. | Genius J, Geiger J, Bender A, Möller HJ, Klopstock T, Rujescu D (2012) Creatine protects against excitoxicity in an in vitro model of neurodegeneration. PloS one 7, e30554 [PubMed:22347384] [show Abstract] Creatine has been shown to be neuroprotective in aging, neurodegenerative conditions and brain injury. As a common molecular background, oxidative stress and disturbed cellular energy homeostasis are key aspects in these conditions. Moreover, in a recent report we could demonstrate a life-enhancing and health-promoting potential of creatine in rodents, mainly due to its neuroprotective action. In order to investigate the underlying pharmacology mediating these mainly neuroprotective properties of creatine, cultured primary embryonal hippocampal and cortical cells were challenged with glutamate or H(2)O(2). In good agreement with our in vivo data, creatine mediated a direct effect on the bioenergetic balance, leading to an enhanced cellular energy charge, thereby acting as a neuroprotectant. Moreover, creatine effectively antagonized the H(2)O(2)-induced ATP depletion and the excitotoxic response towards glutamate, while not directly acting as an antioxidant. Additionally, creatine mediated a direct inhibitory action on the NMDA receptor-mediated calcium response, which initiates the excitotoxic cascade. Even excessive concentrations of creatine had no neurotoxic effects, so that high-dose creatine supplementation as a health-promoting agent in specific pathological situations or as a primary prophylactic compound in risk populations seems feasible. In conclusion, we were able to demonstrate that the protective potential of creatine was primarily mediated by its impact on cellular energy metabolism and NMDA receptor function, along with reduced glutamate spillover, oxidative stress and subsequent excitotoxicity. | Shariff MI, Ladep NG, Cox IJ, Williams HR, Okeke E, Malu A, Thillainayagam AV, Crossey MM, Khan SA, Thomas HC, Taylor-Robinson SD (2010) Characterization of urinary biomarkers of hepatocellular carcinoma using magnetic resonance spectroscopy in a Nigerian population. Journal of proteome research 9, 1096-1103 [PubMed:19968328] [show Abstract] Hepatocellular carcinoma (HCC) is the commonest primary hepatic malignancy worldwide. Current serum diagnostic biomarkers, such as alpha-fetoprotein, are expensive and insensitive in early tumor diagnosis. Urinary biomarkers differentiating HCC from chronic liver disease would be practical and widely applicable. Using an 11.7T nuclear magnetic resonance system, urine was analyzed from three well-matched subject groups, collected at Jos University Teaching Hospital (JUTH), Nigeria. Multivariate factor analyses were performed using principal components analysis (PCA) and partial least-squares discriminant analysis (PLS-DA). All patients were of Nigerian descent: 18 hepatitis B surface antigen (HBsAg)-positive patients with HCC, 10 HBsAg positive patients with cirrhosis, and 15 HBsAg negative healthy Nigerian controls. HCC patients were distinguished from healthy controls, and from the cirrhosis cohort, with sensitivity/specificity of 100%/93% and 89.5%/88.9%, respectively. Metabolites that most strongly contributed to the multivariate models were creatinine, carnitine, creatine and acetone. Urinary (1)H MRS with multivariate statistical analysis was able to differentiate patients with HCC from normal subjects and patients with cirrhosis. Creatinine, carnitine, creatine and acetone were identified as the most influential metabolites. These findings have identified candidate urinary HCC biomarkers which have potential to be developed as simple urinary screening tests for the clinic. | Sakkas GK, Schambelan M, Mulligan K (2009) Can the use of creatine supplementation attenuate muscle loss in cachexia and wasting? Current opinion in clinical nutrition and metabolic care 12, 623-627 [PubMed:19741514] [show Abstract]
Purpose of reviewWeight loss and low BMI due to an underlying illness have been associated with increased mortality, reduced functional capacity, and diminished quality of life. There is a need for well tolerated, long-term approaches to maintain body weight in patients with cachexia or wasting. The purpose of this review is to highlight the scientific and clinical evidence derived from the recent literature investigating the rationale for and potential medical use of creatine supplementation in patients with cachexia or wasting.Recent findingsSome studies have demonstrated that supplementation with creatine can increase creatine reserves in skeletal muscle and increase muscle mass and performance in various disease states that affect muscle size and function. The mechanisms underlying these effects are not clear. It has been suggested that creatine supplementation may increase intramuscular phosphocreatine stores and promote more rapid recovery of adenosine triphosphate levels following exercise, thus allowing users to exercise for longer periods or at higher intensity levels. Other hypothesized mechanisms include attenuation of proinflammatory cytokines, stimulation of satellite cell proliferation and upregulation of genes that promote protein synthesis and cell repair.SummaryCreatine is a generally well tolerated, low-cost, over-the-counter nutritional supplement that shows potential in improving lean body mass and functionality in patients with wasting diseases. However, placebo-controlled studies have shown variable effects, with improvements in some and not in others. Additional studies with longer follow-up are required to identify the populations that might benefit most from creatine supplementation. | Jahangir E, Vita JA, Handy D, Holbrook M, Palmisano J, Beal R, Loscalzo J, Eberhardt RT (2009) The effect of L-arginine and creatine on vascular function and homocysteine metabolism. Vascular medicine (London, England) 14, 239-248 [PubMed:19651674] [show Abstract] Studies with L-arginine supplementation have shown inconsistent effects on endothelial function. The generation of guanidinoacetate (GAA) from L-arginine with subsequent formation of creatine and homocysteine and consumption of methionine may reduce the pool of L-arginine available for nitric oxide generation. Experimental studies suggest that creatine supplementation might block this pathway. We sought to determine the effects of L-arginine, creatine, or the combination on endothelium-dependent vasodilation and homocysteine metabolism in patients with coronary artery disease. Patients with coronary artery disease were randomized to L-arginine (9 g/day), creatine (21 g/day), L-arginine plus creatine, or placebo for 4 days (n = 26-29/group). Brachial artery flow-mediated dilation and plasma levels of L-arginine, creatine, homocysteine, methionine, and GAA were measured at baseline and follow-up. L-arginine and creatine supplementation had no effects on vascular function. L-arginine alone increased GAA (p < 0.01) and the ratio of homocysteine to methionine (p < 0.01), suggesting increased methylation demand. The combination of creatinine and L-arginine did not suppress GAA production or prevent the increase in homocysteine-to-methionine ratio. Unexpectedly, creatine supplementation (alone or in combination with L-arginine) was associated with an 11-20% increase in homocysteine concentration (p < 0.05), which was not attributable to worsened renal function, providing evidence against an effect of creatine on decreasing methylation demand. In conclusion, the present study provides no evidence that L-arginine supplementation improves endothelial function and suggests that l-arginine may increase methylation demand. Creatine supplementation failed to alter the actions of L-arginine on vascular function or suppress methylation demand. The unexpected increase in homocysteine levels following creatine supplementation could have adverse effects and merits further study, since creatine is a commonly used dietary supplement. | Sartorius A, Lugenbiel P, Mahlstedt MM, Ende G, Schloss P, Vollmayr B (2008) Proton magnetic resonance spectroscopic creatine correlates with creatine transporter protein density in rat brain. Journal of neuroscience methods 172, 215-219 [PubMed:18555535] [show Abstract] Creatine (Cr) is an amino acid, which upon phosphorylation is utilized as an energy reservoir in cells with high-energy demand. The ongoing catabolism of creatine to creatinine requires a permanent creatine replenishment into the cells. Because neurons themselves cannot synthesize creatine, they have to take it up via the creatine transporter (CrT). Thus, the concentration of intracellular Cr available for the Cr/PCr shuttle system depends on the expression level of CrT protein. The proton magnetic resonance spectroscopy (MRS) creatine peak (total creatine=tCr) constitutes of two metabolites, namely Cr and phosphocreatine (PCr). We have quantified the level of CrT protein expression with western blotting and compared it to tCr content as estimated by in vitro MRS in Sprague-Dawley rats. Under the assumption of hemispheric symmetry, we took identical samples from left and right hemisphere, which were used for in vitro MRS (tCr) and for western blotting (CrT), respectively. Altogether, it was possible to take 90 corresponding brain samples from 31 animals. A Pearson linear regression analysis for CrT and tCr revealed p<0.0001, explaining 14% of the variance. Since MR-detectable alterations of tCr in the human brain are widespread (e.g. in most major psychiatric disorders proton MRS detectable tCr alterations have been described as regionally and usually state dependent) it is stringent to elucidate their meaning. An influence of tCr on the brain's energy regulating system seems plausible. | Gipson GT, Tatsuoka KS, Ball RJ, Sokhansanj BA, Hansen MK, Ryan TE, Hodson MP, Sweatman BC, Connor SC (2008) Multi-platform investigation of the metabolome in a leptin receptor defective murine model of type 2 diabetes. Molecular bioSystems 4, 1015-1023 [PubMed:19082141] [show Abstract] We describe a multi-platform ((1)H NMR, LC-MS, microarray) investigation of metabolic disturbances associated with the leptin receptor defective (db/db) mouse model of type 2 diabetes using novel assignment methodologies. For the first time, several urinary metabolites were found to be associated with diabetes and/or diabetes progression and confirmed in both NMR and LC-MS datasets. The confirmed metabolites were trimethylamine-n-oxide (TMAO), creatine, carnitine, and phenylalanine. TMAO and phenylalanine were both elevated in db/db mice and decreased in these mice with age. Levels of both creatine and carnitine increase in diabetic mice with age and creatine was also significantly decreased in db/db mice. Additionally, many metabolic markers were found by either NMR or LC-MS, but could not be found in both, due to instrumental limitations. This indicates that the combined use of NMR and LC-MS instrumentation provides complementary information that would be otherwise unattainable. Pathway analyses of urinary metabolites and liver, muscle, and adipose tissue transcripts from the db/db model were also performed to identify altered biochemical processes in the diabetic mice. Metabolite and liver transcript levels associated with the TCA cycle and steroid processes were altered in db/db mice. In addition, gene expression in muscle and liver associated with fatty acid processing was altered in the diabetic mice and similar evidence was observed in the LC-MS data. Our findings highlight the importance of a number of processes known to be associated with diabetes and reveal tissue specific responses to the condition. When studying metabolic disorders such as diabetes, multiple platform integrated profiling of metabolite alterations in biofluids can provide important insights into the processes underlying the disease. | Bender A, Beckers J, Schneider I, Hölter SM, Haack T, Ruthsatz T, Vogt-Weisenhorn DM, Becker L, Genius J, Rujescu D, Irmler M, Mijalski T, Mader M, Quintanilla-Martinez L, Fuchs H, Gailus-Durner V, de Angelis MH, Wurst W, Schmidt J, Klopstock T (2008) Creatine improves health and survival of mice. Neurobiology of aging 29, 1404-1411 [PubMed:17416441] [show Abstract] The supplementation of creatine (Cr) has a marked neuroprotective effect in mouse models of neurodegenerative diseases. This has been assigned to the known bioenergetic, anti-apoptotic, anti-excitotoxic, and anti-oxidant properties of Cr. As aging and neurodegeneration share pathophysiological pathways, we investigated the effect of oral Cr supplementation on aging in 162 aged C57Bl/6J mice. Outcome variables included "healthy" life span, neurobehavioral phenotyping, as well as morphology, biochemistry, and expression profiling from brain. The median healthy life span of Cr-fed mice was 9% higher than in control mice, and they performed significantly better in neurobehavioral tests. In brains of Cr-treated mice, there was a trend towards a reduction of reactive oxygen species and significantly lower accumulation of the "aging pigment" lipofuscin. Expression profiling showed an upregulation of genes implicated in neuronal growth, neuroprotection, and learning. These data show that Cr improves health and longevity in mice. Cr may be a promising food supplement to promote healthy human aging. | Salek RM, Maguire ML, Bentley E, Rubtsov DV, Hough T, Cheeseman M, Nunez D, Sweatman BC, Haselden JN, Cox RD, Connor SC, Griffin JL (2007) A metabolomic comparison of urinary changes in type 2 diabetes in mouse, rat, and human. Physiological genomics 29, 99-108 [PubMed:17190852] [show Abstract] Type 2 diabetes mellitus is the result of a combination of impaired insulin secretion with reduced insulin sensitivity of target tissues. There are an estimated 150 million affected individuals worldwide, of whom a large proportion remains undiagnosed because of a lack of specific symptoms early in this disorder and inadequate diagnostics. In this study, NMR-based metabolomic analysis in conjunction with multivariate statistics was applied to examine the urinary metabolic changes in two rodent models of type 2 diabetes mellitus as well as unmedicated human sufferers. The db/db mouse and obese Zucker (fa/fa) rat have autosomal recessive defects in the leptin receptor gene, causing type 2 diabetes. 1H-NMR spectra of urine were used in conjunction with uni- and multivariate statistics to identify disease-related metabolic changes in these two animal models and human sufferers. This study demonstrates metabolic similarities between the three species examined, including metabolic responses associated with general systemic stress, changes in the TCA cycle, and perturbations in nucleotide metabolism and in methylamine metabolism. All three species demonstrated profound changes in nucleotide metabolism, including that of N-methylnicotinamide and N-methyl-2-pyridone-5-carboxamide, which may provide unique biomarkers for following type 2 diabetes mellitus progression. | Kley RA, Vorgerd M, Tarnopolsky MA (2007) Creatine for treating muscle disorders. The Cochrane database of systematic reviewsCD004760 [PubMed:17253521] [show Abstract]
BackgroundProgressive muscle weakness is a main symptom of most hereditary muscle diseases. Creatine is a popular nutritional supplement among athletes. It improves muscle performance in healthy individuals and might be helpful for treating myopathies.ObjectivesTo evaluate the efficacy of oral creatine supplementation in muscle diseases.Search strategyWe searched the Cochrane Neuromuscular Disease Group Register in May 2004 for randomised trials using the search term 'creatine'. We also searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2005) using the same search term. We adapted this strategy to search MEDLINE (PubMed, from January 1966 to September 2005) and EMBASE (from January 1980 to May 2004). We reviewed the bibliographies of the randomised trials identified, contacted the authors and known experts in the field and approached pharmaceutical companies to identify additional published or unpublished data.Selection criteriaTypes of studies: randomised or quasi-randomised controlled trials.Types of participantspeople of all ages with hereditary muscle disease. Types of intervention: any creatine supplementation of at least 0.03 g/kg body weight/day.Primary outcome measurechange in muscle strength measured by quantitative muscle testing.Secondary outcome measureschange in muscle strength measured by manual muscle testing, change in energy parameters assessed by 31 phosphorous spectroscopy, change in muscle mass or a surrogate for muscle mass, adverse events.Data collection and analysisTwo authors independently applied the selection criteria, assessed trial quality and extracted data. Some missing data were obtained from investigators.Main resultsTwelve trials, including 266 participants, met the selection criteria. One trial compared creatine and glutamine treatment with placebo. In trials with 138 participants with muscular dystrophies treated with creatine, there was a significant increase in maximum voluntary contraction in the creatine group compared to placebo, with a weighted mean difference of 8.47% (95% confidence intervals 3.55 to 13.38). There was also an increase in lean body mass during creatine treatment compared to placebo (weighted mean difference 0.63 kg, 95% confidence intervals 0.02 to 1.25). No trial reported any clinically relevant adverse event. In trials with 33 participants with metabolic myopathies treated with creatine, there was no significant difference in maximum voluntary contraction between the creatine and placebo group (weighted mean difference -2.26%, confidence intervals -6.29 to 1.78). One trial reported a significant increase in muscle pain during high-dose creatine treatment (150 mg/kg body weight) in glycogen storage disease type V.Authors' conclusionsEvidence from randomised controlled trials shows that short- and medium-term creatine treatment improves muscle strength in people with muscular dystrophies, and is well-tolerated. Evidence from randomised controlled trials does not show significant improvement in muscle strength in metabolic myopathies. High-dose creatine in glycogenosis type V increased muscle pain. | Burguera EF, Love BJ (2006) Reduced transglutaminase-catalyzed protein aggregation is observed in the presence of creatine using sedimentation velocity. Analytical biochemistry 350, 113-119 [PubMed:16445883] [show Abstract] Transglutaminases (TGases) are enzymes that catalyze covalent isopeptide crosslinks between reactive lysine and glutamine residues in proteins. Higher than normal local concentrations of TGase have been correlated with increased protein aggregation in vivo. These insoluble protein aggregates are the hallmark of several neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's diseases, although each aggregating protein involved is disease specific. Because TGase is implicated in protein aggregation, there is evidence that its regulation may retard disease progression. Here we report on a laser light transmission technique as an in vitro tool to gauge the efficacy of creatine, a candidate inhibitor, to regulate aggregation. Sedimentation velocities of protein-coated particles in TGase-containing water-glycerol solutions were tracked with different levels of creatine. Sedimentation velocities were converted to apparent aggregate sizes using Stoke's law of sedimentation. The results indicated that creatine promoted up to a 20% reduction in protein aggregation in vitro. This technique may prove to be useful in identifying other functional TGase inhibitors. | Gao F, Bottomley PA, Arnold C, Weiss RG (2003) The effect of orientation on quantification of muscle creatine by 1H MR spectroscopy. Magnetic resonance imaging 21, 561-566 [PubMed:12878267] [show Abstract] Creatine is a central energy metabolite whose N-CH3 group can be detected with 1H MR spectroscopy (1H MRS) with relatively high sensitivity. Prior studies suggest that muscle fiber orientation can influence the appearance of other resonances attributed to total creatine (CR). Our purpose was to determine whether muscle fiber orientation affects muscle CR concentration quantification by 1H MRS with the commonly used N-CH3 resonance at 3.0 ppm. Skeletal muscle CR was quantified with water-referenced 1H MRS in normal subjects with different forearm muscle orientations relative to the static magnetic field at 1.5T. There were no significant differences in mean total [CR] in two different series of experiments separately including two orthogonal orientations and four orientations (0 degrees, 30 degrees, 60 degrees, 90 degrees) of the forearm relative to the static field using either short (TE = 15 ms) or long (TE = 100 ms) echo times for voxels containing or centered on the same tissues. Subtle differences in CR line-width and T2 correction factors were observed with orientation. These observations are consistent with the primary hypothesis that careful water-referenced [CR] quantification, accounting for T2 effects and using the N-CH3 peak at 3.0ppm, is not affected by muscle orientation. | Mendes RR, Tirapegui J (2002) [Creatine: the nutritional supplement for exercise - current concepts]. Archivos latinoamericanos de nutricion 52, 117-127 [PubMed:12184144] [show Abstract] Creatine, a natural nutrient found in animal foods, is alleged to be an effective nutritional ergogenic aid to enhance sport or exercise performance. It may be formed in kidney and liver from arginina and glicina. Creatine may be delivered to the muscle, where it may combine readily with phosphate to form creatine phosphate, a high-energy phosphagen in the ATP-CP system, and is stored. The ATP-CP energy system is important for rapid energy production, such as in speed and power events. Approximately 120 g of creatine is found in a 70 kg male, 95% in the skeletal muscle. Total creatine exists in muscle as both free creatine (40%) and phosphocreatine (60%). It is only recently that a concerted effort has been undertaken to investigate its potential ergogenic effect relative to sport or exercise performance. It does appear that oral creatine monohydrate may increase muscle total creatine, including both free and phosphocreatine. Many, but not all studies suggest that creatine supplementation may enhance performance in high intensity, short-term exercise task that are dependent primarily on the ATP-CP energy system, particularly on laboratory test involving repeated exercise bouts with limited recovery time between repetitions. Short-term creatine supplementation appears to increase body mass, although the initial increase is most likely water associated with the osmotic effect of increased intramuscular total creatine. Chronic creatine supplementation in conjunction with physical training involving resistance exercise may increase muscle mass. However, confirmatory research data are needed. Creatine supplementation up to 8 weeks, with high doses, has not been associated with major health risks; with low doses, it was demonstrated that in 5 years period supplementation, there are no adverse effects. The decision to use creatine as a mean to enhance sport performance is left to the description to the individual athlete. | Davydov VV, Shvets VN, Shvets VN (2002) Adenine nucleotide and creatine phosphate pool in adult and old rat heart during immobilization stress. Gerontology 48, 81-83 [PubMed:11867929] [show Abstract]
BackgroundDisturbances in the heart energy provision is important in the stress-induced injury of myocardium. In order to learn the causes of age-dependent differences in myocardial sensitivity to stress, we determined the level of adenylates, creatine and creatine phosphate in adult and old rat heart during an immobilization stress.MethodsFifty male Wistar rats were used to study the myocardial adenine nucleotides, creatine and creatine phosphate pool and creatine kinase activity during an immobilization period.ResultsThe concentration of adenine nucleotides in old and adult rat hearts was similar. The total concentration of adenylate pool, ATP and ADP in the heart of both age groups was reduced during stress. However, in old rats under stress the concentration of ATP in a less measure and ADP in a greater measure is decreased against that observed in adult animals. The level of inorganic phosphate in old rat heart remains the same as in adult rats.ConclusionThe creatine kinase system may be important in stabilizing the ATP level in myocardium of adult rats during stress. The role of this system in heart energy metabolism during stress is decreased in old rats. Disturbances of isoenzyme creatine kinase activity are responsible for these disorders. | McGuine TA, Sullivan JC, Bernhardt DA (2002) Creatine supplementation in Wisconsin high school athletes. WMJ : official publication of the State Medical Society of Wisconsin 101, 25-30 [PubMed:12085493] [show Abstract]
BackgroundCreatine is a nutritional supplement used to enhance athletic performance in collegiate and professional athletes. There is increasing evidence that high school athletes are using creatine as well. The objective of this study was to describe patterns of creatine supplementation as well as the behaviors and beliefs associated with creatine use in high school athletes.Methods4011 high school student-athletes from 37 public high schools in Wisconsin took part in a cross-sectional, multi-site, anonymous, descriptive survey. Measurements included self-reported patterns of creatine use.Results16.7% of the athletes (25.3% males, 3.9% females) reported using creatine. Creatine use was lowest in the 9th grade (8.4%) and highest in the 12th grade (24.6%). The percentage of participants in each sport who used creatine varied considerably from 1.3% (female cross country) to 30.1% (football). Increased strength was the most likely perceived benefit of creatine supplementation, while dehydration was cited most often as a perceived risk of creatine use. Users were encouraged to take creatine most often by their friends while their parents discouraged its use.ConclusionDespite the lack of research regarding the efficacy or safety of creatine supplementation in high school athletes, creatine was used by 25% of males and 4% of female high school athletes in Wisconsin. High school athletes who use creatine may not be aware of the risks and benefits associated with creatine supplementation. Primary care providers and sports medicine professionals need to educate athletes, coaches and parents about the creatine use as a performance enhancing supplement. | Metzl JD, Small E, Levine SR, Gershel JC (2001) Creatine use among young athletes. Pediatrics 108, 421-425 [PubMed:11483809] [show Abstract]
ObjectiveCreatine is a nutritional supplement that is purported to be a safe ergogenic aid in adults. Although as many as 28% of collegiate athletes admit taking creatine, there is little information about creatine use or potential health risk in children and adolescents. Although the use of creatine is not recommended in people less than 18 years of age, numerous anecdotal reports indicate widespread use in young athletes. The purpose of this study was to determine the frequency, risk factors, and demographics of creatine use among middle and high school student athletes.MethodsBefore their annual sports preparticipation physical examinations, middle and high school athletes aged 10 to 18 in Westchester County, a suburb north of New York City, were surveyed in a confidential manner. Information was collected regarding school grade, gender, specific sport participation, and creatine use.ResultsOverall, 62 of 1103 participants (5.6%) admitted taking creatine. Creatine use was reported in every grade, from 6 to 12. Forty-four percent of grade 12 athletes surveyed reported using creatine. Creatine use was significantly more common (P <.001) among boys (53/604, 8.8%) than girls (9/492, 1.8%). Although creatine was taken by participants in every sport, use was significantly more common among football players, wrestlers, hockey players, gymnasts, and lacrosse players (P <.001 for all). The most common reasons cited for taking creatine were enhanced performance (74.2% of users) and improved appearance (61.3%), and the most common reason cited for not taking creatine was safety (45.7% of nonusers).ConclusionsDespite current recommendations against use in adolescents less than 18 years old, creatine is being used by middle and high school athletes at all grade levels. The prevalence in grades 11 and 12 approaches levels reported among collegiate athletes. Until the safety of creatine can be established in adolescents, the use of this product should be discouraged. | Persky AM, Brazeau GA (2001) Clinical pharmacology of the dietary supplement creatine monohydrate. Pharmacological reviews 53, 161-176 [PubMed:11356982] [show Abstract] Creatine is a dietary supplement purported to improve exercise performance and increase fat-free mass. Recent research on creatine has demonstrated positive therapeutic results in various clinical applications. The purpose of this review is to focus on the clinical pharmacology and therapeutic application of creatine supplementation. Creatine is a naturally occurring compound obtained in humans from endogenous production and consumption through the diet. When supplemented with exogenous creatine, intramuscular and cerebral stores of creatine and its phosphorylated form, phosphocreatine, become elevated. The increase of these stores can offer therapeutic benefits by preventing ATP depletion, stimulating protein synthesis or reducing protein degradation, and stabilizing biological membranes. Evidence from the exercise literature has shown athletes benefit from supplementation by increasing muscular force and power, reducing fatigue in repeated bout activities, and increasing muscle mass. These benefits have been applied to disease models of Huntington's, Parkinson's, Duchenne muscular dystrophy, and applied clinically in patients with gyrate atrophy, various neuromuscular disorders, McArdle's disease, and congestive heart failure. This review covers the basics of creatine synthesis and transport, proposed mechanisms of action, pharmacokinetics of exogenous creatine administration, creatine use in disease models, side effects associated with use, and issues on product quality. | Marescau B, De Deyn PP, Holvoet J, Possemiers I, Nagels G, Saxena V, Mahler C (1995) Guanidino compounds in serum and urine of cirrhotic patients. Metabolism: clinical and experimental 44, 584-588 [PubMed:7752905] [show Abstract] To investigate the metabolic relationship between urea and guanidinosuccinic acid (GSA), we determined the levels of the guanidino compounds, including GSA, and urea in serum and urine of cirrhotic patients. Linear correlation studies between serum urea and GSA levels were performed. Good positive linear correlation coefficients were found in the Child-Turcotte C subgroup (r = .847, P < .001) and in the total subgroup including B and C patients (r = .848; P < .0001). Serum guanidinoacetic acid levels were significantly increased in the Child-Turcotte C subgroup (P < .0001 for men and P < .001 for women). In contrast, GSA levels were significantly (P < .0001) decreased in the three studied subgroups. Similar results were found for urinary GSA excretion levels. Within each subgroup, serum and urinary GSA levels were significantly lower in patients with alcohol-induced cirrhosis than in nonalcoholic cirrhotic patients. Similar results were obtained for urea. The findings in cirrhotic patients clearly demonstrate a metabolic relationship between urea and GSA. They also show that urea and GSA biosynthesis is significantly lower in cirrhotic patients with an alcoholic origin than in cirrhotic patients with a nonalcoholic origin. |
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