Creatine and Creatinine Metabolism

F. Hoffmann-La Roche, Vitamins and Fine Chemicals Division, Basel, Switzerland.
Physiological Reviews (Impact Factor: 27.32). 08/2000; 80(3):1107-213.
Source: PubMed


The goal of this review is to present a comprehensive survey of the many intriguing facets of creatine (Cr) and creatinine metabolism, encompassing the pathways and regulation of Cr biosynthesis and degradation, species and tissue distribution of the enzymes and metabolites involved, and of the inherent implications for physiology and human pathology. Very recently, a series of new discoveries have been made that are bound to have distinguished implications for bioenergetics, physiology, human pathology, and clinical diagnosis and that suggest that deregulation of the creatine kinase (CK) system is associated with a variety of diseases. Disturbances of the CK system have been observed in muscle, brain, cardiac, and renal diseases as well as in cancer. On the other hand, Cr and Cr analogs such as cyclocreatine were found to have antitumor, antiviral, and antidiabetic effects and to protect tissues from hypoxic, ischemic, neurodegenerative, or muscle damage. Oral Cr ingestion is used in sports as an ergogenic aid, and some data suggest that Cr and creatinine may be precursors of food mutagens and uremic toxins. These findings are discussed in depth, the interrelationships are outlined, and all is put into a broader context to provide a more detailed understanding of the biological functions of Cr and of the CK system.

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    • "Levels of NAA, an ubiquitous molecular moiety, is often used to assess neuronal viability using in vivo 1 H MRSI. NAA is an amino acid considered reflective of neuronal density and functional integrity (Coplan et al., 2010). Cho increases have been interpreted to reflect increased cell membrane turnover (Duyn et al., 1993) and Cr is involved in energy-dependent brain function (Wyss and Kaddurah-Daouk, 2000). Cr decreases are presumably associated with an increase in metabolic activity (Coplan et al., 2006). "
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    ABSTRACT: Background: The rostral prefrontal cortex (RPFC) is involved in reflective thought processes such as self-knowledge and person perception. We hypothesized that childhood emotional abuse, which is disruptive of emotional regulation, would differentially impact neurometabolite concentrations of the RPFC, and related neocortical areas, in adults with generalized anxiety disorder (GAD) versus healthy controls. Methods: GAD patients (n=16; females=11) and medically healthy volunteers (n=16; F=10) were assessed using the Childhood Trauma Questionnaire (CTQ), specifically the emotional abuse category. Proton magnetic resonance spectroscopy imaging examined 3 regions of interest (ROI) from the most rostral slice from the Duyn et al. (1993) multivoxel imaging modality: rostral prefrontal cortex (BA 10,9), premotor cortex (BA 6,8) and secondary somatosensory and associated parietal cortex (BA 5,7). Metabolites included N-acetyl-aspartate, creatine, and choline. Results: GAD patients reported higher emotional abuse scores versus controls. An omnibus general linear model including 3 ROI, 3 metabolites, and laterality as dependent variables revealed a significant diagnosis by CTQ emotional abuse score interactive effect. In controls, all 3 ROI for all 3 metabolites on both sides demonstrated a significant inverse relationship with emotional abuse scores; none were significant in GAD patients. Limitations: A major limitation is the uneven distribution of emotional abuse scores between the controls and GAD patients, with GAD patients reporting higher scores. Conclusion: Unlike controls, GAD patients appear compromised in forming a molecular representation reflective of magnitude of childhood emotional abuse. The neurometabolites in GAD patients appear non-aligned to childhood emotional abuse, suggesting potential consequences for normative "theory of mind" processes and emotional function in certain anxiety disorders.
    Journal of Affective Disorders 11/2015; 190:414-423. DOI:10.1016/j.jad.2015.09.019 · 3.38 Impact Factor
    • "Irreversible methylation of GAA by guanidine N-methyltransferase (GNMT, EC utilizes s-adenosylmethionine (SAM) as the methyl donor and results in the formation of creatine and s-adenosylhomocysteine (SAH). In rats, AGAT is mainly expressed in the kidney and the GAMT is mainly localized in the liver resulting in an inter-organ synthesis of creatine (da Silva et al. 2009; Wyss and Kaddurah-Daouk 2000; Edison et al. 2007). The data in human are unclear, and a complete pathway for creatine synthesis may be present in the liver, pancreas, and possibly brain. "
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    ABSTRACT: Creatine kinetics were measured in young healthy subjects, eight males and seven females, age 20-30 years, after an overnight fast on creatine-free diet. Whole body turnover of glycine and its appearance in creatine was quantified using [1-(13)C] glycine and the rate of protein turnover was quantified using L-ring [(2)H5] phenylalanine. The creatine pool size was estimated by the dilution of a bolus [C(2)H3] creatine. Studies were repeated following a five days supplement creatine 21 and following supplement amino acids 14.3 g day(-1). Creatine caused a ten-fold increase in the plasma concentration of creatine and a 50 % decrease in the concentration of guanidinoacetic acid. Plasma amino acids profile showed a significant decrease in glycine, glutamine, and taurine and a significant increase in citrulline, valine, lysine, and cysteine. There was a significant decrease in the rate of appearance of glycine, suggesting a decrease in de-novo synthesis (p = 0.006). The fractional and absolute rate of synthesis of creatine was significantly decreased by supplemental creatine. Amino acid supplement had no impact on any of the parameters. This is the first detailed analysis of creatine kinetics and the effects of creatine supplement in healthy young men and women. These methods can be applied for the analysis of creatine kinetics in different physiological states.
    Amino Acids 10/2015; DOI:10.1007/s00726-015-2111-1 · 3.29 Impact Factor
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    • "565 There are four arginine:glycine amidinotransferases (AGAT-1, AGAT-2, AGAT-3, gatm) identified in 566 planarians. These enzymes catalyze the first step in creatine biosynthesis by transferring the amidino group 567 of arginine to glycine to yield ornithine and guanidinoacetic acid (Wyss, 2000). Creatine plays an important 568 role in muscle energy homeostasis. "
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    ABSTRACT: Neoblasts are an abundant, heterogeneous population of adult stem cells (ASCs) that facilitate the maintenance of planarian tissues and organs, providing a powerful system to study ASC self-renewal and differentiation dynamics. It is unknown how the collective output of neoblasts transit through differentiation pathways to produce specific cell types. The planarian epidermis is a simple tissue that undergoes rapid turnover. We found that as epidermal progeny differentiate, they progress through multiple spatiotemporal transition states with distinct gene expression profiles. We also identified a conserved early growth response family transcription factor, egr-5, that is essential for epidermal differentiation. Disruption of epidermal integrity by egr-5 RNAi triggers a global stress response that induces the proliferation of neoblasts and the concomitant expansion of not only epidermal, but also multiple progenitor cell populations. Our results further establish the planarian epidermis as a novel paradigm to uncover the molecular mechanisms regulating ASC specification in vivo.
    eLife Sciences 10/2015; 4. DOI:10.7554/eLife.10501 · 9.32 Impact Factor
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