title: Creatine biosynthesis and transport in health and disease.
abstract: Creatine is physiologically provided equally by diet and by endogenous synthesis from arginine and glycine with successive involvements of arginine glycine amidinotransferase [AGAT] and guanidinoacetate methyl transferase [GAMT]. A specific plasma membrane transporter, creatine transporter [CRTR] (SLC6A8), further enables cells to incorporate creatine and through uptake of its precursor, guanidinoacetate, also directly contributes to creatine biosynthesis. Breakthrough in the role of creatine has arisen from studies on creatine deficiency disorders. Primary creatine disorders are inherited as autosomal recessive (mutations affecting GATM [for glycine-amidinotransferase, mitochondrial]) and GAMT genes) or X-linked (SLC6A8 gene) traits. They have highlighted the role of creatine in brain functions altered in patients (global developmental delay, intellectual disability, behavioral disorders). Creatine modulates GABAergic and glutamatergic cerebral pathways, presynaptic CRTR (SLC6A8) ensuring re-uptake of synaptic creatine. Secondary creatine disorders, addressing other genes, have stressed the extraordinary imbrication of creatine metabolism with many other cellular pathways. This high dependence on multiple pathways supports creatine as a cellular sensor, to cell methylation and energy status. Creatine biosynthesis consumes 40% of methyl groups produced as S-adenosylmethionine, and creatine uptake is controlled by AMP activated protein kinase, a ubiquitous sensor of energy depletion. Today, creatine is considered as a potential sensor of cell methylation and energy status, a neurotransmitter influencing key (GABAergic and glutamatergic) CNS neurotransmission, therapeutic agent with anaplerotic properties (towards creatine kinases [creatine-creatine phosphate cycle] and creatine neurotransmission), energetic and antioxidant compound (benefits in degenerative diseases through protection against energy depletion and oxidant species) with osmolyte behavior (retention of water by muscle). This review encompasses all these aspects by providing an illustrated metabolic account for brain and body creatine in health and disease, an algorithm to diagnose metabolic and gene bases of primary and secondary creatine deficiencies, and a metabolic exploration by (1)H-MRS assessment of cerebral creatine levels and response to therapeutic measures.
authors.affiliation: Biochemistry and Molecular Biology, Hormonology-Metabolism-Nutrition & Oncology (HMNO), Center of Biology & Pathology (CBP) Pierre-Marie Degand, CHRU Lille, 59037 Lille, France; RADEME Research Team for Rare Metabolic and Developmental Diseases, EA 7364, Université Lille 2, Lille, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Joncquel-Chevalier Curt
authors.affiliation: Clinical Chemistry Laboratory, Dr Schaffner Hospital of Lens, 62307 Lens, France.
authors.forename: Pia-Manuela
authors.initials: PM
authors.lastname: Voicu
authors.affiliation: Biochemistry and Molecular Biology, Hormonology-Metabolism-Nutrition & Oncology (HMNO), Center of Biology & Pathology (CBP) Pierre-Marie Degand, CHRU Lille, 59037 Lille, France; RADEME Research Team for Rare Metabolic and Developmental Diseases, EA 7364, Université Lille 2, Lille, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Fontaine
authors.affiliation: Biochemistry and Molecular Biology, Hormonology-Metabolism-Nutrition & Oncology (HMNO), Center of Biology & Pathology (CBP) Pierre-Marie Degand, CHRU Lille, 59037 Lille, France.
authors.forename: Anne-Frédérique
authors.initials: AF
authors.lastname: Dessein
authors.affiliation: Biochemistry and Molecular Biology, Hormonology-Metabolism-Nutrition & Oncology (HMNO), Center of Biology & Pathology (CBP) Pierre-Marie Degand, CHRU Lille, 59037 Lille, France; Inserm, Lille, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Porchet
authors.affiliation: RADEME Research Team for Rare Metabolic and Developmental Diseases, EA 7364, Université Lille 2, Lille, France; Medical Reference Center for Inherited Metabolic Diseases, Jeanne de Flandres Hospital, CHRU Lille, 59037 Lille, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Mention-Mulliez
authors.affiliation: RADEME Research Team for Rare Metabolic and Developmental Diseases, EA 7364, Université Lille 2, Lille, France; Medical Reference Center for Inherited Metabolic Diseases, Jeanne de Flandres Hospital, CHRU Lille, 59037 Lille, France.
authors.forename: Dries
authors.initials: D
authors.lastname: Dobbelaere
authors.affiliation: Department of Neuroradiology, Roger Salengro Hospital, CHRU Lille, 59037 Lille, France.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Soto-Ares
authors.affiliation: Hospices Civils de Lyon, Service Maladies Héréditaires du Métabolisme et Dépistage Néonatal, Groupement Hospitalier Est, 69677 Bron, France; Lyon University, INSERM U1060, CarMeN Laboratory, University Lyon-1, INSA-Lyon, F-69600 Oullins, France.
authors.forename: David
authors.initials: D
authors.lastname: Cheillan
authors.affiliation: Biochemistry and Molecular Biology, Hormonology-Metabolism-Nutrition & Oncology (HMNO), Center of Biology & Pathology (CBP) Pierre-Marie Degand, CHRU Lille, 59037 Lille, France; RADEME Research Team for Rare Metabolic and Developmental Diseases, EA 7364, Université Lille 2, Lille, France; Inserm, Lille, France. Electronic address: joseph.vamecq@inserm.fr.
authors.forename: Joseph
authors.initials: J
authors.lastname: Vamecq
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000579:Amidinotransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D026923:Amino Acid Transport Systems, Basic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active; D020739:Brain Diseases, Metabolic, Inborn / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D003401:Creatine / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002658:Developmental Disabilities / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism; D050937:Guanidinoacetate N-Methyltransferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015799:Gyrate Atrophy / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D006801:Humans; D022124:Hyperammonemia / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D008607:Intellectual Disability / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D007805:Language Development Disorders / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D038901:X-Linked Intellectual Disability / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D033681:Mitochondrial Membrane Transport Proteins; D009069:Movement Disorders / Q000151:congenital / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009952:Ornithine / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011296:Prenatal Diagnosis; D012436:S-Adenosylmethionine / Q000378:metabolism; D013064:Speech Disorders / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D056806:Urea Cycle Disorders, Inborn / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism
chemical_list: D026923:Amino Acid Transport Systems, Basic; D033681:Mitochondrial Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050480:Plasma Membrane Neurotransmitter Transport Proteins; C442901:SLC25A15 protein, human; C094770:SLC6A8 protein, human; D012436:S-Adenosylmethionine; D009952:Ornithine; C494506:GAMT protein, human; D050937:Guanidinoacetate N-Methyltransferase; D000579:Amidinotransferases; C020681:glycine amidinotransferase; D055372:AMP-Activated Protein Kinases; D003401:Creatine
keywords: AGAT; AMP activated protein kinase; CRTR; Creatine; GAMT; SLC6A8; Secondary creatine disorders