title: Transcriptomic and metabolic analyses reveal salvage pathways in creatine-deficient AGAT(-/-) mice.
abstract: Skeletal muscles require energy either at constant low (e.g., standing and posture) or immediate high rates (e.g., exercise). To fulfill these requirements, myocytes utilize the phosphocreatine (PCr)/creatine (Cr) system as a fast energy buffer and shuttle. We have generated mice lacking L-arginine:glycine amidino transferase (AGAT), the first enzyme of creatine biosynthesis. These AGAT(-/-) (d/d) mice are devoid of the PCr/Cr system and reveal severely altered oxidative phosphorylation. In addition, they exhibit complete resistance to diet-induced obesity, which is associated with a chronic activation of AMP-activated protein kinase in muscle and white adipose tissue. The underlying metabolic rearrangements have not yet been further analyzed. Here, we performed gene expression analysis in skeletal muscle and a serum amino acid profile of d/d mice revealing transcriptomic and metabolic alterations in pyruvate and glucose pathways. Differential pyruvate tolerance tests demonstrated preferential conversion of pyruvate to alanine, which was supported by increased protein levels of enzymes involved in pyruvate and alanine metabolism. Pyruvate tolerance tests suggested severely impaired hepatic gluconeogenesis despite increased availability of pyruvate and alanine. Furthermore, enzymes of serine production and one-carbon metabolism were significantly up-regulated in d/d mice, indicating increased de novo formation of one-carbon units from carbohydrate metabolism linked to NAD(P)H production. Besides the well-established function of the PCr/Cr system in energy metabolism, our transcriptomic and metabolic analyses suggest that it plays a pivotal role in systemic one-carbon metabolism, oxidation/reduction, and biosynthetic processes. Therefore, the PCr/Cr system is not only an energy buffer and shuttle, but also a crucial component involved in numerous systemic metabolic processes.
authors.affiliation: Institute for Molecular and Behavioral Neuroscience, University of Cologne, Cologne, Germany. malte.stockebrand@dzne.de.|German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. malte.stockebrand@dzne.de.|Experimental Neuropediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. malte.stockebrand@dzne.de.|Experimentelle Neurophysiologie, Universitätsklinikum Köln, Kerpener Str. 62, 50937, Cologne, Germany. malte.stockebrand@dzne.de.
authors.forename: Malte
authors.initials: M
authors.lastname: Stockebrand
authors.affiliation: Experimental Neuropediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ali Sasani
authors.initials: AS
authors.lastname: Nejad
authors.affiliation: Experimental Neuropediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Neu
authors.affiliation: Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, USA.
authors.forename: Kusum K
authors.initials: KK
authors.lastname: Kharbanda
authors.affiliation: Experimental Neuropediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Sauter
authors.affiliation: Experimental Neuropediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schillemeit
authors.affiliation: Institute for Molecular and Behavioral Neuroscience, University of Cologne, Cologne, Germany.|German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.|Experimental Neuropediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Isbrandt
authors.affiliation: Experimental Neuropediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Chi-Un
authors.initials: CU
authors.lastname: Choe
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism / Q000473:pathology; D000579:Amidinotransferases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002658:Developmental Disabilities / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008607:Intellectual Disability / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055442:Metabolome; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010085:Oxidative Phosphorylation; D010725:Phosphocreatine / Q000235:genetics / Q000378:metabolism*; D013064:Speech Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059467:Transcriptome
chemical_list: D010725:Phosphocreatine; D000579:Amidinotransferases; C020681:glycine amidinotransferase
keywords: Alanine; Arginine:glycine amidinotransferase (AGAT); Creatine; Glucose; Pyruvate; Skeletal muscle