title: Carnosine and anserine homeostasis in skeletal muscle and heart is controlled by β-alanine transamination.
abstract: Using recombinant DNA technology, the present study provides the first strong and direct evidence indicating that β-alanine is an efficient substrate for the mammalian transaminating enzymes 4-aminobutyrate-2-oxoglutarate transaminase and alanine-glyoxylate transaminase. The concentration of carnosine and anserine in murine skeletal and heart muscle depends on circulating availability of β-alanine, which is in turn controlled by degradation of β-alanine in liver and kidney. Chronic oral β-alanine supplementation is a popular ergogenic strategy in sports because it can increase the intracellular carnosine concentration and subsequently improve the performance of high-intensity exercises. The present study can partly explain why the β-alanine supplementation protocol is so inefficient, by demonstrating that exogenous β-alanine can be effectively routed toward oxidation.
  
  
  
  The metabolic fate of orally ingested β-alanine is largely unknown. Chronic β-alanine supplementation is becoming increasingly popular for improving high-intensity exercise performance because it is the rate-limiting precursor of the dipeptide carnosine (β-alanyl-l-histidine) in muscle. However, only a small fraction (3-6%) of the ingested β-alanine is used for carnosine synthesis. Thus, the present study aimed to investigate the putative contribution of two β-alanine transamination enzymes, namely 4-aminobutyrate-2-oxoglutarate transaminase (GABA-T) and alanine-glyoxylate transaminase (AGXT2), to the homeostasis of carnosine and its methylated analogue anserine. We found that, when transfected into HEK293T cells, recombinant mouse and human GABA-T and AGXT2 are able to transaminate β-alanine efficiently. The reaction catalysed by GABA-T is inhibited by vigabatrin, whereas both GABA-T and AGXT2 activity is inhibited by aminooxyacetic acid (AOA). Both GABA-T and AGXT2 are highly expressed in the mouse liver and kidney and the administration of the inhibitors effectively reduced their enzyme activity in liver (GABA-T for vigabatrin; GABA-T and AGXT2 for AOA). In vivo, injection of AOA in C57BL/6 mice placed on β-alanine (0.1% w/v in drinking water) for 2 weeks lead to a 3-fold increase in circulating β-alanine levels and to significantly higher levels of carnosine and anserine in skeletal muscle and heart. By contrast, specific inhibition of GABA-T by vigabatrin did not affect carnosine and anserine levels in either tissue. Collectively, these data demonstrate that homeostasis of carnosine and anserine in mammalian skeletal muscle and heart is controlled by circulating β-alanine levels, which are suppressed by hepatic and renal β-alanine transamination upon oral β-alanine intake.
authors.affiliation: Department of Movement and Sports Sciences, Ghent University, Ghent, Belgium.
authors.forename: Laura
authors.initials: L
authors.lastname: Blancquaert
authors.affiliation: Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, KT, USA.
authors.forename: Shahid P
authors.initials: SP
authors.lastname: Baba
authors.affiliation: Laboratory of Physiological Chemistry, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kwiatkowski
authors.affiliation: Department of Movement and Sports Sciences, Ghent University, Ghent, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Stautemas
authors.affiliation: Department of Movement and Sports Sciences, Ghent University, Ghent, Belgium.
authors.forename: Sanne
authors.initials: S
authors.lastname: Stegen
authors.affiliation: Department of Movement and Sports Sciences, Ghent University, Ghent, Belgium.
authors.forename: Silvia
authors.initials: S
authors.lastname: Barbaresi
authors.affiliation: Department of Movement and Sports Sciences, Ghent University, Ghent, Belgium.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Chung
authors.affiliation: Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, KT, USA.
authors.forename: Adjoa A
authors.initials: AA
authors.lastname: Boakye
authors.affiliation: Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, KT, USA.
authors.forename: J David
authors.initials: JD
authors.lastname: Hoetker
authors.affiliation: Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, KT, USA.
authors.forename: Aruni
authors.initials: A
authors.lastname: Bhatnagar
authors.affiliation: Department of Clinical Chemistry, Ghent University Hospital, Ghent, Belgium.
authors.forename: Joris
authors.initials: J
authors.lastname: Delanghe
authors.affiliation: Department of Basic Medical Sciences, Division of Physiology, Ghent University, Ghent, Belgium.
authors.forename: Bert
authors.initials: B
authors.lastname: Vanheel
authors.affiliation: Laboratory of Physiological Chemistry, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Maria
authors.initials: M
authors.lastname: Veiga-da-Cunha
authors.affiliation: Department of Movement and Sports Sciences, Ghent University, Ghent, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Derave
authors.affiliation: Department of Movement and Sports Sciences, Ghent University, Ghent, Belgium.
authors.forename: Inge
authors.initials: I
authors.lastname: Everaert
mesh_terms: D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D000861:Anserine / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002336:Carnosine / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018682:GABA Agents / Q000494:pharmacology; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D000637:Transaminases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020888:Vigabatrin / Q000494:pharmacology; D015091:beta-Alanine / Q000097:blood / Q000378:metabolism* / Q000652:urine
chemical_list: D004791:Enzyme Inhibitors; D018682:GABA Agents; D012333:RNA, Messenger; D015091:beta-Alanine; D000625:Aminooxyacetic Acid; D002336:Carnosine; D000637:Transaminases; C019635:Alanine-glyoxylate transaminase; D020888:Vigabatrin; D000861:Anserine