Carnosine and anserine homeostasis in skeletal muscle and heart is controlled by [beta]-alanine transamination

• Published in: The Journal of physiology 2016-09, Vol.594 (17), p.4849
• Main Authors: Blancquaert, Laura, Baba, Shahid P, Kwiatkowski, Sebastian, Stautemas, Jan, Stegen, Sanne, Barbaresi, Silvia, Chung, Weiliang, Boakye, Adjoa A, Hoetker, J David, Bhatnagar, Aruni, Delanghe, Joris, Vanheel, Bert, Veiga-da-Cunha, Maria, Derave, Wim, Everaert, Inge
• Format: Article
• Language: English
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/JP272050

Key points Using recombinant DNA technology, the present study provides the first strong and direct evidence indicating that [beta]-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 [beta]-alanine, which is in turn controlled by degradation of [beta]-alanine in liver and kidney. Chronic oral [beta]-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 [beta]-alanine supplementation protocol is so inefficient, by demonstrating that exogenous [beta]-alanine can be effectively routed toward oxidation. The metabolic fate of orally ingested [beta]-alanine is largely unknown. Chronic [beta]-alanine supplementation is becoming increasingly popular for improving high-intensity exercise performance because it is the rate-limiting precursor of the dipeptide carnosine ([beta]-alanyl-l-histidine) in muscle. However, only a small fraction (3-6%) of the ingested [beta]-alanine is used for carnosine synthesis. Thus, the present study aimed to investigate the putative contribution of two [beta]-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 [beta]-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 [beta]-alanine (0.1% w/v in drinking water) for 2 weeks lead to a 3-fold increase in circulating [beta]-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 eithe