Department of Movement and Sports Sciences, Ghent University, Watersportlaan 2, 9000, Gent, Belgium.
University Centre for Vascular Medicine and Department of Internal Medicine, Technische Universität Dresden, Dresden, Germany.
Eur J Appl Physiol. 2020 Dec;120(12):2749-2759. doi: 10.1007/s00421-020-04501-7. Epub 2020 Sep 18.
Chronic β-alanine supplementation leads to increased levels of muscle histidine-containing dipeptides. However, the majority of ingested β-alanine is, most likely, degraded by two transaminases: GABA-T and AGXT2. In contrast to GABA-T, the in vivo role of AGXT2 with respect to β-alanine metabolism is unknown. The purpose of the present work is to investigate if AGXT2 is functionally involved in β-alanine homeostasis.
Muscle histidine-containing dipeptides levels were determined in AGXT2 overexpressing or knock-out mice and in human subjects with different rs37369 genotypes which is known to affect AGXT2 activity. Further, plasma β-alanine kinetic was measured and urine was obtained from subjects with different rs37369 genotypes following ingestion of 1400 mg β-alanine.
Overexpression of AGXT2 decreased circulating and muscle histidine-containing dipeptides (> 70% decrease; p < 0.05), while AGXT2 KO did not result in altered histidine-containing dipeptides levels. In both models, β-alanine remained unaffected in the circulation and in muscle (p > 0.05). In humans, the results support the evidence that decreased AGXT2 activity is not associated with altered histidine-containing dipeptides levels (p > 0.05). Additionally, following an acute dose of β-alanine, no differences in pharmacokinetic response were measured between subjects with different rs37369 genotypes (p > 0.05). Interestingly, urinary β-alanine excretion was 103% higher in subjects associated with lower AGXT2 activity, compared to subjects associated with normal AGXT2 activity (p < 0.05).
The data suggest that in vivo, β-alanine is a substrate of AGXT2; however, its importance in the metabolism of β-alanine and histidine-containing dipeptides seems small.
慢性 β-丙氨酸补充会导致肌肉组氨酸二肽水平升高。然而，摄入的 β-丙氨酸大部分很可能被两种转氨酶：GABA-T 和 AGXT2 降解。与 GABA-T 不同，AGXT2 在 β-丙氨酸代谢中的体内作用尚不清楚。本研究的目的是研究 AGXT2 是否在 β-丙氨酸稳态中具有功能作用。
在 AGXT2 过表达或敲除小鼠以及具有不同 rs37369 基因型的人类受试者中测定肌肉组氨酸二肽水平，已知 rs37369 基因型会影响 AGXT2 活性。进一步，在摄入 1400mg β-丙氨酸后，从具有不同 rs37369 基因型的受试者中测量血浆 β-丙氨酸动力学并获得尿液。
AGXT2 的过表达降低了循环和肌肉中的组氨酸二肽（>70%降低；p<0.05），而 AGXT2 KO 并未导致组氨酸二肽水平改变。在两种模型中，β-丙氨酸在循环和肌肉中均不受影响（p>0.05）。在人类中，结果支持证据表明降低的 AGXT2 活性与改变的组氨酸二肽水平无关（p>0.05）。此外，在急性给予 β-丙氨酸剂量后，不同 rs37369 基因型的受试者之间的药代动力学反应没有差异（p>0.05）。有趣的是，与具有正常 AGXT2 活性的受试者相比，与低 AGXT2 活性相关的受试者的尿 β-丙氨酸排泄量高 103%（p<0.05）。
数据表明，在体内，β-丙氨酸是 AGXT2 的底物；然而，它在 β-丙氨酸和组氨酸二肽代谢中的重要性似乎很小。
