Department of Movement and Sports Sciences, Ghent University, Ghent, Belgium.
Department of Nutrition, Exercise and Sports, Copenhagen University, Copenhagen, Denmark.
Acta Physiol (Oxf). 2023 Sep;239(1):e14020. doi: 10.1111/apha.14020. Epub 2023 Jul 24.
Histidine-containing dipeptides (HCDs) are pleiotropic homeostatic molecules with potent antioxidative and carbonyl quenching properties linked to various inflammatory, metabolic, and neurological diseases, as well as exercise performance. However, the distribution and metabolism of HCDs across tissues and species are still unclear.
Using a sensitive UHPLC-MS/MS approach and an optimized quantification method, we performed a systematic and extensive profiling of HCDs in the mouse, rat, and human body (in n = 26, n = 25, and n = 19 tissues, respectively).
Our data show that tissue HCD levels are uniquely produced by carnosine synthase (CARNS1), an enzyme that was preferentially expressed by fast-twitch skeletal muscle fibres and brain oligodendrocytes. Cardiac HCD levels are remarkably low compared to other excitable tissues. Carnosine is unstable in human plasma, but is preferentially transported within red blood cells in humans but not rodents. The low abundant carnosine analogue N-acetylcarnosine is the most stable plasma HCD, and is enriched in human skeletal muscles. Here, N-acetylcarnosine is continuously secreted into the circulation, which is further induced by acute exercise in a myokine-like fashion.
Collectively, we provide a novel basis to unravel tissue-specific, paracrine, and endocrine roles of HCDs in human health and disease.
组氨酸二肽（HCD）是一种具有多种内稳作用的内源性分子，具有强大的抗氧化和羰基猝灭特性，与各种炎症、代谢和神经疾病以及运动表现有关。然而，HCD 在组织和物种中的分布和代谢仍不清楚。
使用灵敏的 UHPLC-MS/MS 方法和优化的定量方法，我们对小鼠、大鼠和人体中的 HCD 进行了系统和广泛的分析（分别在 n=26、n=25 和 n=19 个组织中进行）。
我们的数据表明，组织 HCD 水平是由肌肽合酶（CARNS1）独特产生的，该酶优先在快肌纤维和大脑少突胶质细胞中表达。与其他兴奋组织相比，心脏 HCD 水平显著较低。人血浆中的肌肽不稳定，但在人类中优先在红细胞内运输，而在啮齿动物中则不然。低丰度的肌肽类似物 N-乙酰基肌肽是最稳定的血浆 HCD，并在人类骨骼肌中富集。在这里，N-乙酰基肌肽不断被分泌到循环中，并且以肌因子样的方式被急性运动进一步诱导。
总的来说，我们为揭示 HCD 在人类健康和疾病中的组织特异性、旁分泌和内分泌作用提供了新的基础。
