TY - JOUR

T1 - Extensive profiling of histidine-containing dipeptides reveals species- and tissue-specific distribution and metabolism in mice, rats, and humans

AU - Van der Stede, Thibaux

AU - Spaas, Jan

AU - de Jager, Sarah

AU - De Brandt, Jana

AU - Hansen, Camilla

AU - Stautemas, Jan

AU - Vercammen, Bjarne

AU - De Baere, Siegrid

AU - Croubels, Siska

AU - Van Assche, Charles-Henri

AU - Pastor, Berta Cillero

AU - Vandenbosch, Michiel

AU - Van Thienen, Ruud

AU - Verboven, Kenneth

AU - Hansen, Dominique

AU - Bové, Thierry

AU - Lapauw, Bruno

AU - Van Praet, Charles

AU - Decaestecker, Karel

AU - Vanaudenaerde, Bart

AU - Eijnde, Bert O.

AU - Gliemann, Lasse

AU - Hellsten, Ylva

AU - Derave, Wim

N1 - © 2023 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

PY - 2023

Y1 - 2023

N2 - Aim: 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.Methods: 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).Results: 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.Conclusion: Collectively, we provide a novel basis to unravel tissue-specific, paracrine, and endocrine roles of HCDs in human health and disease.

AB - Aim: 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.Methods: 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).Results: 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.Conclusion: Collectively, we provide a novel basis to unravel tissue-specific, paracrine, and endocrine roles of HCDs in human health and disease.

KW - Faculty of Science

KW - Carnosine

KW - Central nervous system

KW - Exercise

KW - Histidine-containing dipeptides

KW - Muscle

U2 - 10.1111/apha.14020

DO - 10.1111/apha.14020

M3 - Journal article

C2 - 37485756

VL - 239

JO - Acta Physiologica

JF - Acta Physiologica

SN - 1748-1708

IS - 1

M1 - e14020

ER -