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

Histidine-containing dipeptides (HCDs) are pleiotropic homeostatic molecules linked to inflammatory, metabolic and neurological diseases, as well as exercise performance. 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, n=19 tissues, respectively). Our data show that tissue HCD levels are uniquely regulated by carnosine synthase, an enzyme preferentially expressed by fast-twitch skeletal muscle fibers and brain oligodendrocytes. Cardiac HCD levels are remarkably low. The low abundant HCD N-acetylcarnosine is enriched in human skeletal muscles. Here, N-acetylcarnosine is continuously secreted into the circulation as the most stable plasma HCD, which is further induced by acute exercise in a myokine-like fashion. Carnosine is preferentially transported within red blood cells in humans but not rodents. We provide a novel basis to unravel tissue-specific, paracrine, and endocrine roles of HCDs in human health and disease.