Identification and regulation of the xenometabolite derivatives cis- and trans-3,4-methylene-heptanoylcarnitine in plasma and skeletal muscle of exercising humans

Authors: SOBHI, H. - Arkansas Children'S Nutrition Research Center (ACNC); ZHAO, X. - Dalian Medical University, China; PLOMGAARD, P. - University Of Copenhagen; HOENE, M. - University Of Tubingen; KARUS, B. - University Of Tubingen; NIESS, A. - University Of Tubingen; HARING, H. - University Of Tubingen; LEHMANN, R. - University Of Tubingen; Ferruzzi, Mario; XU, G. - Dalian Medical University, China; WEIGERT, C. - University Of Tubingen

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/24/2020
Publication Date: 2/26/2020
Citation: Sobhi, H.F., Zhao, X.J., Plomgaard, P., Hoene, M., Karus, B., Niess, A.M., Haring, H.U., Lehmann, R., Adams, S.H., Xu, G., Weigert, C. 2020. Identification and regulation of the xenometabolite derivatives cis- and trans-3,4-methylene-heptanoylcarnitine in plasma and skeletal muscle of exercising humans. American Journal of Physiology - Endocrinology and Metabolism. 318(5):E701-E709. https://doi.org/10.1152/ajpendo.00510.2019.
DOI: https://doi.org/10.1152/ajpendo.00510.2019

Interpretive Summary: Little is known about the biology of xenometabolites ("non-self" metabolites that are in the human body but that come from the naturally-occurring bacteria in the gut), and how the hundreds of these molecules impact human health. Very recently, it was discovered that acute exercise can actually increase the blood levels of select xenometabolites and some components of the diet, suggesting a unique interplay between physical activity and communication with the gut and its resident microbial populations. Previously, an exercise-modifiable, likely xenometabolite derivative, cis-3,4-methylene-heptanoylcarnitine, was reported in human plasma. Here, we identified different forms (isoforms) of 3,4-methylene-heptanoylcarnitine in plasma and skeletal muscle tissue of healthy men. The regulation by exercise and the arterial-to-venous differences of these cyclopropane ring-containing carnitine esters over the hepato-splanchnic bed (liver and intestines) and the exercising and resting leg were analyzed. Exercise increased the blood concentrations of these metabolites, and there was production from the hepato-splanchnic bed. This is the first approach studying kinetics and uptake/release of xenolipid isomers from human tissues under exercised conditions, supporting the hypothesis that hepatic metabolism of cyclopropane ring-containing fatty acids is one source of these metabolites in plasma. The data also provide clear evidence for an exercise-dependent regulation of xenometabolite metabolism, opening perspectives for future studies about the physiological role of this largely unknown class of metabolites. Overall, the results highlight that exercise can significantly change the blood concentrations of "non-self" metabolites derived from the gut, and these patterns suggest that these emerging molecules could play a role in exercise-induced improvements in health.

Technical Abstract: Little is known about xenometabolites in human metabolism, particularly under exercising conditions. Previously, an exercise-modifiable, likely xenometabolite derivative, cis-3,4-methylene-heptanoylcarnitine, was reported in human plasma. Here, we identified trans-3,4-methylene-heptanoylcarnitine, and its isomer cis-3,4-methylene-heptanoylcarnitine, in plasma and skeletal muscle tissue by liquid chromatography-mass spectrometry. We analyzed the regulation by exercise and the arterial-to-venous differences of these cyclopropane ring-containing carnitine esters over the hepato-splanchnic bed and the exercising and resting leg in plasma samples obtained in three separate studies from young, lean and healthy males. Compared to other medium-chain acylcarnitines, the plasma concentrations of the 3,4-methylene-heptanoylcarnitine isomers only marginally increased with exercise. Both isomers showed a >2-fold increase in the skeletal muscle tissue of the exercising leg; this may be due to the net effect of fatty acid oxidation in the exercising muscle and uptake from blood. The latter idea is supported by a >2-fold increased net uptake in the exercising leg only. Both isomers showed a constant release from the hepato-splanchnic bed, with an increased release of the trans-isomer after exercise, which was not detected for the cis-isomer. The isomers differ in their plasma concentration with a four times higher concentration of the cis-isomer. This is the first approach studying kinetics and uptake/release of xenolipid isomers from tissues under exercised conditions, supporting the hypothesis that hepatic metabolism of cyclopropane ring-containing fatty acids is one source of these acylcarnitines in plasma. The data also provide clear evidence for an exercise-dependent regulation of xenometabolite metabolism, opening perspectives for future studies about the physiological role of this largely unknown class of metabolites.