Charting the undiscovered metabolome with synthetic multiplexing implicates ibuprofen-carnitine in myotoxicity
Patan, A.; Xing, S.; Charron-Lamoureux, V.; Hu, Z.; Deleray, V.; Agongo, J.; Zemlin, J.; Gouda, H.; Rajkumar, P.; Yang, J.; El Abiead, Y.; Mannochio-Russo, H.; Mohanty, I.; Abolfathi, L.; McMaugh, A. E.; Heath, H.; Almada-Monter, R.; Lee, C.; Leanos, D.; Weimann, N.; Tsuda, W.; Giddings, S.; Bui, T.; Ding, E.; Kvitne, K. E.; Zhao, H. N.; Zuffa, S.; Portal Gomes, P. W.; Nguyen, V.; Andrade, A.; Pawlowski, M. A.; Ferland, A. C.; Orozco, E.; Goncalves Nunes, W. D.; Caraballo-Rodriguez, A. M.; Caetano David, L.; Giacomini, K.; Jinich, A.; Carver, J.; Bandeira, N.; Wang, M.; Burnett, L.; Siegel, D.
Show abstract
Most molecular features detected in untargeted metabolomics remain uncharacterized due to the limited scope of existing spectral reference libraries. We synthesized >100,000 biologically inspired compounds using multiplexed reactions, of which 91% were absent from existing structural databases, and searched the resulting MS/MS library across >1.7 billion public spectra, increasing annotation rates by 17.4%. This approach revealed previously undescribed exposure-derived metabolites, including ibuprofen-carnitine. Because ibuprofen has been linked to rhabdomyolysis, reduced mitochondrial function, and impaired muscle recovery in carnitine-limited contexts, we investigated the functional relevance of this conjugate. Ibuprofen-carnitine reduced carnitine transport via the OCTN2 transporter, and in a postpartum mouse muscle injury model, ibuprofen delayed muscle repair that could be rescued by carnitine supplementation, with urinary ibuprofen-carnitine:carnitine ratios tracking this effect. These findings support a hypothesis whereby NSAID-carnitine conjugates compete for carnitine transport, impairing energy metabolism and muscle recovery in susceptible individuals. Synthetic multiplexing thus provides a scalable route to annotate the dark metabolome and generate experimentally testable biological hypotheses.
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