Oral octanoylcarnitine alleviates exercise intolerance in mouse models of long-chain fatty acid oxidation disorders

Solo, K. J.; Zhang, Y.; Bharathi, S.; Zhang, B. B.; Richert, A. C.; Schmidt, A. V.; Basu, S.; Van't Land, C.; D'Annibale, O.; Wood, T. C.; Vockley, J.; Goetzman, E. S.

doi:10.1101/2025.06.24.661304

bioRxiv · 10.1101/2025.06.24.661304

Oral octanoylcarnitine alleviates exercise intolerance in mouse models of long-chain fatty acid oxidation disorders

Solo, K. J.·Zhang, Y.·Bharathi, S.·Zhang, B. B.·Richert, A. C.·Schmidt, A. V.·Basu, S.·Van't Land, C.·D'Annibale, O.·Wood, T. C.·Vockley, J.·Goetzman, E. S.

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Abstract

Long-chain fatty acid oxidation disorders (LC-FAODs) cause energy deficits in heart and skeletal muscle that is only partially corrected by current medium-chain lipid therapies such as triheptanoin. We find that heart and muscle lack medium-chain acyl-CoA synthetases, limiting the capacity for {beta}-oxidation of medium-chain fatty acids. Instead, heart and muscle mitochondria robustly respire on medium-chain acylcarnitines. The mitochondrial matrix enzyme carnitine acetyltransferase (CrAT) efficiently converts orally delivered octanoylcarnitine (C8-carnitine) to octanoyl-CoA for energy generation. C8-carnitine exhibits twice the oral bioavailability of triheptanoin and distributes to muscle and heart. A single oral dose markedly enhances grip strength, basal locomotion, and treadmill endurance while attenuating lactate and creatine kinase elevations in multiple mouse models of LC-FAODs. Thus, medium-chain acylcarnitines overcome a previously unrecognized metabolic bottleneck in LC-FAOD muscle and may represent an alternative to triglyceride-based therapies for bioenergetic disorders.

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Solo, K. J., Zhang, Y., Bharathi, S., Zhang, B. B., Richert, A. C., Schmidt, A. V., Basu, S., Van't Land, C., D'Annibale, O., Wood, T. C., Vockley, J., Goetzman, E. S.. 2025-06-25. Oral octanoylcarnitine alleviates exercise intolerance in mouse models of long-chain fatty acid oxidation disorders. https://doi.org/10.1101/2025.06.24.661304

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