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

Authors
Keaton J. Solo, Yuxun Zhang, Sivakama S. Bharathi, Bob B. Zhang, Adam C. Richert, Alexandra V. Schmidt, Shakuntala Basu, Clinton Van’t Land, Olivia D’Annibale, Timothy C. Wood, Jerry Vockley, Eric S. Goetzman


Lab

Journal
bioRxiv

Abstract

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 β-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 LE8700TS 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.

Keywords/Topics
exercise

BIOSEB Instruments Used:
Grip strength test (BIO-GS4),Infrared Actimeter (LE8815)

Source :

https://www.biorxiv.org/content/10.1101/2025.06.24.661304.abstract

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