Oral octanoylcarnitine alleviates exercise intolerance in mouse models of long-chain fatty acid oxidation disorders
Keaton J. Solo, … , Timothy C. Wood, Eric S. Goetzman
Keaton J. Solo, … , Timothy C. Wood, Eric S. Goetzman
Published October 16, 2025
Citation Information: JCI Insight. 2025;10(22):e199443. https://doi.org/10.1172/jci.insight.199443.
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Research Article Genetics Metabolism

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

Abstract

Long-chain fatty acid oxidation disorders (LC-FAODs) cause energy deficits in heart and skeletal muscle that are 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 significantly enhances grip strength and treadmill endurance while attenuating lactic acidosis in 2 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.

Authors

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

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Figure 4

Muscle and heart mitochondria use CrAT to metabolize medium-chain acylcarnitines.

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Muscle and heart mitochondria use CrAT to metabolize medium-chain acylca...
(A) Soleus muscle mitochondria isolated from CPT2 muscle-specific KO mice (CPT2mKO) cannot respire on C16-carnitine, the preferred substrate for CPT2, but respire robustly on C7-carnitine. (B) The tissue specificity of the CPT2mKO allele is demonstrated by the ability of liver and heart to normally convert C16-carnitine to C16-CoA, while muscle has near-zero capacity for this conversion. (C) CPT2mKO soleus muscle mitochondria, while unable to convert C16-carnitine to C16-CoA (B), robustly convert C7-carnitine to C7-CoA. (D) The significant increase in acyl-CoA generating capacity in C is likely due to a compensatory increase in soleus muscle CrAT in the CPT2mKO mouse. (E) Soleus muscle mitochondria isolated from CrAT muscle-specific KO mice (CrATmKO) show the opposite result from CPT2mKO muscle — i.e., high respiration on C16-carnitine but near-zero respiration on C7-carnitine. (F) The intact mitochondria experiments shown in A and E indicate that CrAT is the major contributor to C7-carnitine conversion to C7-CoA, but in vitro, both CPT2 and CrAT are active with medium-chain acylcarnitine substrates. **P < 0.01; ****P < 0.0001 by Student’s t test. Data are shown as mean ± SEM.