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

  • JCI Insight. 2025 Oct 16;10(22):e199443. doi: 10.1172/jci.insight.199443.
Keaton J Solo  1 ,  Yuxun Zhang  1 ,  Sivakama S Bharathi  1 ,  Bob B Zhang  1 ,  Adam C Richert  1 ,  Alexandra V Schmidt  1 ,  Clinton Van't Land  1 ,  Olivia D'Annibale  2 ,  Timothy C Wood  2 ,  Eric S Goetzman  1
Affiliations
  • 1. Department of Pediatrics, Division of Genetic and Genomic Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
  • 2. Department of Pediatrics, University of Colorado Anschutz Medical Campus/Children's Hospital of Colorado, Aurora, Colorado, USA.
PMID: 41100184 DOI: 10.1172/jci.insight.199443
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.

Keywords
Bioenergetics; Genetics; Metabolism; Monogenic diseases; Therapeutics.
Products