Academic Journal
Oral octanoylcarnitine alleviates exercise intolerance in mouse models of long-chain fatty acid oxidation disorders.
| Τίτλος: | Oral octanoylcarnitine alleviates exercise intolerance in mouse models of long-chain fatty acid oxidation disorders. |
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| Συγγραφείς: | Solo KJ; Department of Pediatrics, Division of Genetic and Genomic Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Zhang Y; Department of Pediatrics, Division of Genetic and Genomic Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Bharathi SS; Department of Pediatrics, Division of Genetic and Genomic Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Zhang BB; Department of Pediatrics, Division of Genetic and Genomic Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Richert AC; Department of Pediatrics, Division of Genetic and Genomic Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Schmidt AV; Department of Pediatrics, Division of Genetic and Genomic Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Van't Land C; Department of Pediatrics, Division of Genetic and Genomic Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., D'Annibale O; Department of Pediatrics, University of Colorado Anschutz Medical Campus/Children's Hospital of Colorado, Aurora, Colorado, USA., Wood TC; Department of Pediatrics, University of Colorado Anschutz Medical Campus/Children's Hospital of Colorado, Aurora, Colorado, USA., Goetzman ES; Department of Pediatrics, Division of Genetic and Genomic Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. |
| Πηγή: | JCI insight [JCI Insight] 2025 Oct 16; Vol. 10 (22). Date of Electronic Publication: 2025 Oct 16 (Print Publication: 2025). |
| Τύπος έκδοσης: | Journal Article; Research Support, N.I.H., Extramural |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 101676073 Publication Model: eCollection Cited Medium: Internet ISSN: 2379-3708 (Electronic) Linking ISSN: 23793708 NLM ISO Abbreviation: JCI Insight Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Ann Arbor, Michigan : American Society for Clinical Investigation, [2016]- |
| Ιατρικοί όροι (MeSH): | Carnitine*/analogs & derivatives , Carnitine*/administration & dosage , Carnitine*/pharmacology , Fatty Acids*/metabolism , Lipid Metabolism, Inborn Errors*/drug therapy , Lipid Metabolism, Inborn Errors*/metabolism , Exercise Tolerance*/drug effects, Muscle, Skeletal/metabolism ; Muscle, Skeletal/drug effects ; Carnitine O-Acetyltransferase/metabolism ; Myocardium/metabolism ; Animals ; Mice ; Disease Models, Animal ; Oxidation-Reduction ; Administration, Oral ; Male ; Triglycerides ; Mice, Inbred C57BL |
| Περίληψη: | 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. |
| Σχόλια: | Update of: bioRxiv. 2025 Jun 25:2025.06.24.661304. doi: 10.1101/2025.06.24.661304.. (PMID: 40667310) |
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| Grant Information: | R01 DK090242 United States DK NIDDK NIH HHS |
| Contributed Indexing: | Keywords: Bioenergetics; Genetics; Metabolism; Monogenic diseases; Therapeutics |
| Substance Nomenclature: | S7UI8SM58A (Carnitine) 0 (Fatty Acids) S1HB7P0O16 (octanoylcarnitine) EC 2.3.1.7 (Carnitine O-Acetyltransferase) 0 (Triglycerides) 2P6O7CFW5K (triheptanoin) |
| Entry Date(s): | Date Created: 20251016 Date Completed: 20251124 Latest Revision: 20260902 |
| Update Code: | 20260902 |
| PubMed Central ID: | PMC12643506 |
| DOI: | 10.1172/jci.insight.199443 |
| PMID: | 41100184 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 2379-3708 |
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| DOI: | 10.1172/jci.insight.199443 |