{"doi":"10.1101/2025.06.24.661304","title":"Oral octanoylcarnitine alleviates exercise intolerance in mouse models of long-chain fatty acid oxidation disorders","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 (C 8 -carnitine) to octanoyl-CoA for energy generation. C 8 -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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":569128,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9523,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":458699,"name":"Yuxun Zhang","orcid":"0000-0002-6682-012X","position":1,"is_corresponding":false},{"id":458698,"name":"Sivakama S. Bharathi","orcid":"0000-0003-0611-2778","position":2,"is_corresponding":false},{"id":966590,"name":"Bob B. Zhang","orcid":"0000-0003-0248-3301","position":3,"is_corresponding":false},{"id":1216848,"name":"Adam C. Richert","orcid":"0000-0002-1351-820X","position":4,"is_corresponding":false},{"id":966592,"name":"Alexandra V. Schmidt","orcid":"0000-0002-9293-7786","position":5,"is_corresponding":false},{"id":914771,"name":"Shakuntala Basu","orcid":null,"position":6,"is_corresponding":false},{"id":914274,"name":"Clinton Van’t Land","orcid":"0000-0002-0409-9541","position":7,"is_corresponding":false},{"id":773868,"name":"Olivia D’Annibale","orcid":"0000-0002-6498-2889","position":8,"is_corresponding":false},{"id":650265,"name":"Timothy C. Wood","orcid":"0000-0003-0831-0188","position":9,"is_corresponding":false},{"id":230667,"name":"Jerry Vockley","orcid":"0000-0002-8180-6457","position":10,"is_corresponding":false},{"id":458697,"name":"Eric S. Goetzman","orcid":"0000-0001-9476-309X","position":11,"is_corresponding":false},{"id":914272,"name":"Keaton J. Solo","orcid":"0000-0002-4212-4832","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T02:56:59.652443Z","pmid":"40667310","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}