title: Carnitine Acetyltransferase Mitigates Metabolic Inertia and Muscle Fatigue during Exercise.
abstract: Acylcarnitine metabolites have gained attention as biomarkers of nutrient stress, but their physiological relevance and metabolic purpose remain poorly understood. Short-chain carnitine conjugates, including acetylcarnitine, derive from their corresponding acyl-CoA precursors via the action of carnitine acetyltransferase (CrAT), a bidirectional mitochondrial matrix enzyme. We show here that contractile activity reverses acetylcarnitine flux in muscle, from net production and efflux at rest to net uptake and consumption during exercise. Disruption of this switch in mice with muscle-specific CrAT deficiency resulted in acetyl-CoA deficit, perturbed energy charge, and diminished exercise tolerance, whereas acetylcarnitine supplementation produced opposite outcomes in a CrAT-dependent manner. Likewise, in exercise-trained compared to untrained humans, post-exercise phosphocreatine recovery rates were positively associated with CrAT activity and coincided with dramatic shifts in muscle acetylcarnitine dynamics. These findings show acetylcarnitine serves as a critical acetyl buffer for working muscles and provide insight into potential therapeutic strategies for combatting exercise intolerance.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27704, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Seiler
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University, Durham, NC 27704, USA; Division of Geriatrics, Duke University, Durham, NC 27704, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Koves
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University, Durham, NC 27704, USA.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Gooding
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University, Durham, NC 27704, USA.
authors.forename: Kari E
authors.initials: KE
authors.lastname: Wong
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University, Durham, NC 27704, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Stevens
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University, Durham, NC 27704, USA.
authors.forename: Olga R
authors.initials: OR
authors.lastname: Ilkayeva
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University, Durham, NC 27704, USA.
authors.forename: April H
authors.initials: AH
authors.lastname: Wittmann
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27704, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: DeBalsi
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University, Durham, NC 27704, USA.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Davies
authors.affiliation: Department of Human Biology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands; Department of Radiology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands.
authors.forename: Lucas
authors.initials: L
authors.lastname: Lindeboom
authors.affiliation: Department of Human Biology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schrauwen
authors.affiliation: Department of Radiology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands.
authors.forename: Vera B
authors.initials: VB
authors.lastname: Schrauwen-Hinderling
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27704, USA; Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University, Durham, NC 27704, USA; Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University, Durham, NC 27704, USA. Electronic address: Muoio@duke.edu.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Muoio
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D002332:Carnitine O-Acetyltransferase / Q000378:metabolism*; D015444:Exercise; D006801:Humans; D008810:Mice, Inbred C57BL; D018763:Muscle Fatigue; D009132:Muscles / Q000201:enzymology* / Q000378:metabolism; D010805:Physical Conditioning, Animal
chemical_list: C116917:acylcarnitine; D000105:Acetyl Coenzyme A; D002332:Carnitine O-Acetyltransferase; D002331:Carnitine