title: Acylcarnitines as markers of exercise-associated fuel partitioning, xenometabolism, and potential signals to muscle afferent neurons.
abstract: What is the central question of this study? Does improved metabolic health and insulin sensitivity following a weight-loss and fitness intervention in sedentary, obese women alter exercise-associated fuel metabolism and incomplete mitochondrial fatty acid oxidation (FAO), as tracked by blood acylcarnitine patterns? What is the main finding and its importance? Despite improved fitness and blood sugar control, indices of incomplete mitochondrial FAO increased in a similar manner in response to a fixed load acute exercise bout; this indicates that intramitochondrial muscle FAO is inherently inefficient and is tethered directly to ATP turnover. With insulin resistance or type 2 diabetes mellitus, mismatches between mitochondrial fatty acid fuel delivery and oxidative phosphorylation/tricarboxylic acid cycle activity may contribute to inordinate accumulation of short- or medium-chain acylcarnitine fatty acid derivatives [markers of incomplete long-chain fatty acid oxidation (FAO)]. We reasoned that incomplete FAO in muscle would be ameliorated concurrent with improved insulin sensitivity and fitness following a ∼14 week training and weight-loss intervention in obese, sedentary, insulin-resistant women. Contrary to this hypothesis, overnight-fasted and exercise-induced plasma C4-C14 acylcarnitines did not differ between pre- and postintervention phases. These metabolites all increased robustly with exercise (∼45% of pre-intervention peak oxygen consumption) and decreased during a 20 min cool-down. This supports the idea that, regardless of insulin sensitivity and fitness, intramitochondrial muscle β-oxidation and attendant incomplete FAO are closely tethered to absolute ATP turnover rate. Acute exercise also led to branched-chain amino acid acylcarnitine derivative patterns suggestive of rapid and transient diminution of branched-chain amino acid flux through the mitochondrial branched-chain ketoacid dehydrogenase complex. We confirmed our prior novel observation that a weight-loss/fitness intervention alters plasma xenometabolites [i.e. cis-3,4-methylene-heptanoylcarnitine and γ-butyrobetaine (a co-metabolite possibly derived in part from gut bacteria)], suggesting that host metabolic health regulated gut microbe metabolism. Finally, we considered whether acylcarnitine metabolites signal to muscle-innervating afferents; palmitoylcarnitine at concentrations as low as 1-10 μm activated a subset (∼2.5-5%) of these neurons ex vivo. This supports the hypothesis that in addition to tracking exercise-associated shifts in fuel metabolism, muscle acylcarnitines act as signals of exertion to short-loop somatosensory-motor circuits or to the brain.
authors.affiliation: Anesthesiology Department, University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Anesthesiology Department, University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Light
authors.affiliation: Pharmacology Department, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Hoppel
authors.affiliation: United States Department of Agriculture-Agricultural Research Service Western Human Nutrition Research Center, Davis, CA, USA.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Campbell
authors.affiliation: United States Department of Agriculture-Agricultural Research Service Western Human Nutrition Research Center, Davis, CA, USA.
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Chandler
authors.affiliation: United States Department of Agriculture-Agricultural Research Service Western Human Nutrition Research Center, Davis, CA, USA.
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Burnett
authors.affiliation: United States Department of Agriculture-Agricultural Research Service Western Human Nutrition Research Center, Davis, CA, USA.
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Souza
authors.affiliation: Sports Medicine Program, School of Medicine, University of California, Davis, CA, USA.
authors.forename: Gretchen A
authors.initials: GA
authors.lastname: Casazza
authors.affiliation: Anesthesiology Department, University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Hughen
authors.affiliation: United States Department of Agriculture-Agricultural Research Service Western Human Nutrition Research Center, Davis, CA, USA.|Department of Nutrition, University of California, Davis, CA, USA.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Keim
authors.affiliation: United States Department of Agriculture-Agricultural Research Service Western Human Nutrition Research Center, Davis, CA, USA.|Department of Nutrition, University of California, Davis, CA, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Newman
authors.affiliation: Department of Nutrition Sciences, University of Alabama, Birmingham, AL, USA.|Human Studies Department, University of Alabama, Birmingham, AL, USA.
authors.forename: Gary R
authors.initials: GR
authors.lastname: Hunter
authors.affiliation: Department of Nutrition Sciences, University of Alabama, Birmingham, AL, USA.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Fernandez
authors.affiliation: Department of Nutrition Sciences, University of Alabama, Birmingham, AL, USA.
authors.forename: W Timothy
authors.initials: WT
authors.lastname: Garvey
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Harper
authors.affiliation: Genome Center and West Coast Metabolomics Center, University of California, Davis, CA, USA.|Biochemistry Department, King Abdulaziz University, Jeddah, Saudi-Arabia.
authors.forename: Oliver
authors.initials: O
authors.lastname: Fiehn
authors.affiliation: Arkansas Children's Nutrition Center, Little Rock, AR, USA.|Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Sean H
authors.identifier: 0000-0002-9515-2319
authors.initials: SH
authors.lastname: Adams
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000597:Amino Acids, Branched-Chain / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism*; D002331:Carnitine / Q000031:analogs & derivatives* / Q000378:metabolism; D002952:Citric Acid Cycle / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology; D015444:Exercise / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism; D018482:Muscle, Skeletal / Q000276:immunology* / Q000378:metabolism* / Q000503:physiopathology; D009475:Neurons, Afferent / Q000378:metabolism* / Q000502:physiology*; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption / Q000502:physiology; D015431:Weight Loss / Q000502:physiology
chemical_list: D000597:Amino Acids, Branched-Chain; D015415:Biomarkers; D005227:Fatty Acids; C116917:acylcarnitine; D000255:Adenosine Triphosphate; D002331:Carnitine
keywords: T2DM; branched chain amino acids; muscle fatigue; somatosensory system; xenobiotic; xenometabolome