title: Muscle uncoupling protein 3 overexpression mimics endurance training and reduces circulating biomarkers of incomplete β-oxidation.
abstract: Exercise substantially improves metabolic health, making the elicited mechanisms important targets for novel therapeutic strategies. Uncoupling protein 3 (UCP3) is a mitochondrial inner membrane protein highly selectively expressed in skeletal muscle. Here we report that moderate UCP3 overexpression (roughly 3-fold) in muscles of UCP3 transgenic (UCP3 Tg) mice acts as an exercise mimetic in many ways. UCP3 overexpression increased spontaneous activity (∼40%) and energy expenditure (∼5-10%) and decreased oxidative stress (∼15-20%), similar to exercise training in wild-type (WT) mice. The increase in complete fatty acid oxidation (FAO; ∼30% for WT and ∼70% for UCP3 Tg) and energy expenditure (∼8% for WT and 15% for UCP3 Tg) in response to endurance training was higher in UCP3 Tg than in WT mice, showing an additive effect of UCP3 and endurance training on these two parameters. Moreover, increases in circulating short-chain acylcarnitines in response to acute exercise in untrained WT mice were absent with training or in UCP3 Tg mice. UCP3 overexpression had the same effect as training in decreasing long-chain acylcarnitines. Outcomes coincided with a reduction in muscle carnitine acetyltransferase activity that catalyzes the formation of acylcarnitines. Overall, results are consistent with the conclusions that circulating acylcarnitines could be used as a marker of incomplete muscle FAO and that UCP3 is a potential target for the treatment of prevalent metabolic diseases in which muscle FAO is affected.
authors.affiliation: 2M.-E.H., Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Rd., Ottawa, ON K1H 8M5, Canada. mharper@uottawa.ca.
authors.forename: Céline
authors.initials: C
authors.lastname: Aguer
authors.forename: Oliver
authors.initials: O
authors.lastname: Fiehn
authors.forename: Erin L
authors.initials: EL
authors.lastname: Seifert
authors.forename: Véronic
authors.initials: V
authors.lastname: Bézaire
authors.forename: John K
authors.initials: JK
authors.lastname: Meissen
authors.forename: Amanda
authors.initials: A
authors.lastname: Daniels
authors.forename: Kyle
authors.initials: K
authors.lastname: Scott
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Renaud
authors.forename: Marta
authors.initials: M
authors.lastname: Padilla
authors.forename: David R
authors.initials: DR
authors.lastname: Bickel
authors.forename: Michael
authors.initials: M
authors.lastname: Dysart
authors.forename: Sean H
authors.initials: SH
authors.lastname: Adams
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Harper
mesh_terms: D000818:Animals; D015415:Biomarkers; D004435:Eating; D004734:Energy Metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010805:Physical Conditioning, Animal; D010807:Physical Endurance; D000071247:Uncoupling Protein 3
chemical_list: D015415:Biomarkers; D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604393:Ucp3 protein, mouse; D000071247:Uncoupling Protein 3
keywords: acylcarnitines; exercise mimetic; fatty acid oxidation; mitochondria; oxidative stress