title: Calorie restriction in mice overexpressing UCP3: evidence that prior mitochondrial uncoupling alters response.
abstract: Calorie restriction (CR) without malnutrition is the only intervention to consistently increase lifespan in all species tested, and lower age-related pathologies in mammals including humans. It has been suggested that uncoupling of mitochondrial oxidative phosphorylation, using chemical uncouplers, mimics CR, and that overlapping mechanisms underlie the phenotypic changes induced by uncoupling and CR. We aimed to critically assess this using a unique mouse model of skeletal muscle-targeted UCP3-induced uncoupling (UCP3Tg), and focused our studies mainly on skeletal muscle mitochondria. Compared to ad libitum fed Wt mice, skeletal muscle mitochondria from ad libitum fed UCP3Tg mice showed higher basal uncoupling and lower H(2)O(2) emission, with unchanged maximal oxidative phosphorylation, and mitochondrial content. UCP3Tg CR mice showed some tendency for differential adaptation to CR, with lowered H(+) leak conductance and evidence for higher H(2)O(2) emission from skeletal muscle mitochondria following 2 weeks CR, and failure to lower H(2)O(2) emission after 1 month CR. Differential adaptation was also apparent at the whole body level: while UCP3Tg CR mice lost as much weight as Wt CR mice, the proportion of muscle lost was higher in UCP3Tg mice. However, a striking outcome of our studies was the absence of change with CR in many of the parameters of mitochondrial function and content that we measured in mice of either genotype. Overall, our study raises the question of whether CR can consistently modify skeletal muscle mitochondria; alterations with CR may only be apparent under certain conditions such as during the 2 wk CR intervention in the UCP3Tg mice.
authors.affiliation: Dept. Biochem Microbiol Immunol, University of Ottawa, Ottawa, ON, Canada K1H 8M5.
authors.forename: Carmen
authors.initials: C
authors.lastname: Estey
authors.forename: Erin L
authors.initials: EL
authors.lastname: Seifert
authors.forename: Céline
authors.initials: C
authors.lastname: Aguer
authors.forename: Cynthia
authors.initials: C
authors.lastname: Moffat
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Harper
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001823:Body Composition; D001835:Body Weight / Q000502:physiology; D031204:Caloric Restriction; D002153:Calorimetry, Indirect / Q000379:methods; D004734:Energy Metabolism / Q000502:physiology; D007473:Ion Channels / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008931:Mitochondria, Muscle / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism* / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism*; D009929:Organ Size / Q000502:physiology; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption / Q000502:physiology; D011522:Protons; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071256:Uncoupling Protein 1; D000071247:Uncoupling Protein 3
chemical_list: D000975:Antioxidants; D007473:Ion Channels; D024101:Mitochondrial Proteins; D011522:Protons; D017382:Reactive Oxygen Species; C000604392:UCP3 protein, human; C000604393:Ucp3 protein, mouse; D000071256:Uncoupling Protein 1; D000071247:Uncoupling Protein 3