title: Mitochondrial uncoupling in skeletal muscle by UCP1 augments energy expenditure and glutathione content while mitigating ROS production.
abstract: Enhancement of proton leaks in muscle tissue represents a potential target for obesity treatment. In this study, we examined the bioenergetic and physiological implications of increased proton leak in skeletal muscle. To induce muscle-specific increases in proton leak, we used mice that selectively express uncoupling protein-1 (UCP1) in skeletal muscle tissue. UCP1 expression in muscle mitochondria was ∼13% of levels in brown adipose tissue (BAT) mitochondria and caused increased GDP-sensitive proton leak. This was associated with an increase in whole body energy expenditure and a decrease in white adipose tissue content. Muscle UCP1 activity had divergent effects on mitochondrial ROS emission and glutathione levels compared with BAT. UCP1 in muscle increased total mitochondrial glutathione levels ∼7.6 fold. Intriguingly, unlike in BAT mitochondria, leak through UCP1 in muscle controlled mitochondrial ROS emission. Inhibition of UCP1 with GDP in muscle mitochondria increased ROS emission ∼2.8-fold relative to WT muscle mitochondria. GDP had no impact on ROS emission from BAT mitochondria from either genotype. Collectively, these findings indicate that selective induction of UCP1-mediated proton leak in muscle can increase whole body energy expenditure and decrease adiposity. Moreover, ectopic UCP1 expression in skeletal muscle can control mitochondrial ROS emission, while it apparently plays no such role in its endogenous tissue, brown fat.
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Cyril Nii-Klu
authors.initials: CN
authors.lastname: Adjeitey
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Mailloux
authors.forename: Robert A
authors.initials: RA
authors.lastname: Dekemp
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Harper
mesh_terms: D000244:Adenosine Diphosphate / Q000502:physiology; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D002153:Calorimetry, Indirect; D004435:Eating; D004734:Energy Metabolism / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D007473:Ion Channels / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D050050:Protein Carbonylation / Q000235:genetics / Q000502:physiology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014475:Uncoupling Agents; D000071256:Uncoupling Protein 1
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C000604372:Ucp1 protein, mouse; C000604373:Ucp1 protein, rat; D014475:Uncoupling Agents; D000071256:Uncoupling Protein 1; D000244:Adenosine Diphosphate; D005978:Glutathione; D005947:Glucose
keywords: UCP1; glutathione; obesity; proton leak; reactive oxygen species; redox