UCP1 ectopically expressed in murine muscle displays native function and mitigates mitochondrial superoxide production.
Mitochondrial uncoupling in skeletal muscle has raised a major interest as a therapeutic target for treatment of obesity, insulin sensitivity, and age-related disease. These physiological effects could be demonstrated in several mouse models ectopically expressing uncoupling protein 1 (UCP1). Here, we investigated whether UCP1 expressed under the control of the human skeletal actin (HSA) promoter in mouse skeletal muscle can be regulated, and whether it affects mitochondrial superoxide production. We show that the skeletal muscle UCP1 can be fully inhibited by a purine nucleotide (GDP) and reactivated by fatty acids (palmitate). During mitochondrial resting state (State 4), mitochondrial superoxide production is about 76% lower in transgenic mice. We suggest that this reduction is due to uncoupling activity as the administration of GDP restores superoxide production to wildtype levels. Our study confirms native behaviour of UCP1 in skeletal muscle and demonstrates beneficial effects on prevention of mitochondrial reactive oxygen species production which may reduce age-related deleterious processes.
Keipert
Susanne
S
German Institute of Human Nutrition, Group of Energy Metabolism, 14558 Nuthetal, Germany. susanne.keipert@dife.de
Klaus
Susanne
S
Heldmaier
Gerhard
G
Jastroch
Martin
M
D000818:Animals; D005260:Female; D006153:Guanosine Diphosphate / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007473:Ion Channels / Q000502:physiology*; D007700:Kinetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008931:Mitochondria, Muscle / Q000378:metabolism*; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000502:physiology*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D016877:Oxidants / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010168:Palmitates / Q000378:metabolism; D011522:Protons; D019802:Succinic Acid / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D000071256:Uncoupling Protein 1
D007473:Ion Channels; D024101:Mitochondrial Proteins; D016877:Oxidants; D010168:Palmitates; D011522:Protons; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D013481:Superoxides; D006153:Guanosine Diphosphate; D000226:Mitochondrial ADP, ATP Translocases; D019802:Succinic Acid; D006861:Hydrogen Peroxide; D010100:Oxygen