title: Lack of UCP3 does not affect skeletal muscle mitochondrial function under lipid-challenged conditions, but leads to sudden cardiac death.
abstract: UCP3's exact physiological function in lipid handling in skeletal and cardiac muscle remains unknown. Interestingly, etomoxir, a fat oxidation inhibitor and strong inducer of UCP3, is proposed for treating both diabetes and heart failure. We hypothesize that the upregulation of UCP3 upon etomoxir serves to protect mitochondria against lipotoxicity. To evaluate UCP3's role in skeletal muscle (skm) and heart under lipid-challenged conditions, the effect of UCP3 ablation was examined in a state of dysbalance between fat availability and oxidative capacity. Wild type (WT) and UCP3(-/-) mice were subjected to high-fat feeding for 14 days. From day 6 onwards, they were given either saline or etomoxir. Etomoxir treatment induced an increase in markers of lipotoxicity in skm compared to saline. This increase upon etomoxir was similar for both, WT and UCP3(-/-) mice, suggesting that UCP3 does not play a role in protection against lipotoxicity. Interestingly, we observed 25 % mortality in UCP3(-/-)s upon etomoxir administration vs. 11 % in WTs. This increased mortality in UCP3(-/-) compared to WT mice could not be explained by differences in cardiac lipotoxicity, apoptosis, fibrosis (histology, immunohistochemistry), oxidative capacity (respirometry) or function (echocardiography). Electrophysiology demonstrated, however, prolonged QRS and QTc intervals and greater susceptibility to ventricular tachycardia upon programmed electrical stimulation in etomoxir-treated UCP3(-/-)s versus WTs. Isoproterenol administration after pacing resulted in 75 % mortality in UCP3(-/-)s vs. 14 % in WTs. Our results argue against a protective role for UCP3 on skm metabolism under lipid overload, but suggest UCP3 to be crucial in prevention of arrhythmias upon lipid-challenged conditions.
authors.affiliation: Department of Human Biology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, PO Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Miranda
authors.initials: M
authors.lastname: Nabben
authors.affiliation: Department of Human Biology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, PO Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Bianca W J
authors.initials: BWJ
authors.lastname: van Bree
authors.affiliation: Department of Human Movement Sciences, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: Lenaers
authors.affiliation: Department of Human Biology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, PO Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Joris
authors.initials: J
authors.lastname: Hoeks
authors.affiliation: Department of Human Movement Sciences, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Matthijs K C
authors.initials: MKC
authors.lastname: Hesselink
authors.affiliation: Department of Human Movement Sciences, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Gert
authors.initials: G
authors.lastname: Schaart
authors.affiliation: Department of Molecular Genetics, CARIM School for Cardiovascular Research, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Marion J J
authors.initials: MJJ
authors.lastname: Gijbels
authors.affiliation: Department of Molecular Genetics, CARIM School for Cardiovascular Research, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Jan F C
authors.initials: JFC
authors.lastname: Glatz
authors.affiliation: Department of Cardiology, CARIM School for Cardiovascular Research, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Gustavo J J
authors.initials: GJJ
authors.lastname: da Silva
authors.affiliation: Department of Cardiology, CARIM School for Cardiovascular Research, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Leon J
authors.initials: LJ
authors.lastname: de Windt
authors.affiliation: Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington, Seattle, WA, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Tian
authors.affiliation: Department of Molecular Physiology and Biophysics and Medicine (Cardiology), Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Elise
authors.initials: E
authors.lastname: Mike
authors.affiliation: Department of Molecular Physiology and Biophysics and Medicine (Cardiology), Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Darlene G
authors.initials: DG
authors.lastname: Skapura
authors.affiliation: Department of Molecular Physiology and Biophysics and Medicine (Cardiology), Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Xander H T
authors.initials: XHT
authors.lastname: Wehrens
authors.affiliation: Department of Human Biology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, PO Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schrauwen
mesh_terms: D000818:Animals; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D007473:Ion Channels / Q000172:deficiency / Q000502:physiology*; D008055:Lipids / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000378:metabolism / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000502:physiology*; D018482:Muscle, Skeletal / Q000648:ultrastructure; D010084:Oxidation-Reduction; D000071247:Uncoupling Protein 3
chemical_list: D007473:Ion Channels; D008055:Lipids; D024101:Mitochondrial Proteins; C000604392:UCP3 protein, human; C000604393:Ucp3 protein, mouse; D000071247:Uncoupling Protein 3