title: Skeletal muscle dysfunction is associated with derangements in mitochondrial bioenergetics (but not UCP3) in a rodent model of sepsis.
abstract: Muscle dysfunction is a common feature of severe sepsis and multiorgan failure. Recent evidence implicates bioenergetic dysfunction and oxidative damage as important underlying pathophysiological mechanisms. Increased abundance of uncoupling protein-3 (UCP3) in sepsis suggests increased mitochondrial proton leak, which may reduce mitochondrial coupling efficiency but limit reactive oxygen species (ROS) production. Using a murine model, we examined metabolic, cardiovascular, and skeletal muscle contractile changes following induction of peritoneal sepsis in wild-type and Ucp3(-/-) mice. Mitochondrial membrane potential (Δψm) was measured using two-photon microscopy in living diaphragm, and contractile function was measured in diaphragm muscle strips. The kinetic relationship between membrane potential and oxygen consumption was determined using a modular kinetic approach in isolated mitochondria. Sepsis was associated with significant whole body metabolic suppression, hypothermia, and cardiovascular dysfunction. Maximal force generation was reduced and fatigue accelerated in ex vivo diaphragm muscle strips from septic mice. Δψm was lower in the isolated diaphragm from septic mice despite normal substrate oxidation kinetics and proton leak in skeletal muscle mitochondria. Even though wild-type mice exhibited an absolute 26 ± 6% higher UCP3 protein abundance at 24 h, no differences were seen in whole animal or diaphragm physiology, nor in survival rates, between wild-type and Ucp3(-/-) mice. In conclusion, this murine sepsis model shows a hypometabolic phenotype with evidence of significant cardiovascular and muscle dysfunction. This was associated with lower Δψm and alterations in mitochondrial ATP turnover and the phosphorylation pathway. However, UCP3 does not play an important functional role, despite its upregulation.
authors.affiliation: Bloomsbury Institute for Intensive Care Medicine, University College London, London, United Kingdom; Department of Cell and Developmental Biology, University College London, London, United Kingdom parjam.zolfaghari@bartshealth.nhs.uk.
authors.forename: Parjam S
authors.initials: PS
authors.lastname: Zolfaghari
authors.affiliation: Bloomsbury Institute for Intensive Care Medicine, University College London, London, United Kingdom;
authors.forename: Jane E
authors.initials: JE
authors.lastname: Carré
authors.affiliation: Department of Cell and Developmental Biology, University College London, London, United Kingdom.
authors.forename: Nadeene
authors.initials: N
authors.lastname: Parker
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, United Kingdom; and.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Curtin
authors.affiliation: Department of Cell and Developmental Biology, University College London, London, United Kingdom.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Duchen
authors.affiliation: Bloomsbury Institute for Intensive Care Medicine, University College London, London, United Kingdom;
authors.forename: Mervyn
authors.initials: M
authors.lastname: Singer
mesh_terms: D000818:Animals; D019069:Cell Respiration / Q000235:genetics; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics; D007473:Ion Channels / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D009135:Muscular Diseases / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018805:Sepsis / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology; D000071247:Uncoupling Protein 3
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604393:Ucp3 protein, mouse; D000071247:Uncoupling Protein 3
keywords: metabolism; mitochondria; uncoupling protein 3