Zolfaghari, P.S.; (2012) Whole body metabolism, muscle and mitochondrial function, and the role of uncoupling protein-3 in a mouse model of sepsis. Doctoral thesis , UCL (University College London).

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Abstract

Sepsis, the exaggerated systemic inflammatory response to infection, often leads to multi-organ failure (MOF) and death. Skeletal muscle function is often profoundly affected, with patients requiring prolonged ventilatory support and rehabilitation. The pathophysiology underlying MOF and muscle failure in sepsis remains poorly understood. Recent evidence points to mitochondrial dysfunction and cellular energetic down-regulation, related in part to excess generation of reactive oxygen and nitrogen species (ROS). Substrate oxidation by the mitochondrial respiratory chain generates a proton gradient across the inner mitochondrial membrane that is coupled to ATP production. Mitochondrial uncoupling proteins (UCPs) may reduce mitochondrial ROS formation, though at the expense of oxidative phsophorylation. Notably, UCP3 is up-regulated in sepsis but its physiological role is unknown. I therefore hypothesized that muscle dysfunction in sepsis has a mitochondrial aetiology and increased UCP3 expression offers a protective role. I investigated this in a fluid-resuscitated murine model of faecal peritonitis/MOF (optimized and characterized during this project). I used Ucp3(-/-) mice to explore the role of this uncoupling protein in sepsis. I observed a profound hypothermic and hypometabolic response early in the course of severe sepsis. This was accompanied by respiratory muscle dysfunction and fatigue, as well as a decrease in mitochondrial proton-motive force (measured using novel live-cell 2- photon confocal imaging techniques in freshly isolated ex-vivo diaphragm muscles). By contrast, the mitochondrial proton-motive force was unaffected in septic Ucp3(-/-) mice, but no difference was seen in wholebody metabolic response or respiratory muscle fatigue. Furthermore, proton leak and substrate utilization of mitochondria isolated from whole body skeletal muscle from wild-type septic mice were unchanged, though superoxide production was higher. These findings suggest that upregulation of UCP3 in sepsis has no whole- body metabolic or functional consequence in skeletal muscle. The low global oxygen consumption and diaphragm mitochondrial proton-motive force suggest a reduced cellular metabolic demand in the septic mice.

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