UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Improved Survival in a Long-Term Rat Model of Sepsis Is Associated With Reduced Mitochondrial Calcium Uptake Despite Increased Energetic Demand

Pinto, BB; Dyson, A; Umbrello, M; Carre, JE; Ritter, C; Clatworthy, I; Duchen, MR; (2017) Improved Survival in a Long-Term Rat Model of Sepsis Is Associated With Reduced Mitochondrial Calcium Uptake Despite Increased Energetic Demand. Critical Care Medicine , 45 (8) e840-e848. 10.1097/CCM.0000000000002448. Green open access

[thumbnail of Singer_Mitocho_septic_heart_BBP main paper CCM_REV3.pdf]
Preview
Text
Singer_Mitocho_septic_heart_BBP main paper CCM_REV3.pdf - Accepted Version

Download (725kB) | Preview

Abstract

OBJECTIVES: To investigate the relationship between prognosis, changes in mitochondrial calcium uptake, and bioenergetic status in the heart during sepsis. DESIGN: In vivo and ex vivo controlled experimental studies. SETTING: University research laboratory. SUBJECTS: Male adult Wistar rats. INTERVENTIONS: Sepsis was induced by intraperitoneal injection of fecal slurry. Sham-operated animals served as controls. Confocal microscopy was used to study functional and bioenergetic parameters in cardiomyocytes isolated after 24-hour sepsis. Electron microscopy was used to characterize structural changes in mitochondria and sarcoplasmic reticulum. The functional response to dobutamine was assessed in vivo by echocardiography. MEASUREMENTS AND MAIN RESULTS: Peak aortic blood flow velocity measured at 24 hours was a good discriminator for 72-hour survival (area under the receiver operator characteristic, 0.84 ± 0.1; p = 0.03) and was used in ex vivo experiments at 24 hours to identify septic animals with good prognosis. Measurements from animals with good prognostic showed 1) a smaller increase in mitochondrial calcium content and in nicotinamide adenine dinucleotide fluorescence following pacing and 2) increased distance between mitochondria and sarcoplasmic reticulum on electron microscopy, and 3) nicotinamide adenine dinucleotide redox potential and adenosine triphosphate/adenosine diphosphate failed to reach a new steady state following pacing, suggesting impaired matching of energy supply and demand. In vivo, good prognosis animals had a blunted response to dobutamine with respect to stroke volume and kinetic energy. CONCLUSIONS: In situations of higher energetic demand decreased mitochondrial calcium uptake may constitute an adaptive cellular response that confers a survival advantage in response to sepsis at a cost of decreased oxidative capacity.

Type: Article
Title: Improved Survival in a Long-Term Rat Model of Sepsis Is Associated With Reduced Mitochondrial Calcium Uptake Despite Increased Energetic Demand
Open access status: An open access version is available from UCL Discovery
DOI: 10.1097/CCM.0000000000002448
Publisher version: http://dx.doi.org/10.1097/CCM.0000000000002448
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Critical Care Medicine, General & Internal Medicine, efficiency, heart, mitochondria, myocardial depression, sepsis, INDUCED CARDIAC DYSFUNCTION, PERMEABILITY TRANSITION PORE, SEPTIC SHOCK, PROGNOSTIC VALUE, HEART, CARDIOMYOCYTES, ACTIVATION, MORTALITY, METAANALYSIS, CONTRACTION
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Experimental and Translational Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10043206
Downloads since deposit
0Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item