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

Abstract

Objective: 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. Shamoperated animals served as controls. Confocal microscopy was used to study functional and bioenergetic parameters in cardiomycoytes isolated after 24 h sepsis. Electron microscopy (EM) 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 h was a good discriminator for 72 h survival (AUROC 0.84±0.1, p=0.03) and was used in ex vivo experiments at 24 h to identify septic animals with good prognosis.Measurements from animals with good prognostic showed i) a smaller increase in mitochondrial calcium content and in NADH fluorescence following pacing and ii) increased distance between mitochondria and SR on EM, and iii) NADH redox potential and ATP/ADP 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.4

Chemically synthesized Secoisolariciresinol diglucoside (LGM2605) improves mitochondrial function in cardiac myocytes and alleviates septic cardiomyopathy

“…A prior study, using a different sepsis animal model, reported reduced mitochondrial calcium uptake in isolated non-permeabilized rat cardiomyocytes. They suggested that reduced calcium uptake may underlie lower responsiveness to adrenergic challenge in septic rats [54]. In our study, LGM2605 increased calcium uptake in permeabilized cardiomyocytes but did not improve β-AR responsiveness.…”

The Effect of Sepsis on the Erythrocyte

“…Sepsis has recently been defined as “a life-threatening organ dysfunction caused by a dysregulated host response to infection” [ 1 ]. This dysregulation is particularly evident in the cells, organelles and overall system involved in the delivery and consumption of oxygen, or more specifically, the erythrocytes [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ], mitochondria [ 9 , 10 , 11 , 12 ] and microcirculation [ 13 , 14 , 15 , 16 ]. In this review, we consider the effect of sepsis on the red blood cell (RBC).…”

Mathematical modeling of septic shock: an innovative tool for assessing therapeutic hypotheses

“…3a). In addition, when LPS = 4 the new model showed that energy response was at lower level which correspond the mitochondrial dysfunction and a consequence of a progressive decrease in energy availability during the septic process proposed by Singer et al [64][65][66][67][68][69][70][71][72]. Finally, we considered the result is similar to the immunosuppression mechanism associated with septic shock.…”

“…After introducing these virtual treatments into the initial model (data not shown), the activation of A at 0.2 h interrupted the formation of the irreversible SI* response and hyper-activated E. The results obtained after treatment in the later states (30,72, and 120 h) showed that the activation of anti-inflammation could reduce the hyper-activation of P, activate E, and possibly balance the immune system. By contrast, the inhibition of A in the long term led to the hyper-activation of P and E decreased.…”