Biology subjects

Bourque, S. L.

Publications and source records attributed to Bourque, S. L..

5 recordsLinked to original sources

bioRxiv2026

Mitochondrial-targeted therapy with elamipretide preserves cardiac function and prevents late mortality in murine sepsis-induced cardiac dysfunction.

Sepsis-induced cardiac dysfunction (SICD) occurs in nearly half of septic patients, is associated with increased mortality, and lacks targeted therapy. Emerging evidence implicates impaired mitochondrial function and metabolic inflexibility as central contributors to myocardial depression. Here, we characterized SICD in a murine model of polymicrobial sepsis and evaluated the therapeutic potential of the cardiolipin-stabilizing peptide elamipretide (Ela). Sepsis induced marked impairments in cardiac performance, accompanied by reductions in cardiac cardiolipin content, impaired mitochondrial respiratory capacity localized to complex I, and altered substrate utilization. Integration of stable isotope metabolic flux tracing with lipidomic, metabolomic, and proteomic analyses identified a convergent metabolic bottleneck at the level of the electron transport system. This defect was associated with upstream accumulation of acetyl-CoA, Co-A esters, and ketone bodies, consistent with impaired oxidative flux and energetic failure. Administration of a single early dose of Ela restored cardiolipin content, complex I function, normalized metabolic flux, improved cardiac function during both acute sepsis and recovery, and completely prevented late sepsis-related mortality. These findings identify cardiolipin-dependent mitochondrial dysfunction as a central pathogenic mechanism underlying SICD and position mitochondrial-targeted therapy as a promising therapeutic strategy in sepsis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/736409v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1ca5b47org.highwire.dtl.DTLVardef@2ecfc2org.highwire.dtl.DTLVardef@149ccb9org.highwire.dtl.DTLVardef@1fbcb6_HPS_FORMAT_FIGEXP M_FIG C_FIG Ela improves SICD by stabilizing cardiolipin species and improving mitochondrial complex I function. SICD depicted in red denotes conditions altered compared to healthy control cardiomyocyte, SICD+Ela depicted in green denotes changes relative to SICD. SICD, sepsis-induced cardiac dysfunction; ELA, elamipretide; ADP, adenosine diphosphate; ATP, adenosine triphosphate; ROS, reactive oxygen species.

physiology↗

bioRxiv2026

Real-Time Assessment of Murine Cardiac Oxygenation Using Photoacoustic Imaging

BackgroundPerioperative incidents such as hypoxic cardiac injury often have subtle or nonspecific clinical manifestations. Reduction in myocardial oxygenation precedes biochemical changes, as well as electrical and functional changes. Photoacoustic imaging (PAI) is a modality that uses laser irradiation of tissue to generate ultrasonic waves, enabling spatially resolved quantitative mapping of oxygenated and deoxygenated haemoglobin. We investigated the utility of PAI for real-time monitoring of myocardial and great vessel oxygenation. MethodsMale CD-1 mice were anaesthetised, and photoacoustic and simultaneous B-mode images were acquired of the myocardium and right ventricular outflow tract (RVOT), the pulmonary artery, and aorta. PAI was performed at fractional inspired oxygen levels (FiO2) of 100%, 21%, and then 10%. Separate cohorts of mice were exposed to increasing intravenous doses of either combined phenylephrine and isoprenaline, or individual administration of vasoactive or adrenergic agents. ResultsPAI reliably distinguished changes in oxygenation in the RVOT cavity, pulmonary artery, aorta, and myocardium. PAI detected hypoxia-induced changes in oxygenation, revealing greater desaturation in the myocardium than in the RVOT (-9.85%, 95% CI -14.94 to -4.77, P<0.0001). Escalating doses of phenylephrine and isoprenaline caused a progressive desaturation of the myocardium and RVOT (mean [95% CI]; myocardium 16 mg/kg: -14.64% [-27.62 to -1.65], P=0.0038 and RVOT 32 mg/kg: -18.71% [-32.15 to -5.27], P=0.0003). Myocardial deoxygenation was detected before changes in systolic function or electrical abnormalities. ConclusionsThis work demonstrates that PAI can reliably monitor cardiac oxygen desaturation, potentially offering an earlier warning of cardiac dysfunction and injury compared to existing monitoring tools.

physiology↗

bioRxiv2026

A neonatal rat sepsis score captures the time course and severity of disease in a clinically relevant rat peritonitis model.

BackgroundNeonatal sepsis is a major cause of infant morbidity and mortality worldwide, particularly in preterm and very low birthweight babies. Fundamental differences between neonates and adults warrant clinically relevant models of neonatal sepsis. Here, we describe a preclinical fecal-slurry (FS)-induced peritonitis model of polymicrobial sepsis in neonatal rats, along with a novel neonatal rat sepsis score (nRSS) to monitor illness severity. MethodsPeritonitis was induced in 3-day-old Sprague Dawley rats by intraperitoneal injection of various doses (0.3-1.5mg/g body weight) of fecal slurry (FS); control pups received equivalent doses of vehicle. All pups received analgesics (buprenorphine), antibiotics (ampicillin and gentamicin), and fluids (saline) to model clinical standards of sepsis treatment. Time-dependent changes in circulating cytokines (IL-6, IL-1{beta}) and biomarkers of sepsis pathology (hemoglobin, glucose, alanine transaminase [ALT] levels) were assessed and correlated with nRSS scores. ResultsFS administration caused a dose-dependent increase in severity of sepsis over time, as indicated by increases in mortality rates (based on predefined criteria for euthanasia), nRSS scores, as well as time-dependent changes in circulating glucose, hemoglobin, IL-6, IL-1{beta}, and ALT activity levels. nRSS scores correlated with all quantitative measures of sepsis pathology. Notably, females showed higher mortality and higher early NRSS scores than males at moderate to high FS doses, yet biochemical markers and time of death did not differ between sexes, suggesting that the apparent female vulnerability may reflect more conspicuous behavioral manifestations of illness rather than greater underlying physiological severity. ConclusionInduction of peritonitis in rats at postnatal day 3 produced a consistent and reproducible model of polymicrobial neonatal sepsis. Illness severity was monitored using a newly developed nRSS. By minimizing distress and incorporating standards of care, this model and scoring system may serve as a platform for future investigations into the underlying mechanisms and potential therapeutic interventions for neonatal sepsis. ImpactO_LIA clinically relevant rat model of neonatal polymicrobial sepsis was developed, incorporating standards of care (analgesics, antibiotics, and fluid resuscitation) to better reflect the clinical context in which preclinical findings must ultimately translate. C_LIO_LIA novel neonatal rat sepsis scoring system (nRSS) was developed and validated, providing a sensitive, non-invasive measure of disease severity that correlates with biochemical markers and predicts mortality. C_LIO_LIFemale pups showed higher mortality and earlier behavioral signs of illness than males despite equivalent biochemistry, highlighting that clinical scores may capture sex-dependent vulnerability not apparent in standard biochemical measures. C_LIO_LITogether, this model and scoring system offer a refined platform for mechanistic and therapeutic studies of neonatal sepsis while advancing the welfare-conscious 3Rs principles essential to rigorous preclinical research C_LI

physiology↗

bioRxiv2026

Maternal iron deficiency remodels cardiac mitochondria and alters stress responses in hypertensive pregnancy

Maternal iron deficiency (ID) during pregnancy is associated with cardiovascular adaptations, including reduced blood pressure and improved cardiac efficiency in hypertensive pregnancy. However, whether these apparent functional gains are accompanied by preserved cardiac mitochondrial function remains unclear. Given the high metabolic demands of the maternal heart and irons central role in oxidative metabolism, we examined how maternal ID affects cardiac mitochondrial ultrastructure, respiration, dynamics, and redox status in pregnant spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. Female SHR and WKY rats were fed iron-replete or iron-restricted diets before and throughout gestation. On gestational day 21, cardiac mitochondrial ultrastructure was assessed by transmission electron microscopy, respiration by high-resolution respirometry, mitochondrial dynamics and quality control proteins by immunoblotting, and antioxidant gene expression by RT-qPCR. Iron restriction reduced maternal hemoglobin levels in both strains. ID dams exhibited enlarged, morphologically heterogeneous mitochondria with reduced cristae density and lower succinate-supported respiration. SHR dams exhibited reduced fusion signalling, reflected by a lower L-OPA1:S-OPA1 ratio, lower MFN2 abundance, and further ID-associated reductions in MFN1 and MFN2. In contrast, DRP1 phosphorylation increased in ID-WKY dams. Iron restriction increased LC3-II:I ratio and BNIP3 in SHR, increased PINK1 in both strains, and increased antioxidant gene expression in ID-SHR but decreased in ID-WKY dams. Despite these alterations, downstream apoptosis activation was not observed. Maternal ID was associated with remodelling of myocardial mitochondrial ultrastructure and selectively constrains iron-dependent respiration in hypertensive pregnancy, suggesting favourable hemodynamic adaptations may coexist with underlying bioenergetic constraints in the maternal heart.

physiology↗

bioRxiv2026

Early sex-specific organ transcriptional divergence without physiological differences in a murine model of fecal-induced peritonitis

Sepsis is defined as a dysregulated response to infection, leading to life-threatening organ dysfunction that particularly affects parenchymal organs. Clinical studies remain inconclusive regarding the impact of biological sex on sepsis, and preclinical studies are predominantly performed in male animals. We examined early (8 h) septic responses in male and female mice using a fecal-induced peritonitis (FIP) model. Blood biochemical parameters, body temperature, and murine sepsis scores provided evidence of a septic response in animals randomized to FIP compared to controls, but showed no physiological differences between male and female mice. Transcriptomic analysis of the liver, kidney, and lung showed consistent inflammatory activation in response to sepsis as compared to controls. Notably, in the kidney and lung, female mice exhibited stronger immune activation and a heightened inflammatory response compared to males. Thus, biological sex differences in the septic response can be detected in early acute sepsis without apparent physiological differences.

pathology↗