bluuebunny/crossref_metadata_2025_split huggingface dataset:
Untargeted lipidomics to identify characteristic signatures and mechanisms of mitochondrial diseases according to genetic origin
Authors: Ichkhan Gabriel , Deschênes Sonia , Daneault Caroline , Robillard Frayne Isabelle , Bouchard Bertrand , Des Rosiers Christine , Ruiz Matthieu 
Published: May 2024

Background: The major challenge in mitochondrial diseases relies in their great heterogeneity, in terms of genetic origin (i.e. nuclear or mitochondrial), mutation diversity and clinical manifestations. The underlying mechanisms are still unclear and often considered common to most mitochondrial diseases. Hypothesis: According to the genetic origin, the different lipidomic profiles will reveal common as well as mutation-dependent signatures. Aims: i) Establish the characteristic signatures of human fibroblasts from mitochondrial diseases of distinct genetic origins: either nuclear: LRPPRC and MTFMT, or mitochondrial: NDUFS4, UQCRC2 and ECHS1 compared with healthy fibroblasts and, based on the established signatures, ii) identify the underlying mechanisms. Methods: We used a mass spectrometry-based untargeted lipidomics approach to scan for thousands lipid signals. Based on the identified signatures, selected players were evaluated by quantitative PCR. Results: Principal component analysis shows that each cell line differs from the others. Our lipidomics analyses show that few lipids were modulated in a similar way irrespective of the genetic origin, and especially the increase in cholesterol esters. In contrast, ganglioside metabolism was differentially changed according to the genetic origin. More specifically, while GM3 forms were mostly and significantly increased for MTFMT, UQCRC2 and ECHS1 and moderately increased for NDUFS4, GM3 were decreased for LRPPRC. In addition, the GA1 and GM2 forms produced from GM3 were reduced in all cell lines except for LRPPRC and NDUFS4 where their signals remained unchanged. Since the formation of GA1 and GM2 involves the B4GALNT1 enzyme, we measured its mRNA expression and observed a drastic decrease up to 90% for MTFMT, while it remained unchanged for LRPPRC. Conclusion: The use of untargeted lipidomics is a relevant and powerful approach for the identification of specific signatures and underlying mechanisms of mitochondrial disorders, illustrated here by differentially affected ganglioside metabolism according to genetic origin, providing a starting point that will ultimately guide towards nutritional and therapeutic alternatives. Montreal Heart Institute Fundation, Lactic Acidosis Association and FRQS. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Elevation of miR-150-5p in Brain Microvascular Endothelial Cells as a Result of Prenatal Alcohol Exposure Is Mediated by Transcriptional Mechanisms
Authors: Westenskow Marissa , Gardiner Amy 
Published: May 2024

Fetal Alcohol Spectrum Disorders (FASD) encompass a variety of conditions impacting development in children exposed to alcohol in utero. Vascular alterations such as defective angiogenesis, blood brain barrier permeability, vessel reactivity, and blood flow have been found in various animal models of prenatal alcohol exposure (PAE). The underlying mechanisms of these vascular defects are not fully understood. Our lab previously showed that miR-150-5p was upregulated in brain microvascular endothelial cells (BMVECs) isolated from embryonic mouse cortices following moderate PAE. We identified downstream vascular targets of miR-150-5p in BMVECs and demonstrated that miR-150-5p inhibition could counter alcohol-mediated effects on BMVECS and the cortical microvasculature in vitro and in vivo, respectively. Here, we investigate upstream mechanisms that contribute to miR-150-5p elevation in BMVECs following PAE. We hypothesized that multiple mechanisms, including pathways at the transcriptional level, contribute to increased miR-150-5p abundance in BMVECs following ethanol (EtOH) exposure. Overall transcriptional activity at the miR-150 promoter was increased in BMVECs with EtOH treatment, and pri-miR-150, the primary transcript for miR-150-5p, was elevated in EtOH-treated BMVECs. Additionally, miR-150 promoter methylation was decreased in PAE cortices compared to saccharine-exposed controls (SAC). Current work aims to confirm the role of DNA methylation in transcriptional regulation of the miR-150 promoter in BMVECs and characterize DNA methyltransferase activity in BMVECs during PAE. We also assessed transcription factor binding at the miR-150 promoter and found that miR-150 promoter activation by several transcription factors was blunted with EtOH treatment. Current work involves the investigation of global transcription factor activation in BMVECs in PAE versus SAC. In summary, our research sheds light on multiple mechanisms of miR-150-5p regulation that may contribute to brain microvascular defects as a result of PAE. American Physiological Society Porter Physiology Development Fellowship University of New Mexico Health School of Medicine Department of Cell Biology and Physiology. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Neurophysiological Mechanisms of Exertional Dyspnea in Patient’s Post-Pulmonary Embolism: The Effect of Inhaled Nitric Oxide
Authors: Phillips Devin , James Matthew , Vincent Sandra , Smyth Reginald , Chau Bridgett , Milne Kathryn , D'Arsigny Christine 
Published: May 2024

Following pulmonary embolism (PE), up to a third of patients develop persistent activity-related dyspnea, even in those without chronic thromboembolic pulmonary hypertension (CTEPH). It has been shown that heightened exertional dyspnea in patients post-PE (without CTEPH) is linked to greater inspiratory neural drive (IND) during exercise. The heightened IND, in turn, is secondary to increased physiological dead space (VD/VT) and greater ventilatory requirements for CO2 (VE/VCO2). The reasons for the increased VD/VT and VE/VCO2 are unclear, although pulmonary microvascular dysfunction and the corresponding capillary hypoperfusion is a potential mechanism. Thus, the current study tested the hypothesis that inhaled nitric oxide (iNO), a selective pulmonary vasodilator, would lower exertional IND and dyspnea, and improve exercise endurance in patients post-PE. In turn, the reduced IND and dyspnea would be linked to reductions in VD/VT and VE/VCO2. In this randomized, double-blind, placebo-controlled crossover study, 14 clinically stable patients with chronic activity related dyspnea post-PE (without evidence of PH) completed symptom-limited constant work rate cycle exercise tests while breathing iNO (40 ppm) or placebo (21% O2), on separate days. IND (assessed by diaphragm electromyography), VD/VT and VE/VCO2 (expired and arterialized blood gas), and dyspnea intensity (modified Borg 0-10 scale) were compared throughout exercise. At rest, right-ventricular systolic pressure (RVSP) with placebo or iNO was estimated by echocardiography. At the highest individual standardized exercise time (5.8±2.0 min), iNO decreased VD/VT (0.22±0.09 vs 0.27±0.07, p=0.02), VE/VCO2 (33.0±3.5 vs 34.5±3.8 units, p=0.04), IND (48.8±10.3 vs 57.6±11.8 %, p=0.02) and dyspnea intensity (3.0±1.0 vs 4.0±1.4 Borg units, p<0.01), compared with placebo. Throughout exercise, estimated alveolar ventilation, O2 saturation, O2 pulse and operating lung volumes were unaffected by iNO (all p>0.05). iNO increased exercise endurance time (8.1±3.5 vs 6.5±2.3 min, p<0.001), compared with placebo. iNO reduced resting RVSP by 2.5±2.0 mmHg. iNO decreased exertional IND and dyspnea, and improved exercise endurance in patients with post-PE. The reduced IND, in turn, may be linked to decreased VD/VT and VE/VCO2, reflecting improved ventilation/perfusion. These data provide preliminary evidence of a partially reversible pulmonary vasculopathy, that contributes to dyspnea and exercise limitation in symptomatic patients post-PE. Queen’s University Spear Endowment Grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
The effect of acute estrogen suppression on cutaneous endothelium-dependent vasodilation in women with endometriosis
Authors: Colburn Abigail , Leone Cheryl , Alexander Lacy , Stachenfeld Nina 
Published: May 2024

Cardiovascular disease risk is elevated in women with endometriosis and may be exacerbated by treatments that suppress estrogen. The purpose of this study was to determine the effects of acute estrogen suppression on endothelial function in women with endometriosis. We hypothesized that estrogen suppression would attenuate cutaneous endothelium-dependent vasodilation in endometriosis patients (ENDO; n = 2, 30 (1) y, 21.4 (0.2) kg·m2) but not in healthy controls (CON; n = 6, 28 (5) y, 24.9 (5.2) kg·m2). Trials were conducted with (POST) and without (PRE) 4 days of estrogen suppression (400 mg/day gonadotropin-releasing hormone antagonist, Elagolix®) during the first week of separate menstrual cycles. The cutaneous circulation was utilized as a model of microvascular vasodilatory function. Laser Doppler flowmetry was continuously measured during graded perfusions of acetylcholine through intradermal microdialysis (ACh, 1x10−10 – 1x10−1 M). Maximal vasodilation was elicited via 28 mM sodium nitroprusside perfusion and local heating (42°C). Cutaneous vascular conductance was calculated as LDF/mean arterial pressure (MAP). Dose response curves were generated with nonlinear modeling of normalized data with constraints and compared via median effective ACh dose (ED50) and HillSlope. Data are presented as mean (SD) and significance was set at α = 0.05. Baseline MAP was similar between trials for CON (PRE, 80.70 (6.32) mmHg; POST, 82.30 (5.37) mmHg; t[5] = -0.74, P = 0.49) and ENDO (PRE, 72.22 (0.31) mmHg; POST, 79.17 (7.31) mmHg; t[1] = -1.29, P = 0.42). ED50 was not impacted by estrogen suppression in CON (PRE, -3.61 (2.19) logM; POST, -2.80 (1.13) logM; t[5] = -1.04, P = 0.35) or ENDO (PRE, -3.08 (1.74); POST, -2.85 (0.68); t[1] = -0.13, P = 0.91). Similarly, HillSlope was not altered in CON (PRE, 1.00 (0.96); POST, 0.99 (1.14); t[5] = 0.01, P = 0.99) or ENDO (PRE, 0.81 (0.72); POST, 1.16 (1.15); t[1] = -0.26, P = 0.84). Acute estrogen suppression did not impact cutaneous endothelium-dependent vasodilation in healthy controls or women with endometriosis. A greater sample size will further evaluate this relationship. National Institutes of Health Grant 1R01HL161000. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Long-duration bed rest augments sympathetic neurovascular responses to simulated orthostatic stress among females
Authors: Iannarelli Nathaniel , Greaves Danielle , Arbeille Philippe , Hughson Richard , Klassen Stephen , Shoemaker Kevin 
Published: May 2024

Our understanding of the impact of long-duration head-down bed rest (HDBR) on sympathetic neurovascular regulation during orthostatic stress remains incomplete. Through retrospective analysis of the WISE-2005 long-duration bed rest trial, this study aimed to investigate the impact of 60 days of -6° HDBR on the transduction of integrated muscle sympathetic nerve activity (MSNA; peroneal microneurography) into total peripheral resistance (TPR; Finometer Modelflow) responses during rest and graded lower body negative pressure (LBNP; -20, -30, and -45 mmHg). Signal averaging quantified sympathetic transduction for 12 cardiac cycles (ECG) following integrated MSNA bursts in healthy females ( n = 12; 25-40 years). Mixed-effects modeling and post-hoct-tests assessed the impact of HDBR on sympathetic transduction during rest (5-min) and graded LBNP (3-min per level). Data are presented as mean ± SD. Long-duration HDBR did not affect resting total MSNA (pre-HDBR: 909 ± 368 AU/min, post-HDBR: 910 ± 254 AU/min; p = 0.999). HDBR did not affect total MSNA responses to -20 mmHg LBNP (pre-HDBR: 1430 ± 599 AU/min, post-HDBR: 1823 ± 433 AU/min), -30 mmHg LBNP (pre-HDBR: 1574 ± 549 AU/min, post-HDBR: 1924 ± 587 AU/min), or -45 mmHg LBNP (pre-HDBR: 1950 ± 819 AU/min, post-HDBR: 2328 ± 880 AU/min; p = 0.191). HDBR did not affect resting sympathetic transduction to TPR (pre-HDBR: 0.002 ± 0.16 mmHg/L/min, post-HDBR: -0.091 ± 0.12 mmHg/L/min; p = 0.296). However, HDBR augmented TPR transduction responses to graded LBNP (HDBR-by-LBNP interaction: p = 0.050). Pre-HDBR, TPR transduction responses were unchanged with graded LBNP (all p > 0.05). In contrast, post-HDBR, TPR transduction responses increased progressively with graded LBNP (rest: -0.09 ± 0.12 mmHg/L/min, -20 mmHg: 0.22 ± 0.31 mmHg/L/min, -30 mmHg: 0.30 ± 0.34 mmHg/L/min, -45 mmHg: 0.44 ± 0.12 mmHg/L/min; all p < 0.005). The same effect of HDBR was observed when sympathetic transduction of mean arterial pressure was analyzed (data not shown). These data suggest that long-duration HDBR augments sympathetic neurovascular responses to integrated MSNA bursts during orthostatic stress among females. This work was supported by the Canadian Space Agency, the French “Centre National d’Etudes Spatiales”, the European Space Agency, and the National Aeronautics and Space Administration of the USA. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
The Effects of Puberty Blocking Treatment (Gonadotropin Releasing Hormone Agonist) on Reproductive Function in Young Female Rats
Authors: Jones Brandon , Hydock David 
Published: May 2024

The number of adolescents identifying as transgender has been increasing with many transgender youth receiving treatment with a gonadotropin releasing hormone agonist (GnRHa) that suppresses sex hormone production (i.e., puberty blocker). Transgender individuals taking a GnRHa to block puberty have reported improved mental wellbeing, but the physiological impact on reproductive function needs to be examined. Objective: To investigate the effects of puberty blocking treatment using GnRHa on reproductive morphology and function in young female rats. It was hypothesized that puberty blocking treatment would decrease fertility. Methods: Four-week old female Sprague Dawley rats were given daily subcutaneous injections of the GnRHa triptorelin or saline as control. After four weeks of treatment a group of rats were euthanized and the uterus and ovaries were removed for H&E staining to assess morphology. An additional group was taken off GnRHa treatment for 4-weeks to examine recovery of reproductive organ morphology. The final group was taken off GnRHa treatment and housed with fertile males to determine reproductive performance. Results: GnRHa treatment led to a reduction in the mass of uteri and ovaries which recovered after 4-weeks of drug withdrawal. The myometrial and endometrial thickness of the uterus was reduced in GnRHa treated animals. The ovaries of puberty blocked animals exhibited a disruption in follicle development and corpora lutea health. The morphology of the uterus and ovaries recuperated after 4-weeks of drug withdrawal. No significant difference in pregnancy rate was detected; however, both the number of days until pregnancy detection and number of days until giving birth were considerably longer in GnRHa rats following withdrawal. The number of pups per litter was also significantly reduced by puberty blocking treatment but no abnormalities were observed in the pups. Conclusion: Young female rats treated with a GnRHa had significantly delayed development of the reproductive organs. After 4 weeks of GnRHa withdrawal reproductive organ mass and morphology recovered. A minor disruption in reproductive function was detected immediately following GnRHa withdrawal. These physiological effects on reproductive health should be considered when administering a GnRHa to block puberty. No external funding was used to support this research. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Mitochondrial AKAP1 Is Necessary for Obesity- and Angiotensin II-induced Hypertension
Authors: Zhao Yuying , Guo Dengfu , Strack Stefen , Rahmouni Kamal 
Published: May 2024

Best known as the powerhouse of the cell, mitochondria play a crucial role in obesity and associated cardiovascular diseases. A-kinase anchoring protein 1 (AKAP1) is a mitochondrial scaffold protein that regulates mitochondria function by promoting protein kinase A (PKA)-mediated phosphorylation of Dynamin-related protein 1 at Ser637 through recruitment of PKA to the outer mitochondrial membrane. However, the role of mitochondrial AKAP1 in the regulation of blood pressure and the development of hypertension is not known. Here, we used mice harboring the Akap1 gene deletion to investigate the importance of AKAP1 in obesity- and angiotensin II (Ang II)-induced hypertension. AKAP1−/− mice and wild type (WT) littermates were maintained on a high fat high sucrose diet (HFHSD) for 12 weeks starting from 4 weeks of age. Interestingly, AKAP1−/− mice fed HFHSD displayed significantly attenuated weight gain compared to control mice fed HFHSD (male: 39.5 ± 1.7 vs 47.3 ± 2.3 g, and female: 29.7 ± 1.3 vs 32.5 ± 1.5 g, p<0.05 for both). This was associated with decreased fat mass in AKAP1−/− mice-fed HFHSD (male:16.2 ± 0.9 g and female: 8.7 ± 1.1 g) compared to controls (male: 21.2 ± 1.7 g and female: 13.9 ± 1.6 g, p<0.05 for both). Transmission electron microscope analysis of neuronal mitochondrial in the accurate nucleus of the hypothalamus showed that AKAP1−/− mice fed HFHSD have remarkably reduced mitochondria size (0.14 ± 0.05 vs 0.20 ± 0.07 μm2, p<0.05) and mitochondria length (0.57 ± 0.10 vs 0.50 ± 0.10 μm, p<0.05) relative to controls. Next, using the radio-telemetry system, we found that blood pressure was lower in AKAP1−/− male mice fed HFHSD compared to WT mice fed HFHSD (systolic: 118.2 ± 3.2 mmHg vs 126.7 ± 4.3 mmHg, p = 0.05, n= 5WT and 6 AKAP1−/−). Furthermore, infusion of Ang II (600ng/kg/min for 14 days) via osmotic minipumps in normal chow-fed male mice tended to evoke less increase in mean blood pressure in AKAP1−/− mice compared to WT controls (35.2 ± 3.5 vs 45.7 ± 10.1 mmHg, n=3). Taken together, our findings point to the importance of mitochondrial AKAP1 for the development of hypertension induced by obesity and Ang II. Veterans Affairs NIH. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Pioglitazone does not affect exogenous glucose oxidation or metabolic clearance rate during steady-state aerobic exercise at high altitude
Authors: Margolis Lee , Wilson Marques , Drummer Devin , Carrigan Christopher , Murphy Nancy , Allen Jillian , Dawson M. Alan 
Published: May 2024

Background: Hypoxia-induced insulin insensitivity decreases exogenous glucose oxidation and metabolic clearance rate (MCR, proxy for peripheral glucose uptake) in native lowlanders exercising during the initial hours of high-altitude (HA) exposure compared sea level. These data suggest that administering an insulin sensitizing drug before HA exposure may increase exogenous glucose oxidation rate by stimulating peripheral glucose uptake. Objective: To compare the effects of pioglitazone (PIO) and placebo (PLA) on exogenous glucose oxidation and MCR during steady-state aerobic exercise at HA. We hypothesized that exogenous glucose oxidation and MCR would be higher with PIO than PLA. Methods: Using a randomized, crossover design, native lowlanders (n = 7 males, mean ± SD, age: 23 ± 6 y, body mass: 84 ± 11 kg) consumed 145 g (1.8 g/min) of glucose while performing 80-min of metabolically-matched (1.43 ± 0.16 VȮ2 L/min) treadmill exercise at HA (460 mmHg) after being administered PIO (15 mg) or PLA (microcrystalline cellulose pill) daily for five days. Substrate oxidation and glucose turnover were determined using indirect calorimetry, oral 13C-glucose and [6,6-2H2]-glucose primed, continuous infusions. Results: Exogenous glucose oxidation rate was not different between PIO (0.31 ± 0.03 g/min) and PLA (0.32 ± 0.09 g/min). Total carbohydrate oxidation with PIO (1.65 ± 0.22 g/min) was the same as PLA (1.68 ± 0.32 g/min). There were no treatment effects on glucose rate of appearance (PIO: 2.46 ± 0.27, PLA: 2.43 ± 0.27 mg/kg/min) disappearance (PIO: 2.19 ± 0.17, PLA: 2.20 ± 0.22 mg/kg/min), and MCR (PIO: 1.63 ± 0.37, PLA: 1.73 ± 0.40 mL/kg/min). Conclusion: These data do not support our hypothesis that exogenous glucose oxidation during exercise at HA can be restored through the short-term administration of PIO. Findings from this study may suggest that hypoxia-induced insulin resistance may be a symptom and not the primary etiology of dysregulated glucose metabolism during acute HA exposure. Supported by MOMRP; authors’ views not offcial US Army or DoD policy. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.