bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Intravenous Delivery of N,N Dimethyltryptamine on Sleep-Wake States in Rat
Authors: Summerfield Rachel , Groenhout Trent , Liu Tiecheng , Vanini Giancarlo , Mashour George A. , Pal Dinesh
Published: May 2024

Psychedelics, including N, N, Dimethyltryptamine (DMT), are being increasingly explored for therapeutic potential to treat psychiatric disorders such as depression, anxiety, and post-traumatic stress disorder. These and other psychiatric conditions have a bidirectional relationship with sleep patterns but the impact of psychedelics, particularly DMT, on sleep architecture is incompletely understood. Therefore, in this study, we determined the effect of intravenous DMT administration on sleep-wake states in male and female rats. Under surgical isoflurane anesthesia, adult Sprague Dawley rats (n=10, 5 male, 5 female) were instrumented with electrodes to record electroencephalogram (EEG) from across the cortex and electromyogram (EMG) from dorsal nuchal muscles. In addition, a chronic catheter was positioned in jugular vein for the infusion of DMT or 0.9% saline (as vehicle control). Each rat received an intravenous bolus (100 uL/min over 5 min) of either one of two doses of DMT (low dose: 3.75 mg/kg, high dose: 7.5 mg/kg) or 0.9% saline. The DMT and saline infusions were performed 30-minutes after the start of the lights-ON period (8:00 am) after which EEG and EMG data were recorded for 24h across the light and dark cycle. EEG and EMG data were manually scored (SleepSign, Kissei Comtec) in 4-second intervals and classified as wakefulness, slow-wave sleep, or rapid eye movement sleep, then averaged in 3h bins across the 24h recording period. A linear mixed model was used to compare the changes in percent time spent in each state, mean duration per episode for each state, and mean number of episodes for each state, between vehicle control and DMT infusion sessions. There was a statistically significant increase in the time spent in wakefulness in the first 3h bin after DMT infusion (p<0.02 for low dose, p<0.03 for high dose). In the same 3h bin, a significant decrease in slow-wave sleep (p<0.02 for low and high dose DMT) was observed. DMT infusion produced a significant increase in the latency to the onset of rapid eye movement sleep (p<0.01), but no statistical effect was observed on the time spent in rapid eye movement sleep during the light period. Our results with DMT align with previous reports showing an increase in wakefulness after administration of serotonergic psychedelics. Further analysis of neurophysiologic data is needed to understand the neural dynamics associated with DMT-induced increases in wakefulness.

Department of Anesthesiology, University of Michigan. RS was partly supported by Magnificent Michigan Summer Undergraduate Research fellowship, University of Michigan.

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.
Technology-Mediated Learning in Higher Education Physiology Classes: The Use of MeGli App to Teach Glycemic Control
Authors: de Gouvêa Fernandes Ana Clara , Magalhães Carneiro Everardo
Published: May 2024

Glycemic control is a fundamental physiological concept in diabetes and obesity. Proper training of healthcare professionals in this content is essential for disease prevention and management. Active learning methods, including technology-mediated learning (TML), are important for effective education and student engagement. Given the complexity of physiology, educational technology can facilitate the visualization of its dynamic processes. Thus, we've developed the MeGli smartphone application as an educational tool to teach glycemic control and related conditions, aimed at undergraduate students in health and biological courses. Our hypothesis is that the use of MeGli in Physiology classes promotes student learning and satisfaction. MeGli ( https://t.ly/crEwT ) is a didactic simulator for glycemic metabolism, allowing users to observe postprandial and fasting events, interact with objects, and explore cellular processes. The aim of this study was to conduct and evaluate a TML class using the app and its impact on students' outcomes in Biological Sciences Physiology classes at University of Campinas (n = 23). We analyzed pretest-posttest knowledge questionnaires using the Wilcoxon matched-pairs signed rank test (p ≤ 0.05) due to non-normal data (Shapiro-Wilk normality test). Additionally, we applied a Likert scale opinion survey. Prior to the intervention, students provided informed consent, ensuring anonymous participation. The use of MeGli in a non-expository class, where students consulted the app in an active-learning process for answering and discussing questions, led to a significant improvement in their performance on the topic of glucose metabolism and diabetes (pretest mean 5,739± 0,3784 versus 8,652± 0,2142 on posttest; p < 0.0001). In terms of student feedback, opinion questionnaire results were overwhelmingly positive. All students agreed that the app was useful for learning and helped in their understanding of diabetes mechanisms. 87% understood the importance of healthy eating and physical exercise through the app. 91.3% reported a higher acquisition of knowledge due to the app's use and found the app-integrated class more stimulating and engaging. These findings strongly support the effectiveness of the MeGli application in facilitating physiology education, leading to a more motivating educational experience. Consequently, this study is significant in introducing an innovative tool that mediates active learning with technology, enhancing physiology teaching strategies and improving the education of future healthcare professionals.

CNPq (441028/2020-9), FAPESP (2018/26080-4), CEPID (2013/07607-8).

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 opioid buprenorphine differentially affects laryngeal and tracheal sensory receptors
Authors: Frazure Michael , Morimoto In , Iceman Kimberly , Pitts Teresa
Published: May 2024

The current study aims to determine mechanisms of impaired airway protection following opioid administration. Experiments were performed on N=10 anesthetized male Sprague Dawley rats. Bipolar fine wire electromyogram (EMG) wires were implanted in various muscles to evaluate breathing and swallowing. Swallows were evoked by activation of laryngeal touch receptors, tracheal mechanoreceptors, and tracheobronchial c-fibers as follows: A) Light laryngeal touch with a Von Frey filament; B) Rapid inflation of a balloon in the proximal trachea; C) Stimulation of the carina with thin polyethylene tubing. Trials were performed before and after buprenorphine administration (0.01 mg/kg IV). 2-Way ANOVA detected an effect of drug [F(1,16)=40.6, p<0.0001] and stimulus [F(2,19)=4.2, p=0.03] on swallow frequency. Post hoc comparisons showed that after buprenorphine administration, laryngeal touch evoked significantly more swallows (10±4) than tracheal distension (1±1, p=0.03) or carina stimulation (1±3, p=0.04), suggesting that laryngeal sensation is critical for airway protection following opioid administration. This has implications for prevention of aspiration pneumonia in populations that have an increased risk of reduced laryngeal sensation and are commonly treated with opioids (e.g., post-surgical, critically ill, and/or head and neck cancer patients).

Research reported in this abstract was supported by NIH grants NS110169, HL155721, HL163008, HD110951, NS097781, OT20D001983, the Craig H. Neilsen Foundation Pilot Research Grant 546714, Kentucky Spinal Cord and Head Injury Research Trust, and the Commonwealth of Kentucky Challenge for Excellence.

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.
Down to the Wire and Under Pressure: a historical perspective of the development of small vessel myography
Authors: Kosmach Anna , Mitchell Ray , Bagher Pooneh
Published: May 2024

Wire and pressure myography are both isolated vessel preparations that developed in the 1970s and '80s to study the microvasculature. These two in vitro methods shaped the possibilities for experimentation on small vessels, including arteries, veins, and lymphatics. In this work, publications and book chapters were used to synthesize a historical record of the emergence and landmark developments of wire and pressure myography. Following the creation of these techniques, vascular physiologists could now obtain either isometric measurements of vessel tension (wire myography) or isobaric measurements of vessel diameter (pressure myography). Further, vascular smooth muscle cells and endothelial cells could be individually assessed using pharmacological agents or following denudation, the process of removing the endothelial cell layer. This work examines the role of wire and pressure myography in furthering our understanding of microvascular physiology, highlights the different values of these two techniques, and acts as a supplement to enrich the current understanding of the standard practice of wire and pressure myography. These techniques left a lasting impact on the field of vascular physiology and, today, benefit researchers across fields, especially when linked to other tools including calcium imaging, electrophysiology, and disease or transgenic animal models.

Project supported by NIH Grant R01HL155618.

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.
Actin cytoskeletal proteins in mice cortical microvessels decreased with aging
Authors: Chandra Partha , Panner Selvam Manesh Kumar , Rutkai Ibolya , Castorena-Gonzalez Jorge , Sikka Suresh , Katakam Prasad , Mostany Ricardo
Published: May 2024

Background: The actin cytoskeleton regulates many important cellular processes in the brain, including cell division and proliferation, migration, and differentiation. The interactions of actin microfilaments with plaque proteins zonula occludens (ZO)-1, -2, -3 are required ensuring the formation of a polarized brain endothelium which ultimately drives development of blood-brain barrier (BBB). In this study, we carried out an extensive evaluation of proteins involved in the structure and function of mouse brain cortical microvessels (MVs) using a discovery-based quantitative proteomic approach. Methods: Cortical MVs were isolated from equal number of age-matched, male and female, young (4–6 months), middle-aged (12–14 months), and old (20–21 months) mice obtained from Jackson Laboratory [Tg(Thy1-EGFP)MJrs/J] and bred in a C57B16J background (n = 6/group). The presence of end-arterioles, capillaries, and venules in MVs was confirmed by light microscopy and by alkaline phosphate staining. Proteomics analysis was performed using liquid chromatography/mass spectrometry. Results: We quantified 4746, 4216, and 4579 differentially expressed proteins by proteomics in brain cortical MVs of young, middle-aged, and old mice, respectively. We found that several actin cytoskeletal-related alpha actinin-1, -2, -3 (ACTN1/2/4), actin-related protein -2, -3, -3B (ACTR2/3/3B), actin-related protein 2/3 complex subunit -1A, -2, -4, -5 (ARPC1A/2/4/5), and [F-actin]-monooxygenase MICAL3 proteins were significantly downregulated in mice cortical MVs with aging. Under physiological conditions, cerebral endothelial cells are connected by tight junctions (TJs) and adherens junctions (AJs). The TJ and AJ proteins are anchored to the actin cytoskeleton by multiple accessory proteins, ZO-1, ZO-2 and ZO-3. Interestingly, we observed that several TJ, AJ, and their signaling (PKC-α/γ/ε, RHOA, RAB3 and YES1) proteins were significantly downregulated in mice cortical MVs with aging. Moreover, we previously documented that oxidative stress during aging leads to adverse protein profile changes of brain cortical MVs that affect mRNA/protein stability and ATP synthesis capacity in mice. Conclusions: We suggest that increased oxidative stress during aging leads to protein expression profile changes of brain cortical MVs that affect ATP synthesis capacity, which leads to actin cytoskeletal dysregulation, and accelerating to endothelial and BBB dysfunction in the brain microvasculature with aging.

Funding: AG075988, HL148836, AG063345, AG074489, NS114286, AG047296, HL141143, HL168568, and the Louisiana Board of Regents Endowed Chairs for Eminent Scholars program.

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.
Cellular Mechanisms for pH Regulation and Energy Metabolism in Sharks and Rays
Authors: Roa Jinae , Tresguerres Martin
Published: May 2024

Similar to mammalian kidney distal tubule cells, specialized shark and ray gill epithelial cells maintain blood pH homeostasis. These shark and ray gill cells are either enriched with the Na+/K+-ATPase (NKA) and responsible for acid secretion or enriched for the vacuolar H+-ATPase (VHA) and responsible for base secretion. Moreover, both cell types contain abundant mitochondria and glycogen, and glycogen content decreases in active acid-base regulatory cells in vivo. Additional experiments with isolated gill cells in vitro show that glycogen coincides with the subcellular localization of NKA and VHA. Under control conditions, glycogen and NKA are at the cell membrane of acid-secreting cells while glycogen and VHA are in the cytoplasm of base-secreting cells. During exposure to alkalosis, NKA and glycogen localization remains unchanged in acid-secreting cells; however, both VHA and glycogen translocate to the cell membrane of base-secreting cells. Interestingly, this process is prevented by pharmacological inhibition of the acid-base sensing enzyme, soluble adenylyl cyclase (sAC). This suggests a novel mechanism, a coupling of glycogen metabolism with acid-base regulation that sustains ATPase function during sudden periods of increased energy demand. Since VHA, sAC, and glycogen are evolutionarily widespread, this mechanism is likely to apply broadly to other organisms and systems, perhaps including chronic kidney disease.

APS Porter Predoctoral Fellowship and National Science Foundation Postdoctoral Research Fellowship in Biology #1709911 to JR, National Science Foundation Grant IOS 1354181 to MT.

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.
Aquaporin-9 (AQP9) exerts a role in the early phase of the systemic inflammation of a murine model of endotoxic shock
Authors: Tesse Angela , Garra Sabino , Zagaria Nicola , Mentino Donatella , Rützler Michael , Gena Patrizia , Calamita Giuseppe
Published: May 2024

Septic shock is the most severe complication of sepsis, characterized by a systemic inflammatory response following bacterial infection, leading to multiple organ failure and dramatically high mortality. AQP9 is an aquaglyceroporin/peroxiporin mainly expressed in hepatocytes and neutrophils and recently associated with inflammatory and infectious responses. Here, we evaluated whether AQP9 has a role in mouse systemic inflammation during endotoxic shock. Wild-type ( Aqp9+/+; WT) and Aqp9−/− knockout (KO) male mice were submitted to endotoxic shock by i.p. injection of LPS (40 mg/kg) and the related survival times were followed for 72 h. Nitric oxide (NO) and superoxide anion (O2−) production, and the expression of inducible NO‐synthase (iNOS) and cyclooxigenase‐2 (COX‐2) were measured in liver, kidney, aorta, heart and lung of mice. LPS‐treated KO mice survived significantly longer than WT mice, and 25% of the KO mice fully recovered from LPS treatment. The LPS‐injected KO mice had lower inflammatory NO and O2− productions and reduced iNOS and COX‐2 through impaired NF‐κB p65 activation in liver, kidney, aorta, and heart as compared to LPS‐treated WT mice. Treatment of rodent hepatoma FaO cells with the AQP9 blocker HTS13286 prevented the LPS‐induced increase of NO and O2−. AQP9 seems to have a role in the early acute phase of LPS‐induced endotoxic shock likely involving the NF‐κB pathway, potentially through mediating uptake of extracellular H2O2, and PTP-dependent signaling.

Support from Italian Government to GC: “Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale 2017” PRIN2017 grant # 2017J92TM5 and “Fondo Integrativo Speciale per la Ricerca 2020”-FISR 2020 CoVAPin grant # FISR2020IP_04051); Support from University of Bari Aldo Moro to GC: grant “Horizon Europe Seeds 2022-2023” NextgenerationEU Programma MUR-Fondo Promozione e Sviluppo-DM 737/2021-Uniba Euroseeds ID #S10. Support from Regione Puglia to PG: “Research for Innovation (REFIN)”, POR Puglia 2014/2020—Asse X—Azione 10.4, UNIBA132-ID #091C54A8.

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.
Contributors to Diminished Cardiorespiratory Fitness in Young Users of Electronic Cigarettes
Authors: Simovic Tijana , Matheson Chloe , Cobb Kolton , Tunon Enrique , Nana-Sinkam Patrick , Rodriguez-Miguelez Paula
Published: May 2024

Background: Cardiorespiratory fitness, an independent marker of cardiovascular health, represents the ability of respiratory, cardiovascular, and muscular systems to effciently deliver and utilize oxygen (O2) during exercise. Recently, reduced cardiorespiratory fitness was identified in young and healthy, regular users of electronic (e-) cigarettes; however, its limiting factors are not established. Thus, the purpose of this study was to investigate the contributors to impaired cardiorespiratory fitness in young regular users of e-cigarettes. Methods: An evaluation of hemodynamics, chronotropic response, and oxygen utilization during exercise was completed in nineteen regular users of e-cigarettes (EU, age: 23±3 yr; e-cigarette usage 4±2 yr.) and sixteen demographically matched non-users (NU, age: 23±3 yr.). Hemodynamics were accessed via a non-invasive signal morphology impedance cardiography device, while chronotropic responses were measured as changes in peak heart rate (HR). Oxygen extraction ratio (difference in arterial and venous O2 content) at baseline and peak exercise was also recorded. Fold changes from rest to peak exercise were assessed to provide insight into potential factors that limit cardiorespiratory fitness. Results: At peak exercise, users of e-cigarettes exhibited significantly higher chronotropic incompetence ( p=0.033) and lower ( p=0.047) peak HR than non-users, with no differences in other hemodynamic assessments. Significantly ( p=0.025) lower skeletal muscle O2 extraction (EU=51±11 vs. NU=61±10%) was also observed in users of e-cigarettes during peak exercise. Fold changes in chronotropic (HR; p=0.915) and hemodynamic (cardiac output; p=0.279) responses were similar between both groups, while significant ( p=0.048) differences in oxygen extraction ratio were identified between the users of e-cigarettes (0.5±0.3 fold change) and non-users (0.8±0.3 fold change). Conclusions: Results from our study demonstrate that young, regular users of e-cigarettes exhibit abnormal chronotropic responses and impaired skeletal muscle oxygen utilization during exercise when compared to non-users, suggesting reduced cardiovascular and muscle health. Overall, our findings contribute to the growing body of evidence that supports the negative effects of regular e-cigarette use on young individuals.

Supported in part by a Rapid Response Project NIDA/FDA (PRM).

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.
Comparing changes to the skeletal muscle transcriptome of young and aged mice to young and aged humans in response to acute eccentric contractions
Authors: Gordon Bradley , Boykin Jake , Laskin Grant , Vied Cynthia
Published: May 2024

Resistance exercise alters several molecular events in skeletal muscle that change muscle size and function, including changes to the transcriptome. The signals altering the muscle transcriptome in response to resistance exercise remain ill defined. Defining those regulatory signals in muscle requires non-human models where manipulations can assess cause and effect. The electrically induced, unilateral eccentric contraction model of resistance exercise in rodents is widely used to mimic resistance exercise. However, the transcriptional changes that occur in response to eccentric contractions in the rodent model and the continuity of the rodent model to resistance exercise in humans are not well known. The purpose of this study was to define the transcriptional changes in skeletal muscle that occur in response to acute eccentric contractions in young and aged mice and define their continuity to transcriptional changes in the muscle of young and aged humans. Four-month-old and 24-month-old male C57BL/6 mice were subjected to a bout of electrically induced, unilateral eccentric contractions of the tibialis anterior (TA) muscle. RNA was isolated from the TA and subjected to RNA Sequencing. Lists of differentially expressed genes (DEGs) from the TA of young and aged mice were compared to RNA Sequencing datasets generated from the vastus lateralis muscle of young and aged humans following acute eccentric contractions. L andscape I n S ilico deletion A nalysis (Lisa) was used to predict the magnitude of transcription factor regulation of the DEGs. DEGs for mice or humans were categorized into age specific DEGs (specific to young or aged) or DEGs shared by both ages. The number of DEGs for mice or humans were distributed equally to each category, showing an age specific distribution that was conserved in both mice and humans. However, the DEGs in young and aged mice had very little overlap to the DEGs in young and aged humans. Only 113 DEGs were common across all ages and species. Interestingly, the relationship of transcription factors predicted to regulate DEGs between young and aged mice or young and aged humans was very strong. However, the relationship of transcription factors predicted to regulate DEGs of young mice and young humans or aged mice and aged humans was rather weak. In all, these data highlight the consistencies and differences in the muscle transcriptomic response to eccentric contractions.

This work was supported in part by NIH R03AG073445 (BSG).

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.
Myeloid Specific Hypoxia Inducible Factor 1 Alpha contributes to Immune Metabolic Reprogramming in Human Salt Sensitive Hypertension
Authors: Haynes Alexandria Porcia , Saleem Mohammad , Jamison Sydney , Pitzer Mutchler Ashley , Kirabo Annet
Published: May 2024

Salt-sensitivity of blood pressure (SSBP), acute changes in blood pressure that mirror dietary salt intake, is a major risk factor for cardiovascular disease independent of hypertension. We previously found that oxidative lipid protein modification via NADPH oxidase (NOX2) reactive oxygen species (ROS) production in antigen presenting cells (APCs) contributes to SSBP. Hypoxia Inducible Factor 1 Subunit Alpha (HIF1α) plays a role in metabolic reprogramming and maturation of dendritic cells but its role in the pathogenesis of SSBP is not known. I hypothesize that HIF1α expression specifically in APCs contributes to SSBP by promoting a switch to anaerobic energy production through glycolytic enzyme induction. To test this hypothesis, we performed both bulk and single cell transcriptomic analysis in circulating immune cells following both in vitro and in vivo salt-loading/depletion protocols to phenotype people for SSBP. We found that compared to normal (150 mMol/L), isolated monocytes from women (N =11) treated with high sodium (190 mMol/L) in vitro for 72 hours exhibited a marked increase in expression of HIF1α (16149 ± 6246.1 vs. 42233 ± 20836, p = 2.28E-05). This was associated with increased downstream expression of glycolytic enzymes LdhA (29600 ± 12391 vs. 55998 ± 17118, p = 0.013928), which catalyzes the conversion of pyruvate to lactate under anaerobic conditions, and PDK1 (1422.2 ± 880.80 vs. 2651.3 ± 1216.2, p = 0.0091) which attenuates the conversion of pyruvate to acetyl-CoA through inhibition of pyruvate dehydrogenase, stopping its entry to the citric acid cycle. Moreover monocyte-specific expression of PDK1 correlated with a decrease in systolic blood pressure from salt-loading to salt-depletion (r = 0.6753, p = 0.06608). Our data indicate that HIF1α may play a role the pathogenesis of SSBP by contributing to immune metabolic reprogramming.

1R03HL155041-01 (Kirabo, PI)1R01HL144941-01A1 (Kirabo, PI).

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.
Postnatal diaphragm muscle and phrenic motor neuron development is impaired in Spastic mice
Authors: Kopper Leo , Brandenburg Joline , Zhan Wen-Zhi , Fogarty Matthew , Sieck Gary C.
Published: May 2024

In rats, there is a strong association between the emergence of mature diaphragm muscle (DIAm) myosin heavy chain isoform expression and the expansion of phrenic motor neuron (PhMN) size (from ~21-28 days postnatal (P)), alongside the manifestation of mature morphological and functional properties. In the Spastic ( Spa) mutant mouse, mutated glycine receptors lead to a spasticity phenotype emerging between P14-28, concomitant with DIAm and PhMN development. In adult Spa mice, DIAm weakness, fiber atrophy and loss of larger PhMNs is evident. We aim to characterize whether these DIAm and PhMN deficits occur contemporaneously to spasticity. Using wildtype (WT) and Spa mice at P14, P21, P28, and P90 (maturity) we evaluated DIAm and PhMN physiologic properties. Ex vivo DIAm strips were used for functional assessments of maximum specific force (Po) and fatigue. DIAm strips were also fresh-frozen, and 8 μm cross-sections were cut and stained with H&E to evaluate cross-sectional area (CSA) of individual DIAm fibers. PhMNs were labelled via rhodamine phrenic nerve dip, processed for longitudinal cryosectioning (70 μm) and prepared for confocal imaging and PhMN assessment. In WT mice, DIAm specific force increased at each age (P14, P21, P28 and P90), whilst in Spa mice, DIAm specific force was reduced from P21 compared to WT. Similarly, DIAm fiber CSA was reduced in Spa compared to WT mice at P21, P28 and P90. The number of PhMNs was similar between genotypes at P21, with a reduction in the number of PhMNs in Spa mice compared to WT evident at P28 continuing to P90. In Spa mice, PhMN size was smaller compared to WT at P21, unchanged at P28 and reduced at P90. The changes in Spa DIAm and PhMNs during the first postnatal month are consistent with the emergence of spasticity from P14 to P28. As most changes occur at ~P21, we are optimistic that interventions prior to weaning may promote the normal growth of DIAm and survival of PhMNs and may stave off later life DIAm behavioral deficits.

HL166204 and HL146114.

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.
Exercise training cycles persistently improve glucose homeostasis and alters hepatic fatty acid oxidation
Authors: Huang Yi-Heng , Weidenhamer Clay , Hernández-Saavedra Diego
Published: May 2024

Obesity is a metabolic disease associated with a lower capacity for fatty acid oxidation (FAO) that contributes to insulin resistance and reduces metabolic fuel flexibility. Conversely, the long-term consequences of obesity can be reversed through exercise training. While studies suggest that exercise elicits long-lasting and persistent adaptations in muscle akin to an “exercise memory”, how a hepatic memory is established remains unknown. This is key given that beneficial adaptations to the exercised muscle cannot occur without support from the liver. Thus, we hypothesize that exercise training elicits a hepatic “exercise memory” that persists after exercise cessation and is accentuated by retaining to improve metabolic health and FAO. Here, we used male SEDentary (static cages; SED) and exercise-TRAINed (wheel running, TRAIN) chow-fed mice and investigated how exercise impacts whole body glucose homeostasis (glucose tolerance test [GTT], insulin tolerance test [ITT], pyruvate tolerance test [PTT]) and hepatic FAO following training (4wks), detraining (8wk), and retraining (12wk) in three independent cohorts. Exercise training reduced adiposity ( p<0.01) and improved glucose tolerance (GTT) ( p<0.05), compared to SED. Metabolic improvements in TRAIN mice were accompanied by higher gene expression of FAO enzyme Hadha ( p<0.05). Further, improvements to adiposity and glucose handling disappear after detraining. Nevertheless, after detraining, TRAIN mice had a higher expression of lipid uptake ( Lpl, p<0.05), mitochondrial function ( Sdha, Sdhb, p< 0.05), and FAO genes ( Acadvl, p=0.053). Following retraining, we observed a significant enhancement of basal glucose ( p<0.05) and a main effect of exercise training on glucose homeostasis (GTT, ITT, PTT) across timepoints (factorial ANOVA p< 0.001). However, mitochondrial and FAO gene expression ( Sdha, Sdhb, p<0.05, Acadvl, p=0.053) were reduced with retraining in TRAIN mice, compared to SED. In conclusion, we observed that exercise training improves glucose homeostasis, which is further potentiated through exercise retraining. This effect was accompanied by dynamic changes in expression of genes related to mitochondrial function, FAO, and lipid uptake. Our data may suggest a dynamic reprogramming of hepatic fatty acid handling with training, that may persist with detraining, and can be enhanced with retraining.

Funding was provided by the University of Illinois Urbana-Champaign.

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 influence of perceived discrimination on aortic hemodynamics in young Black adults
Authors: Griffn Leila , Via Jeremy , Reid Jill , Simulick Summer , Segears Zion , Turley Miranda , Bramble Cole
Published: May 2024

Black adults experience the greatest prevalence of cardiovascular disease (CVD) risk factors and higher CVD mortality of any racial or ethnic group in the United States. The chronic stress from experiencing racial discrimination may exert a weathering effect that contributes to cardiovascular health inequities observed among Black adults. Prior evidence has suggested that Black adults experience greater aortic stiffness as compared with white adults. However, there is limited information regarding perceived racial discrimination and aortic hemodynamics in young adults. Purpose/Hypothesis: The purpose of this study was to determine whether perceived racial discrimination was associated with worse aortic hemodynamics in young Black adults. Methods: Black adults aged 18-25 (n=18, 44% female) volunteered to participate in this study. Participants arrived at the lab at 7:00AM in a fasted state. Following 30 minutes of rest, central pressure waveforms were derived from the radial artery waveform acquired via applanation tonometry and the use of the generalized transfer function. We report aortic augmentation pressure (AP, mmHg), augmentation index (AIx, %), augmentation index normalized to a heart rate of 75bpm (AIx75), round trip transit time (Tr, ms), and the subendocardial viability ratio (SEVR, %), also known as the Buckberg Index. Peak oxygen consumption (VO2 peak) was measured via Indirect calorimetry during a graded treadmill test. Participants completed a questionnaire that assessed personal-level and group-level discrimination. Partial correlations (Pearson’s r controlled for VO2 peak) were used to assess the association between perceived racial discrimination and aortic hemodynamics. Results: Perceived group-level discrimination was positively associated with AP (r = 0.571, p = 0.026), AIx (r = 0.580, p = 0.023), and AIx75 (r = 0.571, p = 0.026), signifying worse central hemodynamics that are indicative of increased left ventricular systolic load. However, perceived personal-level discrimination was not associated with aortic hemodynamics (ps>0.05). VO2peak was positively associated with Tr (r = 0.511, p = 0.043), signifying a later return of the reflected wave (i.e, better) to the heart to facilitate coronary perfusion during diastole. VO2 peak was also inversely associated with AIx75 (r = -0.657, p = 0.006). Conclusion: These preliminary data indicate that young Black adults who report higher group-level discrimination have an increased left ventricular systolic afterload in the aorta. Future studies investigating coping strategies or the effects of increased fitness to improve central hemodynamics in Black adults are warranted.

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.
Beta cell-derived exosomes from KDM6A KO mice enhances glucose uptake via upregulation of GLUT4 in skeletal muscles and adipocytes
Authors: Zhang Bo , Wang Shirley , Sun Zhongjie
Published: May 2024

Exosomes are small extracellular vesicles secreted by various cell types which have gained prominence as potent mediators of intercellular communication. Beta cells play a critical role in glucose homeostasis through the production and secretion of insulin. Lysine demethylase 6A (KDM6A) belongs to the KDM6 family of histone H3 lysine 27 (H3K27) demethylases which is important for the development of various organs. Our previous study showed that beta cell-specific knockout of KDM6A increased glucose tolerance and enhanced peripheral insulin sensitivity in mice. The aim of this study is to investigate whether beta cell-derived exosomes, particularly those derived from KDM6A knockout (INS1-KDM6A-KO) beta cells, regulates glucose uptake in skeletal muscles and adipocytes. We found that serum exosome concentrations were increased significantly in the INS1-KDM6A-KO group. Skeletal muscles were isolated from WT and INS1-KDM6A-K mice. GLUT4 protein expression was upregulated in skeletal muscles in INS1-KDM6A-KO mice. Moreover, pancreatic islets isolated from the INS1-KDM6A-KO mice exhibited a notable increase in exosome release. Interestingly, exosomes from beta islets largely enhanced glucose uptake in cultured skeletal muscle cells and 3T3-L1 adipocytes. Meanwhile, beta cell-derived exosomes from KDM6A-KO mice upregulated GLUT4 in NOR-10 cells, especially in the presence of insulin. The findings suggest that beta cell-derived exosomes may play an important role in KDM6A deficiency-induced enhancement in insulin sensitivity likely via upregulation of GLUT4 in skeletal muscle cells and adipocytes.

This work was supported by NIH R01 Grants - HL154147 and AG062375.

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 Accelerator and Brake Modulatory System of Carotid Body Sensitivity
Authors: Gold Olivia M.S , Pauza Audrys G , F.R Paton Julian
Published: May 2024

The carotid body (CB) is the primary sensor of arterial gases in the human body that through reflex pathways maintains cardiovascular homeostasis. It is known that CB chemosensitivity increases upon repeated stimulation as well as disease states; however, the molecular basis for this remains elusive. Objectives: To investigate the effect of excitatory and inhibitory amino acids in mediating CB afferent activity. Hypothesis: We hypothesised that glutamate and γ-aminobutyric acid (GABA) act to modulate CB sensitivity. Methods: Electrophysiological recordings of carotid sinus nerve (CSN) afferent discharge were made from an ex vivo arterially perfused common carotid artery bifurcation preparation. Effects of agents on CB sensitivity were assessed from responses evoked by cyanide (CN−) (1.23 μmol bolus). Results: The CSN response to CN− consisted of a rapid high amplitude discharge that was quenched abruptly, leading to a low amplitude tail. Glutamate administration augmented the CSN response to CN− by 2-fold compared to baseline ( p=0.0005). In contrast, GABA administration suppressed the CN− response by 2-fold ( p = 3.71 x 10−5). An N-methyl-D-aspartic acid (NMDA) receptor antagonist (MK801; 100 μM) increased the response amplitude resulting in one single high amplitude discharge (160% increase from baseline), abolishing the low amplitude tail. Such an effect was also observed following GABAA receptor blockade with bicuculline (500 μM), when an 80% increase was observed. The CN− response was blocked by PPADS (a P2X receptor antagonist; 100 μM) (242 ± 154 vs 4.82 ± 2.23 % change from baseline; p=0.03), suggesting it to be solely mediated by purinergic transmission. Summary of the data: We propose that CN-evoked excitation of CB chemosensory cells leads to the co-release of ATP and glutamate. ATP activates directly P2X receptors on petrosal chemosensory afferents, while glutamate acting via NMDA receptors on chemosensory cells leads to activity-induced potentiation of ATP release and co-release of GABA to quench ATP-mediated CSN discharge in a time-controlled manner. This is supported by our finding that blockade of either excitatory (NMDAR) or inhibitory (GABAA) receptors both heighten the CN− evoked CB response. A statement of the conclusions: Our results suggest an intrinsic ‘accelerator and brake’ paracrine mechanism within the CB involving glutamate and GABA controlling CB afferent sensitivity.

Research was supported by the Health Research Council of New Zealand and the Sidney Taylor Trust.

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.
Histamine Receptors Are Altered in Colorectal Cancer
Authors: Edens Rachel , Engevik Kristen , Engevik Mindy , Engevik Amy
Published: May 2024

Background: Histamine is an endogenous amine that acts on a wide variety of cell types throughout the body. Its activity is mediated by four distinct receptors: HRH1, HRH2, HRH3 and HRH4. Each of these receptors induces a distinct signaling cascade that has diverse output. Histamine has been postulated to influence cancer progression, but little is known about the distribution of histamine receptors in the gut epithelium or its exact role in colorectal cancer. The aim of this study was to define the distribution of histamine receptors in the colonic epithelium in the setting of health and cancer. Methods & Results: We utilized publicly available single cell sequencing databases to examine the distribution of histamine receptors in the normal colon. We found that HRH1 was highly expressed in all colonic epithelial cells. Interestingly, HRH2, HRH3 and HRH4 were not expressed in any cell type in the colon. To confirm these findings, we grew human colonic organoids and found by qPCR analysis that HRH1 was the only receptor present in this epithelial specific system. In the setting of cancer, we found that HRH1 was elevated in colorectal cancer tumors compared to normal controls. Immunostaining of a tissue array confirmed that colon cancer tissue specimens had higher concentrations of immune associated HRH1; suggesting that immune cells were contributing to the higher levels of HRH1 observed in tumors. Single cell RNAseq data demonstrated that macrophages and monocytes had the highest expression of HRH1 among immune cells. Examination of immune infiltration and HRH1 expression in the Cancer Genome Atlas revealed a positive correlation between monocyte and macrophage HRH1 expression. Conclusions: These data suggest that HRH1 is the only receptor expressed in the colonic epithelium and that in cancer, infiltration of monocytes and macrophages harboring HRH1 elevate overall expression levels of this receptor in tumors.

DDRC Pilot and Feasibility Award (Amy Engevik) Career Development Award (K01) (Amy Engevik) DK121869-01.

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.
Epigenetic Effects of Finasteride on Dopaminergic Signaling Pathways: A potential contributor to Post-Finasteride Syndrome
Authors: Ihentuge Churchill J , Csoka Antonei B
Published: May 2024

Dopamine, a widely-distributed neurotransmitter in the brain and elsewhere, is important for regulating reward-motivated behavior, sexual impetus, concentration, pleasure, emotions, and genital arousal. Findings have previously implicated aberrant dopaminergic neurotransmission in mental disorders, as well as sexual and erectile dysfunction. To evaluate the epigenetic effects of finasteride on dopaminergic signaling pathways, we treated human Leydig cells with finasteride and identified several dopaminergic pathways that were altered by differential methylation of component genes. These genes included those involved in the regulation of dopamine secretion and transport (OR56A4, OR13F1 and SYT4), the Phospholipase C-activating dopamine receptor signaling pathway (OR56A4 and OR13F1), the dopaminergic synapse (CALML4, COMT, GNAI2, GNAS, GNG10, GRIA1, GSK3A, GSK3B, KCNJ9, PPP2R2C, PPP2R3B, PPP2R3C, PPP2R5A, PPP2R5E) and the dopamine receptor activity and binding pathway (OR56A4, OR13F1). This alteration of gene methylation suggests a potential role of altered epigenetic regulation of dopaminergic pathways in the etiology and pathophysiology of post-finasteride syndrome (PFS), which should be further investigated.

National Institutes of Health (NIH) R25 Resource Grant (1 R25 AG047843-01) to ABC.

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.
Body Position Dependent Participation of Abdominal and Thoracic Breathing Movements During the Breathing Cycle
Authors: Decker Szonja , Takacs Johanna , Deak Darina , Horváth Tamás , Koller Akos
Published: May 2024

Aims: Both abdominal and thoracic breathing movements play important roles in the mechanics of breathing, participating differently in various body positions with abdominal breathing having a greater role. Recent studies showed that an early proning position of awake, non-intubated patients during the COVID-19 pandemic, even during pregnancy (PMID: 32320506, PMID: 33309507, PMID: 34915799) significantly affected the ventilatory parameters and mortality of SARS-CoV-2 patients. Thus, we hypothesized that in different body positions the participation of abdominal (AB) and thoracic breathing (TB) during the complete respiratory cycle (CRC) is different. To test this, we measured the participation of AB and TB to the CRC in different body positions under resting conditions. Methods: In young participants (N=26) age between 18 and 24 (M=21.3±1.6), changes in abdominal and chest circumferences were measured using plethysmography respiratory belts, during inhalation and exhalation in standing (ST), sitting (SI), supine (SU), prone (PR), and all on fours (AF) body positions. Respiratory frequency was also measured. Results: In different positions, the contribution of AB and TB to CRC were significantly different (F(4,100)=4.999, p=0.004, η2p=0.17). AB was significantly higher than TB in all positions (p<0.001). More specifically, AB gradually increased, while TB gradually decreased in the following order: SU(AB/TB) = 74.8±12.9%/25.2%, ST = 69±16%/31%, PR = 66.8±20.2%/33.2%, SI = 65.5±14.8%/34.5%, AF = 61.1±15.1%/38.9%. A significantly higher value was measured in the SU position compared to AF (p<0.001) and SI (p=0.011) positions; PR and ST positions showed intermediate values, which were not significantly different from those yielded by either of the other positions. Respiratory frequency was similar in different body positions. Conclusions: These data show that different body positions significantly affect the participation of abdominal and thoracic breathing during resting condition, underscoring not only the importance of respiratory distress patients positioning during hospitalization, but its usefulness in developing a respiratory training plan for elite athletes to optimize their physical and mental performance in competitive sports.

AK: Ministry of Innovation and Technology (MIT) of Hungary-NRDI TKP2020-NKA-17, TKP2021-EGA-37, and National Research, Development, and Innovation Offce (NKFIH) OTKA K 132596 K_19, and Hungarian Academy of Sciences, Post-Covid 2021-34, and HUN-REN-SU: 02068 of Hungary, JT: ÚNKP-22-4-II-SE-4 (JT), TKP2021-EGA-25.

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.