bluuebunny/crossref_metadata_2025 huggingface dataset:
Science Communication Training for Graduate Exercise Physiology Students
Authors: Elmer Steven
Published: May 2024

Physiologists have a responsibility to inform the public about how new discoveries and challenges will impact the health of society. However, most physiologists do not have formal training in science communication. The purpose of this study was to implement a science communication training pilot program for graduate students. Students (n = 23) were introduced to science communication training that emphasized key skill development (writing, public speaking, leadership, project management, teaching) as part of their advanced exercise physiology course. Subsequently, students carried out service-learning projects that tasked them with presenting evidence-based health information to public audiences (e.g., community members, clinicians, K-12 students, journalists, policy makers). In a subset of students (n = 8), a survey was administered to assess students’ perceptions of the value of science communication and their ability to communicate to different audiences. Service-learning projects that students completed included blog posts, infographics, podcast series, visits with K-12 schools, and public townhall presentations. Most students (≥75%) agreed that completing the science communication training helped them develop confidence speaking to a range of audiences. After completing the science communication training, students were more interested in learning about how to better communicate science concepts to the public compared to before the training (88% vs. 25%). Collectively, these preliminary results suggest that science communication training helped graduate exercise physiology students recognize the gap between science and society, develop confidence speaking to a range of audiences, and communicate more effectively. These results support findings from other disciplines such as biology and medicine. Implementation of science communication training is paramount, and the approach described here could be useful for physiology students, educators, and departments.

American Physiological Society - Teaching Career Enhancement Award.

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.
Proteomics Approach to Identify Anthracycline-induced Cardiotoxicity Mechanisms in Human Cardiac Fibroblasts
Authors: Bagchi Ashim , Holdiness Ryan , Dhar Anya , Stolarz Amanda , Bagchi Rushita
Published: May 2024

Doxorubicin-induced cardiotoxicity (DIC) is a major life-threatening side-effect of chemotherapy in cancer patients. DIC leading to heart failure is caused by numerous mechanisms, including impaired mitochondrial function, disruption of calcium homeostasis, and altered gene and protein response that triggers cell death and, eventually, fibrosis. We performed a preliminary investigation of the effect of doxorubicin (DOX) on the cardiac fibroblast proteome using mass-spectrometry. Quantitative analysis showed significantly altered expression of 186 proteins. Nine out of forty-two Dox-upregulated proteins and seventeen out of twenty-four Dox-downregulated proteins showed a reciprocal trend in expression upon inhibiting a structural scaffold protein involved in cardiac calcium channel regulation. Overall, our data suggests the involvement of pathways in regulating mitochondrial energy metabolism, matrix remodeling, cell cycle/arrest, and cell survival via Rho/Rac nuclear exchanger proteins. DIC is multifactorial, and based on our pilot data, modulation of calcium channel regulators may be a promising strategy to mitigate the progression of DIC to heart failure.

Research support received from the American Heart Association, NIH and the University of Arkansas for Medical Sciences.

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.
Empagliflozin Extends Lifespan While Reducing Physical Activity in Drosophila Melanogaster: Insights into Non-Glycemic Pharmacological Effects
Authors: Brim-Edwards Jackson , Harris Hailey , Vrailas-Mortimer Alysia , Robinson Matthew , Newsom Sean
Published: May 2024

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), such as empagliflozin (EMPA), are primarily used to manage hyperglycemia in type 2 diabetes (T2D). Beyond their role in glycemic control, SGLT2i can elicit off-target effects, including induction of a mild energetic stress phenotype—a state previously associated with increased longevity in various organisms. Drosophila melanogaster lack the SGLT2 protein and, therefore, can be used to model the effects of SGLT2i independent of renal glucose reuptake. We tested the hypothesis that EMPA would promote and increase longevity and physical activity (PA) by providing adult virgin female Drosophila with either DMSO (vehicle) or EMPA in the diet at concentrations of 5 μM, 25 μM, and 50 μM. EMPA treatment resulted in a significant extension of median lifespan at all concentrations: 4% (p=0.049) for 5 μM, 24% (p=0.035) for 25 μM, and 8% (p=0.025) for 50 μM, compared with DMSO. A linear mixed model analysis also demonstrated significant interactions between EMPA treatment and time on PA levels—5 μM (p=0.001), 25 μM (p=0.04), and 50 μM (p=5.85e-07)—indicating a pronounced reduction in PA over time in EMPA-treated groups compared with DMSO. Our findings that EMPA promotes longevity and lowers physical activity in Drosophila demonstrate that SGLT2i can have significant physiologic impacts that are independent of inhibition of SGLT2.

Supported by funding from the Valley Fellowship (Oregon State University) awarded to SAN.

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.
Cardiorenal Effects of Chronic High Phosphate Diet in Female Rats
Authors: Williams Adaysha , Yunker Lauren , Kriegel Alison
Published: May 2024

Cardiorenal Syndrome Type 4 (CRS4) refers to the development of cardiovascular dysfunction as a result of chronic kidney disease. The accumulation of circulating phosphate in the later stages of chronic kidney disease (CKD) has been positively associated with cardiac hypertrophy and dysfunction. In our previous work, we found that male Sprague Dawley rats that underwent 5/6 nephrectomy (5/6Nx) to induce CKD phenotypes also developed cardiac pathology when serum phosphorus levels became elevated. Small RNA sequencing of left ventricle tissue revealed upregulated microRNA-21-5p and -3p expression in 5/6Nx rats, when compared to sham-operated controls, and suppression of miR-21-5p attenuated left ventricle pathology in male 5/6Nx rats. We hypothesize that hyperphosphatemia, independent of CKD, can impair cardiac function and that miR-21 may mediate these effects. It has been recently reported that females exhibit higher urinary phosphate excretion in response to high dietary phosphate intake than males. In this study, hyperphosphatemia was induced by placing 9-week old female wild-type (WT) Sprague Dawley and global miR-21 knockout (miR-21−/−; lacking both miR-21-5p and -3p rats) (n=4-9/group) on either high phosphate (2% Pi) or control diet (0.6% Pi) for 8 weeks. Echocardiography and renal ultrasound were performed under anesthesia to assess cardiac function and renal cross-sectional area, respectively, prior to tissue collection at endpoint. Rats of either genotype fed 2% Pi diet exhibited increased left kidney weight, left kidney/body weight, and left kidney cross-sectional area (2-way ANOVA, main effect of diet; p<0.05). In animals fed 2% Pi, miR-21−/− rats had significantly higher left ventricle fractional shortening than WT rats (57.06 ± 3.32 vs. 43.96 ± 1.34; 2-way ANOVA with Tukey multiple comparisons; p<0.05). This study allowed the cardiovascular effects of chronically elevated phosphate to be isolated from other uremic toxins elevated in CKD. We find that loss of miR-21 augments cardiac function, supporting a role for miR-21 in mediating phosphate-related pathology. Ongoing studies are focused on identifying specific molecular mechanisms driving these changes.

This study was supported by T32HL007852 and R01HL128332.

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.
Rapsyn overexpression improves recovery of the neuromuscular junction from tourniquet-induced ischemia-reperfusion injury in mouse hindlimb
Authors: Tu Hui Yin , Barksdale Aaron N , Wadman Michael C , Li Yu-Long
Published: May 2024

The neuromuscular junction (NMJ) is an important factor to influence skeletal muscle contractile function. Tourniquet-induced ischemia-reperfusion (IR) results in the fragmentation of nicotinic acetylcholine receptors (nAChR) clusters in the NMJ and impairs neural controlled skeletal muscle contraction. Rapsyn, a cytoplasmic nAChR-associated protein concentrates and anchors nAChRs in the postsynaptic membrane and participates in the nAChR assembly at NMJ. Here, we observed the effect of overexpression of Rapsyn on morphological and functional recovery of the NMJ from tourniquet-induced IR injuries in mouse hindlimb. Unilateral hindlimb of C57/BL6 mice were subjected to 3 hours of ischemia by placing a rubber band and followed 6 weeks of reperfusion. Ad-m-RAPSN (5.2 x 1010 PFU/ml) was injected into gastrocnemius muscle (50 μl) by Hamilton microliter syringe after 2 weeks of tourniquet-induced IR. After 6 weeks of IR, the sciatic nerve-stimulated gastrocnemius muscle contraction and endplate potential (EPP) were recorded in in-situ muscle samples; the NMJs were labelled with alpha-bungarotoxin (BTX) and nerofilment-200 (NF-200) + synaptophysin (Syn) antibodies, and NMJ images were captured with Zeiss LSM 800. After 6 weeks of IR, NMJs in the gastrocnemius muscle showed significantly fragmented nAChR clusters (9.3 ± 0.7 vs. sham 1.7 ± 0.1 for numbers of fragments) with low rapsyn expression, and the EPP (15.29 ± 0.93 mV vs. sham 26.87 ± 0.89 mV) and nerve-stimulated muscle contraction (117.2 ± 8.5 g vs. sham 157.9 ± 4.9 g) were reduced. Ad-m-RAPSN injection increased rapsyn expression, mitigated fragmentation of nAChR clusters (3.2 ± 0.3), increased the EPP (20.35 ± 0.86) and nerve-stimulated muscle contraction (138.1 ± 3.5 g). The data suggest that tourniquet-related IR induces AChR cluster fragmentation and impairs NMJ function, and rapsyn overexpression improves the morphological and functional recovery of the NMJ from tourniquet-induced IR injuries..

This research is supported by the NIH/NIGMS 1R01GM145736 to Y-LL.

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.
Addressing the enigma of treating heart failure with preserved ejection fraction with P2X3 receptor antagonism
Authors: Pachen Mridula , Chen Robert , Chang Joshua , F.R Paton Julian , Ramchandra Rohit
Published: May 2024

Heart failure with preserved ejection fraction (HFpEF) is a major health burden and a primary cause of death globally, yet there remains no curative treatment. Previous studies have indicated an important role for P2X3 receptors (P2X3R) in mediating high levels of sympathetic drive in hypertension (1). Given the high sympathetic drive in HFpEF(2), we investigated whether P2X3R antagonism would improve this condition. We tested the hypotheses that in HFpEF, P2X3R activation causes high levels of blood pressure and excessive vasoconstriction in the hindlimb vasculature during exercise. Following unilateral renal artery clipping, an ovine model of HFpEF was established in female sheep displaying hypertension and diastolic dysfunction. A sham-operated group acted as a control. Mean arterial pressure (MAP), heart rate (HR), and hindlimb blood flow (HLBF) were recorded before and during treadmill exercise, and the effect of either a P2X3R antagonist (L227, 10mg/kg) or vehicle was assessed. The clipping of one renal artery increased MAP (91±5 vs. 131±6, p≤0.05). The administration of the P2X3R antagonist reduced both MAP (-6±7 mmHg, p≤0.05) and HR (-6±6 bpm, p<0.05) in HFpEF sheep but no effect in sham-operated animals. HLBF during exercise was attenuated in the HFpEF model compared to sham-operated sheep (an increase of 2±1 vs. 4±2 L/min, respectively, p<0.05). Importantly, P2X3R blockade improved the change in HLBF during exercise from 1±0.1 to 2±0.4 L/min in HFpEF sheep, but there was no change in the sham-operated animals. There was no change in the MAP or HR response to the exercise with the P2X3R blockade. P2X3R plays a role in the aetiology of hypertension and in the attenuation of HLBF responses during exercise in HFpEF. P2X3R antagonism may provide a novel target to alleviate symptoms of HFpEF and improve exercise tolerance through increased HLBF.

1. Pijacka W, Moraes DJ, Ratcliffe LE, Nightingale AK, Hart EC, da Silva MP, Machado BH, McBryde FD, Abdala AP, Ford AP and Paton JFR. Purinergic receptors in the carotid body as a new drug target for controlling hypertension. Nature medicine 22: 1151-1159, 2016. 2. Seravalle G, Quarti-Trevano F, Dell’Oro R, Gronda E, Spaziani D, Facchetti R, Cuspidi C, Mancia G, and Grassi G. Sympathetic and baroreflex alterations in congestive heart failure with preserved, midrange and reduced ejection fraction. Journal of Hypertension 37: 443-448, 2019.

Health Research Council of New Zealand and 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.
Designing and testing an Integrated Study Strategy: Core Concepts in physiology and Mind Maps
Authors: Gomez-Camacho Sarahi , Galván Zorrilla Dana Camila , García-Muñoz Katya Michelle , Sánchez-Briones María Eugenia
Published: May 2024

This abstract shows the result of an innovative approach for learning physiology by combining two widely recognized methods: Core Concepts in physiology and Mind Maps. The objective is demonstrating the graphic product that visualize conceptual relationships holistically (mind map) combined with core concepts in cardiovascular physiology generated by a group of students enrolled to the integrative physiology course (2nd-year medical students, medical bachelor's degree, Professional Studies Faculty, Autonomous University of San Luis Potosí, México) during the semester august to December 2023. Methods: the curriculum content of cardiovascular physiology includes excitation-contraction coupling of the heart, the heart cycle, determinants of arterial pressure and peripheric vascular characteristics, including special circulations. The development of the mind map was according to the academic content of the course (4 weeks). The group of students worked with a training physiology teacher (including core concept training) for one 2-hour session per week (total= 4 sessions). The result is a mind map that includes the aspects of cardiovascular physiology addressed by the core concepts tool. Conclusion: Contemporary education faces increasing challenges in information retention and comprehension., and in this context, the integration of these two strategies emerges as a promising solution. This combination of learning tool is applicable in environments of low socioeconomical status because not involve doesn´t involve any monetary investments.

Curricular Commission and the Academy or Clinical and Basic Sciences belonging to the bachelor´s degree of the Professional Studies Faculty, Autonomous University of San Luis Potosí, México.

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 effcacy of short-term tetrahydrobiopterin administration to improve locomotor muscle microvascular function in heart failure with preserved ejection fraction
Authors: Bunsawat Kanokwan , Jarrett Catherine , Broxterman Ryan , Craig Jesse , Francisco Michael , Alpenglow Jeremy , Iacovelli Jarred
Published: May 2024

Background: Patients with heart failure with preserved ejection fraction (HFpEF) exhibit locomotor muscle microvascular dysfunction due partly to reduced nitric oxide (NO) bioavailability. Tetrahydrobiopterin (BH4) is a requisite cofactor for the enzymatic production of NO by NO synthase (NOS). BH4 insuffciency promotes NOS uncoupling, which reduces NO production and augments cellular oxidative stress. Given the potential of BH4 to improve NO bioavailability, we tested the hypothesis that short-term BH4 administration would improve locomotor muscle microvascular function in patients with HFpEF. Methods: Eight patients with HFpEF (74±7 years; 31.3±4.9 kg/m2) participated in a randomized, double-blind, crossover study, having consumed either BH4 (Sapropterin, 10 mg/kg) or placebo for 10 days, separated by a 14-day washout period. Locomotor muscle microvascular function was assessed as leg blood flow (LBF) and leg vascular conductance (LVC) responses to passive leg movement (PLM) before (pre) and after (post) each treatment. PLM-induced LBF and LVC responses were expressed as peak change (Δpeak) or total hyperemic response (area under the curve above baseline; AUC). Results: LBFΔpeak did not change following BH4 (267 ± 136 mL/min vs. 250 ± 101 mL/min) or placebo (317 ± 119 mL/min vs. 269 ± 97 mL/min) administration (pre vs. post; p>0.05). Similarly, LVCΔpeak was unchanged following either BH4 (396 ± 165 mL/min/100mmHg vs. 465 ± 180 mL/min/100mmHg) or placebo (579 ± 238 mL/min/100mmHg vs. 496 ± 185 mL/min/100mmHg) administration (pre vs. post; p>0.05). The changes in LBFAUC and LVCAUC were not affected by either treatment (LBFAUC; BH4: Δ91 ± 103 mL vs. Δ82 ± 69 mL; placebo: Δ148 ± 119 mL vs. Δ87 ± 81 mL; LVCAUC; BH4: Δ65 ± 55 mL/100mmHg vs. Δ98 ± 78 mL/100mnHg; placebo: Δ182 ± 127 mL/100mmHg vs. Δ105 ± 94 mL/100mmHg) (pre vs. post; p>0.05). Conclusion: Short-term BH4 administration did not improve locomotor muscle microvascular function in patients with HFpEF.

This project was funded, in part, by the National Institutes of Health (HL118313, D.W.W.; T32HL139451, K.B.; the U.S. Department of Veterans Affairs (I01RX001311, D.W.W.; IK2RX003670, to K.B.), and the American Heart Association (18POST33960192; K.B.).

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.
Measuring Body Composition and Functional Strength: Implications for the Clinical Assessment of Skeletal Muscle
Authors: Anderson Garret , Garcia Cedric J. , Sweed Tyler , Medler Scott
Published: May 2024

Skeletal muscle represents the largest single component of the body, comprising up to 50% of total mass in healthy individuals. Body composition assessment has largely focused on overweight and obese individuals, but healthy skeletal muscle is also an important indicator of health and wellbeing. We hypothesized that estimates of lean body mass and empirical measures of functional strength should be directly correlated with one another. In the current study, we estimated body composition using two different field methods. Bioimpedance spectroscopy (BIS) employs 256 frequencies of low energy electrical current to estimate body composition. We used BIS (Impedimed SFB7) to determine percent body fat and fat free mass in physically active volunteers, ranging in age from 18 – 62 years. In addition, we used the Jackson and Pollock 3-site skin fold method to estimate these parameters from the same individuals. We also measured functional strength with a whole body dynamometer to determine mid-thigh pull strength, and a grip dynamometer to assess grip strength (Baseline Evaluation Instruments). Data collected from more than 75 men and women revealed significant correlations between fat-free mass (FFM) and both measures of functional strength. Interestingly, men and women fell along the same trend line, with women exhibiting similar strength for a given FFM. Moreover, functional strength standardized to FFM provides an objective measure of relative strength that was not different between men and women. The American Medical Association released a new policy statement about body mass index (BMI) in June of 2023, highlighting that BMI is an imprecise measure of body composition and recommending that alternative measures, such as more precise measurement of body composition, also be used. Indeed, we found that for individuals with a BMI of less than 30, there was direct relationship between FFM and functional strength. By contrast, percent body fat was not correlated with BMI within this range. We suggest that FFM and functional strength could be used to assess healthy weight, in conjunction with BMI. These measures could also be used to screen for sarcopenia, cachexia, and other conditions associated with significant muscle loss. Skeletal muscle represents an often underappreciated component of health and a more precise assessment of muscle mass and strength should be used as a measure of overall health.

This work was supported by a Keenan Award at St. Bonaventure University.

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.
Distinct Neuronal Populations in the Bed Nuclei of the Stria Terminalis (BNST) Control IL1-β - mediated Stress Responses
Authors: Hashimoot Okito , Hepler Tyler , Tynan Aisling , Tracey Kevin J. , Chavan Sangeeta S.
Published: May 2024

The immune and nervous systems are intricately linked. However, mechanistic pathways linking cytokine-mediated stress networks in the brain to peripheral immune and cardiac functions remain poorly understood. Here, we identify a specific population of neurons in the bed nucleus of the stria terminalis (BNST), which shape diverse responses to interleukin-1β (IL-1β)-mediated stress phenotype. Using activity-dependent cell labeling in mice, we identify distinct neuronal ensembles in the BNST that are active in response to IL-1β. Interestingly, re-exposure of mice to acute restraint stress results in the labeling of same populations in the BNST that were responsive to IL-1β administration. Chemogenetic reactivation of these IL-1β-responsive neuronal subsets in the BNST is suffcient to broadly retrieve the stress-induced responses. Specifically, reactivation of these IL-1β -responsive neurons in the BNST recapitulates tachycardia and inflammation induced by acute restraint stress, whereas specific ablation of IL-1β-responsive neurons in the BNST attenuates stress-induced serum IL-6 levels and IL-1β-induced tachycardia. Our data define a neuronal population in the BNST that is both necessary and suffcient for mediating IL-1β-associated stress responses, revealing a role for BNST coordination of inflammatory responses.

Supported in part by grants from NIH, NIGMS, 1R35 GM118182 to KT and 1R01AR083159-01 to SC.

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-Term Intrauterine Hypoxia Disrupts Calcium Sparks in Middle Cerebral Arterial Myocytes of Fetal Sheep
Authors: Nelapudi Nikitha , Boskind Madison , Mallari David , Chan Michelle , Romero Monica , Zhang Lubo , Blood Arlin
Published: May 2024

Local activation of ryanodine receptors (RyRs) on the sarcoplasmic reticulum in vascular smooth muscle cells (VSMCs) generates rapid subcellular changes in cellular Ca2+ that are commonly known as Ca2+ sparks. These Ca2+ sparks are well regarded for their role in the autoregulation of vascular contractility and cerebral blood flow through activation of potassium channels and feedback modulation of the membrane potential. Gestational hypoxia disrupts cerebrovascular development, increasing the risk of intracranial hemorrhage and stroke in the newborn. Due to the role of RyR’s in regulating neonatal cerebrovascular blood flow, understanding intracellular Ca2+ release patterns in VSMCs can offer insight into hypoxia-related perinatal cerebrovascular disease. The central aim of this study is to determine the extent to which gestational hypoxia disrupts RyR activity. This was achieved through examination of RyR activity in VSMCs of fetal ovine middle cerebral arteries (MCAs). MCAs were isolated from term fetal sheep (~140 days of gestation) delivered by cesarean section from ewes held at low- (700 m) and high-altitude conditions (3801 m) for 100+ days of gestation. Arteries were bathed in a physiological buffer with 5 mm K+ (control) or were treated with either 30 mM K+ (30K), to depolarize myocytes and increase Ca2+ spark events, in the presence or absence of 10 μM ryanodine, to block RyR mediated Ca2+ release. Ca2+ spark activity was measured in situ using line scan confocal microscopy fluorescence imaging techniques. Automated analysis of Ca2+ sparks in the records was conducted using SparkLab 5.8. Membrane depolarization with 30K increased Ca2+ spark activity. Long term hypoxia, however, reduced spark activity in the 30K group. Ryanodine attenuated Ca2+ spark activity in both low- and high-altitude groups. Hypoxia’s influence on the spatial and temporal aspects of Ca2+ sparks in fetal myocytes varied. These findings corroborate previous evidence demonstrating that long-term hypoxia attenuates Ca2+ spark activity. The disruption in Ca2+ spark activity could impact brain blood flow in the neonate, potentially impacting brain development and the likelihood of a traumatic event.

R01HL155295, R01HL149608, Advanced Imaging and Microscopy Core Loma Linda University School of Medicine.

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.
Amyloid β reduces mechanical sensation by attenuating the function of TRPV4 channels in rat small dorsal root ganglion neurons
Authors: Fukazawa Ayumi , Hori Amane , Estrada Juan , Kim Han Kyul , Iwamoto Gary , Smith Scott , Vongpatanasin Wanpen
Published: May 2024

Amyloid β (Aβ) is well known to be a key trigger for the progression of Alzheimer's disease and dementia. Aβ forms oligomers that develop into amyloid plaques, causing neuronal death and dysfunction. Aβ-induced neuronal dysfunction has been reported in peripheral neurons as well as in the brain. We previously reported that transient receptor potential vanilloid 4 (TRPV4) channels play an important role in mechanical sensation in sensory neurons innervating skeletal muscle. However, to date, it remains unclear whether Aβ modulates mechanosensation or TRPV4 channel activity in peripheral sensory neurons. As such, we hypothesized that Aβ acutely impairs the response of small dorsal root ganglion (DRG) neurons to mechanical stimuli by attenuating the function of TRPV4 channels. Purpose: The aim of this investigation was to determine the effects of Aβ1-40 and 1-42 on mechanosensation in small DRG neurons. Method: In in vitro whole-cell patch clamp recordings from cultured rat DRG neurons (Sprague-Dawley rat, n = 4, body weight: 316 ± 57 g), mechanically-activated (MA) current amplitudes or GSK1016790A (a selective agonist of TRPV4, 1 μM)-induced inward currents were measured before and 5 min after application of either HEPES buffered solution (control), Aβ1-40 (2.5 ng/μL), Aβ1-42 (2.5 ng/μL) or Aβ1-40/42 solution (2.5 ng/μL, respectively). Results: MA current amplitude was significantly decreased 5 min after application of both Aβ1-40 (Before vs. After: -71.7 ± 14.5 vs. -13.5 ± 4.8 pA. P < 0.01) and Aβ1-42 (Before vs. After: -63.7 ± 16.2 vs. -14.5 ± 5.9 pA. P < 0.05) while HEPES application did not alter MA currents (Before vs. After: -69.5 ± 17.9 ± -66.2 ± 13.9 pA. P = 0.36). Likewise, GSK1016790A-induced inward current was significantly suppressed by Aβ1-40/42 solution (Fold change in total charge transfer: HEPES vs. Aβ1-40/42: 0.92 ± 0.47 vs. 0.33 ± 0.06. P < 0.05). Conclusion: The data demonstrate that both Aβ1-40 and 1-42 suppress 1) the cellular response to mechanical stimulation and 2) TRPV4 currents in rat small DRG neurons. These findings suggest that both Aβ1-40 and 1-42 attenuate mechanical sensation in DRG neurons by inhibiting TRPV4 channels.

Supported by NIH HL-151632 and JSPS 23KJ2207.

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.
Multi-modal Magnetic Resonance Imaging to Assess Cerebrovascular Function in Atrial Fibrillation Patients
Authors: Walsh Harvey , Morgan Catherine , Webster Mark , Lip Gregory , Dubowitz David , Fisher James
Published: May 2024

Atrial fibrillation (AF) is associated with an increased risk of cognitive decline, dementia, and stroke. Low cerebral blood flow (CBF) and low cerebrovascular carbon dioxide reactivity (CVRCO2) are associated with poor brain health outcomes. In the current study we employed magnetic resonance imaging (MRI) to quantify resting CBF and CVRCO2 in patients with AF and age-matched normal sinus rhythm (NSR) controls. We hypothesised that both resting CBF and CVRCO2 would be lower in patients with AF. Patients with AF (n=11, 65±14 years, 2 women) and NSR (n=12, 63±9 years, 7 women) underwent arterial spin labelling (ASL) at rest, and blood oxygen level-dependent (BOLD) MRI during a single-step increase in partial pressure of carbon dioxide (measured by end-tidal carbon dioxide (PETCO2)) induced by changing the fraction of inspired CO2 to 5% (21% O2, balance N2). Region of interest time courses were extracted with grey matter, middle cerebral artery, and posterior cerebral artery territory masks. CVRCO2 was defined as the percentage change (%Δ) in BOLD signal vs %Δ in PETCO2. Baseline CBF was not different between NSR and AF in grey matter (62±17 vs. 58±10 ml/min/100g, respectively; p=0.226), middle cerebral artery (59±16 vs. 56±14 ml/min/100g; p=0.361) and posterior cerebral artery (61±17 vs 53±15 ml/min/100g; p=0.138) territories. BOLD-derived CVRC02 was not different between NSR and AF groups in grey matter (0.11±0.04 vs. 0.12±0.03 %ΔBOLD/%ΔmmHg, respectively; p=0.372), middle cerebral artery (0.09±0.04 vs. 0.10±0.03 %ΔBOLD/%ΔmmHg; p=0.405) and posterior cerebral artery (0.13±0.04 vs. 0.14±0.05 %ΔBOLD/%ΔmmHg; p=0.367) territories. Collectively, these pilot data suggest that MRI-derived cerebrovascular CO2 responsiveness is not different in patients with AF and age-matched NSR controls that have similar resting CBF. Further investigations are required to extend these preliminary findings to a larger cohort to fully elucidate the effects of AF on cerebrovascular function.

Support provided by the Royal Society of New Zealand Te Apārangi Marsden Fund (19-UOA-170).

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.
Characterization of Middle Cerebral Artery Velocity Kinetics in Response to Isometric Handgrip Exercise in Healthy Adults
Authors: Baron John , Pearson Andrew , Corkery Adam , Loggie Nicole A. , Fico Brandon G. , Moir M. Erin , Narayanan Shrey
Published: May 2024

Cerebral blood flow (CBF) is known to increase in response to both dynamic and isometric exercise. However, middle cerebral artery blood velocity (MCAv) kinetics in response to small-muscle isometric exercise, and sex differences in this kinetic response, require further investigation. Previous work suggests that MCAv response times to stressors may be indicative of cerebrovascular function, so the kinetics of this response to isometric exercise would add to the understanding of cerebrovascular health. The objective of this study was to characterize MCAv kinetics in response to isometric handgrip exercise and investigate potential sex differences in the response. We expected that MCAv at baseline would be higher in females than in males. However, we hypothesized that this sex difference would disappear during isometric handgrip exercise. In addition, we hypothesized that the time constant (τ) would be shorter in females compared with males, with a higher maximum response amplitude in females compared with males. Twenty-six healthy older adults with an average age of 56.8 ± 5.0 years (11 male (M) – aged 59.4 ± 4.8 years; 15 female (F) – aged 54.6 ± 4.1 years) completed an isometric handgrip exercise protocol. The exercise protocol consisted of the following: 1) performing a maximum voluntary contraction (MVC) with a handgrip device in the participants’ left hand (on a separate visit); 2) performing a sustained contraction until failure at 40% of the participant’s MVC. MCAv was continuously measured at rest and during handgrip exercise. The time constant was calculated as 63% of the time until steady-state MCAv during handgrip exercise. There was a trend for higher MCAv at baseline (57.8 ± 11.0 cm/s) in females (61.5 ± 11.2 cm/s) compared with males (53.6 ± 9.6 cm/s) that did not reach significance (p=0.08). There were no significant differences between the sexes for max amplitude of MCAv response to isometric handgrip exercise (M: 20.7 ± 11.1 cm/s; F: 15.4 ± 10.0 cm/s; p = 0.24) or time constant (M: 20.5 ± 9.8 sec; F: 18.6 ± 11.3 sec; p = 0.65). These results suggest no significant differences in MCAv between males and females at baseline. There also appear to be no significant sex differences in the kinetic response of MCAv to handgrip exercise. Future work could model MCAv kinetics in response to isometric handgrip exercise. The relationship between age and MCAv kinetics could also be investigated, along with the effect of menopause on MCAv kinetics in females.

American Heart Association (19IPLOI34680015; JNB); American Heart Association COVID Supplement (19IPLOI34680015; JNB).

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.
Cdc42 Rho GTPase Activity Sustains Epithelial Barrier Function in the Cystic Fibrosis Intestine
Authors: Woode Rowena , Young Sarah , Williams Estela , Ericsson Aaron , Clarke Lane
Published: May 2024

Increased paracellular permeability is a common manifestation of cystic fibrosis (CF) intestinal disease in people with CF and in CF mouse models. Increased paracellular permeability has been found in CF airway epithelium cultured in the absence of inflammatory factors, suggesting an inherent defect in CF epithelial barrier function (Weiser et al., Cell Physiol Biochem. 2011;28(2):289-96). CF transmembrane conductance regulator knockout ( Cftr KO) mouse intestinal crypts demonstrate an increase in epithelial cell proliferation, which correlates with an alkaline intracellular pH (pHi), a pHi-dependent increase in lateral cell membrane localization of the Wnt transducer Disheveled (Dvl), and increased Wnt/β-catenin signaling (Strubberg et al., Cell Mol Gastroenterol Hepatol. 2017 Dec 7;5(3):253-271). We hypothesized that the alkaline pHi of Cftr KO crypts also facilitates Dvl-dependent noncanonical Wnt signaling to increase Rho GTPase activity and thereby tight junction remodeling during increased proliferation. In Dvl2-eGFP rescue mice, Dvl2-eGFP intensity near the apical membrane of Cftr KO enteroid crypts was greater versus wild-type (WT) at both the crypt base and the transit-amplifying zone. Immunofluorescence studies of both freshly isolated crypts and early passage enteroids also found increased accumulation of the Rho GTPase Cdc42 at the tight junctions of Cftr KO versus WT crypts. Live imaging revealed a small increase in leak pathway permeability (3kD dextran) in Cftr KO as compared to WT murine enteroids. Increased leak permeability and Cdc42 tight junction localization were normalized in Cftr KO enteroids by suppressing proliferation through inhibition of Wnt/β-catenin signaling. There was no difference in Cdc42 expression in Cftr KO fresh crypts or enteroids, but initial studies show increased Cdc42 GTP-loaded activity in Cftr KO enteroids relative to WT. Similarly, CFTR KO human intestinal epithelial Caco-2 cells, which also show an alkaline pHi, increased Wnt/β-catenin signaling and a hyperproliferative phenotype, demonstrated a significant increase in GTP-loaded Cdc42 activity compared to WT cells. Inhibition of Cdc42 activity with ML141 (R&D Systems) resulted in a significant disruption of the Cftr KO epithelial barrier, whereas WT enteroid permeability was not affected by Cdc42 inhibition, Wnt inhibition or Wnt3a-induced proliferation. We conclude that increased Cdc42 Rho GTPase activity is cell-autonomous and is necessary for maintaining barrier integrity of the Cftr KO crypt epithelium.

This work was supported by the Cystic Fibrosis Foundation grant CLARKE20G0 and the Crohn’s and Colitis Foundation grant #693938.

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.
A New Genetic Mouse Model of Lean NAFLD Uncovers a Sexual Dimorphism for Hepatic Damages and Cardiometabolic Impairments
Authors: Clapatiuc Valentin , Burelle Charlotte , Deschênes Sonia , Cuillerier Alexanne , De Loof Marine , Higgins Marie-Ève , Boel Hugues
Published: May 2024

Background: The prevalence of non alcoholic fatty liver disease (NAFLD) is ~30% higher in the obese population. However, among patients living with NAFLD, 40% are not obese and half of them are lean. Although being mostly studied in obese individuals, the progression of NAFLD in lean patients may involve cardiac manifestations as well. Our hypothesis states that lean NAFLD patients also develop cardiac complications, independently of pre-existent metabolic disruptions, mechanisms of which remain to be fully understood, especially when considering the sexual dimorphism of the disease. Method: To address the underlying mechanisms of the progression of NAFLD independently of obesity, we used a murine model of hepatic mitochondrial deficiency, achieved through a hepato-specific knockout (KO) of Lrpprc. KO mice thus develop microvesicular steatosis without obesity in both sexes which was extensively characterized at the molecular and metabolic level in liver, plasma and heart. Our results unveiled a sex-dependent hepatic and cardiac phenotypic remodeling. KO male mice, to a greater extent than females, showed sustained fasting hypoglycemia and increased insulin sensitivity. Males also showed a more inflammatory hepatic profile characterized by a significant increase of F4/80 staining in immunohistological analyses (3-fold). Furthermore, only males exhibited an increase in the circulating hepatokine FGF21 (1.74-fold) and an increase in VLDLs lipoproteins while HDLs lipoproteins were decreased. In contrast, KO females showed a modest and global decrease of the lipoprotein profile. As such, sex differences occurred also in the heart since only males showed diastolic dysfunction while females’ cardiac function remained unaffected despite mitochondrial defects such as impairments in mitochondrial biogenesis, dynamics and oxidative capacities. Noteworthy, we also observed a significant and inverse correlation between glycemia and an index for cardiac relaxation only in males. Conclusion: Overall, this study underscores the value of this model for NAFLD without obesity where sex-dependent damage in the liver, the plasma and the heart are highlighted.

Canadian Institutes of Health Research (CIHR), Montreal Heart Institute Foundation, Heart and Stroke Foundation of Canada, Cardiometabolic Health, Diabetes and Obesity Research Network.

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.
Ventilatory Variability Is Increased at Rest in Pulmonary Arterial Hypertension
Authors: Plunkett Michael , Sayegh Ana , McWilliams Tanya , Sithamparanathan Sasiharan , F.R Paton Julian , Fisher James
Published: May 2024

Ventilatory instability is associated with adverse outcomes in left heart failure, with periodic breathing during awake, rest, sleep and exercise (exercise oscillatory ventilation) associated with increased mortality. Increased peripheral and central chemoreflex sensitivities and impairment of cardiac output have been implicated as causative mechanisms of ventilatory instability in heart failure. As these factors are also present in pulmonary arterial hypertension (PAH), we tested the hypothesis that variability of breath-by-breath ventilation at rest would be increased in PAH compared with healthy controls. In fourteen patients with PAH (9 female, age 48.4±12.8 years, mean ± SD) and 14 healthy participants (9 female, age 49.4±14.2 years) breath-by-breath measurement of tidal volume and breathing frequency was undertaken with a pneumotachometer connected via a mouthpiece with nose-clip for 10 minutes while they rested awake and supine. Ventilatory (V̇E) variability was assessed using root mean square of successive differences (RMSSD), standard deviation (SD), average real variability (ARV, i.e., sum of absolute differences in successive observations), coeffcient of variation (CoV), as well as Poincaré analysis and compared between PAH and healthy controls (Student’s t-test). Correlations between measures of ventilatory variability and pulmonary hemodynamic characteristics, exercise capacity and function were assessed with Pearson’s correlation coeffcient. Resting V̇E was higher in PAH compared to healthy controls (14.3±1.1 and 12.1±0.5 L·min−1 respectively; p=0.009). Measures of variability for V̇E were increased in PAH compared to healthy controls. More specifically, RMSSD (3.59±1.36 vs. 2.48±0.87 L·min−1, p=0.017), SD (2.92±1.14 vs. 1.98±0.53 L·min−1, p=0.012), ARV (2.47±0.97 vs. 1.67±0.60 L·min−1, p=0.016), Poincaré SD1 (short-term variability, p=0.020) and SD2 (long-term variability, p=0.028) were increased in PAH compared to healthy controls, respectively. No correlations were found between measures of ventilatory variability and pulmonary hemodynamics (mean pulmonary artery pressure, pulmonary vascular resistance, and cardiac output), six-minute walk distance or WHO functional class. In summary, resting ventilatory variability is increased in PAH and not associated with haemodynamic factors and exercise capacity. Whether such raised ventilatory variability in PAH is related to increased chemoreflex sensitivity requires exploration.

This study received funding support from the Greenlane Research and Educational Fund (21/01/4153), Health Research Council of New Zealand (19/687), 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.
Sex Differences In The Phenotype Of Sleep-Disordered Breathing In C57BL/6J Mice
Authors: Kim Lenise , Pham Luu , Polotsky Vsevolod
Published: May 2024

Sex differences in sleep-disordered breathing (SDB) are widely recognized. SDB is more prevalent in men, but women appear to exhibit more symptoms at lower levels of SDB severity, including insomnia symptoms. Mechanisms underlying sex differences in SDB are unknown. In this study, we compared the sleep architecture and breathing patterns during sleep between male and female mice and examined the effects of ovariectomy on SDB. We hypothesized that female and male mice differed in sleep and SDB, which are related to differences in carbon dioxide (CO2) chemosensitivity between sexes. Adult male (n=9) and female (n=10) C57BL/6J mice underwent full-polysomnography inside a whole-body plethysmography chamber. Arousals from sleep and apneas were manually scored. Breathing variability was assessed with Poincaré plots of minute ventilation. Hypercapnic ventilatory response (HCVR) was assessed during wakefulness and NREM sleep by acute administration of 8% CO2. In female mice, we performed bilateral ovariectomy and repeated sleep studies after 14 days. We found that arousal index was 55% increased in females compared to males, but sleep fragmentation was mainly attributed to spontaneous arousals in both groups. Surprisingly, apnea severity was significantly increased in female mice compared to males (32.4±6.7 vs 11.8±4.5, P=0.001). Breathing instability was also increased in females. HCVR was positively correlated with apnea index (r=0.55, P=0.05) and was significantly augmented in females compared to males. Ovariectomy did not affect sleep fragmentation, but attenuated CO2 sensitivity and improved breathing stability during sleep. Our results have suggested different SDB phenotypes between male and female C57BL/6J mice. SDB in female mice is associated with a hyperarousal state and increased HCVR compared to males. An exacerbated CO2 responsiveness related to ovarian hormones in females is an important determinant of differences in SDB severity and respiratory patterns between male and female sex.

American Heart Association Postdoctoral Fellowship Award 828142 (to L.J.K.), NHLBI grant 2R01 HL133100-05, NIH R01 HL128970, and R01 HL13892 (to V.Y.P.), 1K23HL155730 and American Academy of Sleep Medicine Foundation 238-BS-20 (to L.V.P.).

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.