bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex difference in cardiac autonomic function in African American adults
Authors: Nyarko Ruby , Dalve Ashlesha , Perez Justo , Fatahimeiabadi Zahra , Dombroski Lindsay , Fadel Paul , Kaur Jasdeep
Published: May 2024

African American (AA) individuals in the United States have the highest prevalence of hypertension, with an age-adjusted prevalence of 55.8% in AA men and 56.9% in women. Compared to other racial groups, the AA population also has a two- to three-fold higher mortality rate resulting from hypertension-related causes. Furthermore, AA men exhibit a higher mortality rate than AA women. Previous studies have demonstrated sex differences in some biological mechanisms linked to the increased cardiovascular disease risk in the AA population —such as impaired vascular function and elevated oxidative stress. However, it is unknown whether sex differences are present in baroreflex sensitivity (BRS) and heart rate variability (HRV), which are key mechanisms that may contribute to the pathogenesis and clinical outcomes of hypertension. Herein, we tested the hypothesis that young AA men exhibit impaired cardiac autonomic function (spontaneous BRS and HRV) compared to AA women. We studied 26 young normotensive AA adults (13 women) [Age (men: 22 ± 3; and women: 19 ± 1yr; mean ± SD, p = 0.03); BMI (men: 24 ± 3; and women: 24 ± 2 kg/m2; p = 0.92)]. Heart rate (HR; ECG) and beat-to-beat blood pressure (BP; finger plethysmography) were continuously recorded during 10 min of rest to assess HRV and cardiac BRS. Resting HR (men, 61 ± 8; and women: 65 ± 9 bpm; p = 0.18), diastolic BP (men, 66 ± 6; and women: 65 ± 5 mmHg; p = 0.48) and respiratory rate (men, 17 ± 3; and women, 17 ± 3 bpm; p = 0.97) were similar between the groups. Mean BP and systolic BP were higher in AA men, though within the normotensive range for both groups [mean BP (men: 84 ± 5; and women: 76 ± 5 mmHg; p = 0.001); SBP (men: 119 ± 4; and women: 103 ± 7 mmHg; p < 0.001)]. HRV [root mean square of successive differences between normal heartbeats (RMSSD); men, 113 ± 78; and women, 79 ± 43 ms; p = 0.18] and cardiac BRS (overall gain; men, 25 ± 13; and women, 28 ± 12 ms/mmHg; p = 0.66) were not different between groups. These results indicate that BRS and HRV, which are markers of cardiac autonomic regulation, do not differ based on sex among young normotensive African American individuals.

Supported by: Kinesiology and Health Education UT Austin Start-up Account 19-2635-91; and TACSM 2023 Student Research Development 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.
Trpv4 Mechanosensing Mediates Valvular Interstitial Cell Differentiation to Myofibroblast
Authors: Mukherjee Pritha , Mahanty Manisha , Dutta Bidisha , Rahaman Shaik O.
Published: May 2024

Aortic valve stenosis (AVS) is a heart disease that gradually worsens, marked by the fibrosis, inflammation, and stiffening of the aortic valve leaflets, which results in obstructed blood flow and increased pressure on the left ventricle. This condition is associated with a significantly high risk of death. As AVS progresses, valvular interstitial cells (VICs) transform into myofibroblasts due to various soluble and physical cues, leading to detrimental changes in the surrounding cellular matrix. The transformation of VICs into myofibroblasts and the subsequent stiffening of the aortic valve are key factors in the advancement of AVS. Published work by our group and others show that Trpv4 (Transient Receptor Potential subfamily V member 4), a mechanosensitive, calcium-permeant channel/receptor, is activated by a range of soluble and physical stimuli. In mice, Trpv4 deficiency is associated with fibrosis and inflammation. In this study, we tested the hypothesis that Trpv4 regulates the transformation of VICs into myofibroblasts. Our research yielded several key findings: 1) Trpv4 is active in mouse VICs; 2) blocking Trpv4 activity in VICs prevents their transformation into myofibroblasts when exposed to TGF or matrix stiffness; 3) Trpv4 is needed for traction force generation in VICs as determined by traction force microscopy; and 4) Trpv4 residues 100 to 130 are required for myofibroblast differentiation and traction force generation. Altogether, our results highlight the crucial role of Trpv4 mechanosensing in regulating the transformation of VICs to myofibroblasts, a central process in AVS. We believe these findings could lead to novel Trpv4-targeted treatments to mitigate the effects of AVS.

NIH (R01 AI172086) grant to Shaik O. Rahaman.

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 regulation of salt appetite in Spontaneously Hypertensive Rats after loss of interoceptive input from the kidney
Authors: Veiga Amanda , Almutlaq Rawan , Ruiz Lauar Mariana , Ross Jaryd , Osborn John , Emy Nishi Erika , Dayton Alex
Published: May 2024

The average American consumes 3,400 mg/day of sodium, 1000mg over the American Heart Association’s recommended maximum daily allowance. Excessive salt intake accelerates the progression of many diseases including hypertension, congestive heart failure, and chronic kidney disease. Reducing sodium intake has beneficial effects on a population level and in at risk patients. In previous studies we have shown that afferent renal nerves are involved in the regulation of sodium intake in DOCA hypertensive rats. Like DOCA hypertensive rats, Spontaneously Hypertensive rats (SHR) are a model with increased salt appetite. Here, we tested the hypothesis that afferent renal nerves regulate sodium intake in SHR. Secondarily, it is well documented that estrogens modulate salt intake. To examine the effect of sex on sodium intake we compared salt-appetite between male and female SHR. Bilateral afferent renal denervation (ARDN) was performed using the periaxonal application of 33mM capsaicin. In sham rats the renal arteries were isolated but not treated. Mean arterial blood pressure (MAP) was assessed using radiotelemetry, with the catheter implanted in the femoral artery. Four groups of rats were studied: male SHR-sham (n=9), female SHR-sham (n=3), male SHR+ARDN (n=8) and female SHR+ARDN (n=4). All rats were given ad libitum access to two bottles, one containing dH2O and the other containing 1.8% NaCl. The bottle position was rotated, and fluid intake was recorded daily for 21-days. ARDN caused a significant reduction in 1.8% intake in female but not male SHR rats (p=0.02, female SHR-sham v female SHR-ARDN, p>0.99 male SHR v male SHR-ARDN). This effect was specific for saline intake, water intake was not altered by ARDN in the female SHR (p=0.3). The female SHR drank more saline than male SHR when normalized to body weight (p=0.04 female SHR-sham v male SHR-sham). MAP was not reduced by ARDN in the male SHR (p=0.39), and ongoing studies are examining MAP in response to ARDN in female SHR. The data presented demonstrate for the first time that ARDN decreases salt appetite in female but not male SHR. We also found that baseline saline intake was higher in female SHR than male SHR. In future studies we will examine the renal mechanisms underlying these sex differences. Together, these data suggest that reduced sodium intake may offer an additional therapeutic benefit of renal denervation in female patients with hypertension and cardiovascular disease.

LE is funded by R01HL152166; ACV is funded by FAPESP.

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.
TRPM3-mediated inhibition of active Na-K transport by the ocular lens epithelium
Authors: Shahidullah Mohammad , Rahman Faiz Ur , Shiels Alan , Delamere Nicholas
Published: May 2024

Purpose: The TRPM3 channel is selectively expressed in the lens epithelium, a monolayer at the anterior lens surface, but undetectable in fiber cells that make up the lens bulk. A point mutation in TRPM3 gene (substitution of isoleucine by methionine at codon 65; I65M) causes early onset autosomal dominant cataract in humans and in mice. From studies on transgenic mice, it is apparent the I65M TRPM3 mutation disrupts lens Na-K homeostasis. However, the normal role of lens TRPM3 in the lens is currently unknown. Here, we explore the lens response to TRPM3 activation. Methods: Studies were carried out using intact mouse lenses, cultured mouse lens epithelial cells and a human lens epithelium cell line (HLEB3). Active Na-K transport was studied by using rubidium (Rb) as a tracer for potassium entry. Rb was detected by atomic absorption spectrophotometry. Intracellular calcium was measured in nonconfluent single cells by Fura-2 ratiometric imaging. Results: Rb uptake was measured over a period of 10 min in intact mouse lenses exposed to a TRPM3 agonist CIM0216 (10 μM). CIM0216 reduced the rate of Rb uptake by ~20% (Ctrl 6.4±0.4 vs CIM 4.5±0.4 mmoles/kg lens dry weight/10 min, n=7, p<.01). The concentration dependence of the response to CIM0216 (1 to 50 μM) was examined in primary cultured mouse lens epithelium and Rb uptake was reduced by CIM0216 concentrations > 10 μM. The TRPM3 agonist reduced Rb uptake to a similar extent (~20%) in mouse lens epithelium, HLEB3 cells and HLEB3 cells that had been stably transfected with the I65M mutant TRPM3. However, the mutant cells responded to CIM0216 at a 10-fold lower concentration than WT mouse and HLEB3 cells. The Rb uptake response to CIM0216 was significantly inhibited by a TRPM3 antagonist, primidone (50 μM), and was abolished when cells were bathed in calcium-free solution. To study calcium entry, Fura2-loaded mouse lens epithelial cells were exposed to the TRPM3 agonist pregnenolone (100 μM). Pregnenolone caused an immediate increase in cytoplasmic calcium that was inhibited by primidone (Peak calcium concentration Ctrl 201±37 vs primidone 137±8 nM, n=5, p<.001). In cultures lens epithelium, agents that increase cellular cAMP, including IBMX, forskolin and 8p-CPT-cAMP, all caused a marked reduction of Rb uptake. Conclusions: TRPM3 activation causes a significant reduction in the rate of active Na-K transport and the response is associated with calcium entry. Because most lens Rb uptake is ouabain-sensitive, the response points to Na,K-ATPase inhibition. Studies are under way to test whether the Na-K transport response to TRPM3 activation involves cAMP signaling.

This work was supported by NIH grants R01EY029171 and R01EY009532.

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.
Non-invasive Blood Glucose Monitoring Using a Radiofrequency Sensor and a Machine Learning Model
Authors: Klyve Dominic , Anderson James , Curie Kaptain , Ward Carl , Pandya Kinara , Somers Virend
Published: May 2024

Diabetes Mellitus (DM) affects over 530 million people globally and is a condition characterized by high blood glucose (BG) that can result in severe long-term health consequences if poorly managed. To mitigate the risks associated with DM, it is crucial to regulate BG levels through regular monitoring. Current methods of monitoring BG come with drawbacks in the form of pain and expense. With the rapid increase in prevalence of DM, there is an increasing need for economical, accurate, and non-invasive continuous measures of BG. Here we present a validation for a novel sensor that rapidly scans through a wide range of radio frequencies (RF) and uses machine learning (ML) techniques for the purpose of non-invasive BG measurement. After model training, the RF sensor and ML techniques employed in this study can predict BG at a level significantly better than chance, as shown below. Data were collected from 13 healthy participants over a series of tests lasting 2 – 3 hours. During each test, participants placed their forearm on an RF sensor that measured their BG levels using sweeps across the 500 MHz – 1500 MHz range at 0.1 MHz intervals. Participants ingested 37.5 grams of glucose solution to generate BG readings across normoglycemic and hyperglycemic ranges. Each sweep took approximately 22 seconds, including a one second pause between sweeps. Across 110 tests, we collected 3,311 BG observations. Concurrent measurements from a Continuous Glucose Monitor (CGM) were taken as reference. Data were divided using a 60-20-20 (training-validation-test) split and trained on a Light Gradient-Boosting Machine (lightGBM) model to predict BG values. A ‘blind’ evaluation of model performance was determined using the held-out test dataset. We predicted BG values in the held-out test dataset with a Mean Absolute Relative Difference (MARD) of 10.8% in the normoglycemic range and 15.9% in the hyperglycemic range (11.27% overall MARD). These results were significantly better than a chance model (two-sample t-test, p <0.01). In a Surveillance Error Grid analysis of model accuracy, 89.0% of predictions fell in Risk Level 0, 10.1% in Risk Level 1, and 0.9% in Risk Level 2. These results demonstrate that the novel RF sensor and ML techniques described can predict a reference BG value in the population under study. More research is underway to refine and expand these methods using a gold-standard blood glucose reference device and among a broader participant population with an expanded glucose range. DK and VS are consultants for and own stock in Know Labs. JA and KC are employed by and have stock options in Know Labs. CW and KP are consultants for Know Labs.

NA.

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 Cholesterol on Resting Brain Blood Flow and Cognition in Middle-Aged Adults
Authors: Decker Kevin , Sanjana Faria , Rizzi Nicholas , Kramer Mary , Cerjanic Alexander , Johnson Curtis , Martens Christopher
Published: May 2024

Total cholesterol increases with age, with peak values observed in middle-aged adults (50-64 years old). Middle-aged adults are vulnerable to experiencing future cognitive decline, in which the concurrent reductions in resting brain blood flow with aging have been linked to cognitive impairments. PURPOSE: To determine the influence of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol on resting brain blood flow and cognition in middle-aged adults (50-64 years old). Methods: LDL and HDL cholesterol were measured in 18 healthy adults (57 ± 4 years old). Resting cerebral and hippocampal blood flow were assessed using a pseudo-continuous arterial spin labeling (pCASL) sequence from the Human Connectome Project inside a Siemens Prisma 3T MRI scanner. Cognitive function was assessed using the Hopkins Verbal Learning Test (HVLT) and the National Institute of Health (NIH) Toolbox’s Flanker Inhibitory Control and Attention Test and Pattern Comparison Processing Speed Test. The influence of cholesterol on resting brain blood flow and cognition was analyzed using Pearson correlations. Results: LDL cholesterol (123 ± 23 mg/dL) was negatively correlated with resting cerebral (70.1 ± 12.5 ml.100g−1.min−1; r = -0.78, p = 0.0001) and hippocampal (67.6 ± 13.1 ml.100g−1.min−1; r = -0.74, p = 0.0005) blood flow. There were no significant associations for HDL cholesterol (67 ± 17 mg/dL) on resting cerebral (r = -0.03, p = 0.9) nor hippocampal (r = -0.04, p = 0.9) blood flow. Among the cognitive function tests, only hippocampal-dependent memory retention from the HVLT was positively associated with HDL cholesterol (r = 0.51, p = 0.03). A follow-up analysis revealed participants with a higher resting brain blood flow presented a tendency for higher scores in the Pattern Comparison Processing Speed Test (r = 0.44, p = 0.06). CONCLUSION: LDL cholesterol, a cardiometabolic risk factor, was negatively associated with resting cerebral and hippocampal blood flow whereas the potentially cardioprotective factor HDL cholesterol was not. HDL cholesterol was positively associated with memory-related outcomes. Our results suggest cholesterol may impact resting brain blood flow and should be considered a target in preventing or delaying age-related memory loss. Further data are required to elucidate the underlying mechanisms. SIGNIFANCE: The cardiometabolic effects of cholesterol may have additional implications on cerebrovascular and brain health.

NIH/NIGMS - P20 GM113125.

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.
Vimentin Expression Following Mechanical Overload Induced Skeletal Muscle Hypertrophy Appears To Be Satellite Cell Dependent
Authors: Godwin Joshua , Michel Max , Fruge Andrew , Kavazis Andreas , Fry Christopher , Mobley brooks , Roberts Michael
Published: May 2024

Introduction: Vimentin (VIM) is an intermediate filament that plays a key role in development and regeneration of various tissue types. However, the expression of VIM during skeletal muscle hypertrophy has not been fully elucidated. Therefore, the purpose of this study was to determine the response of VIM following mechanical overload (MOV) with or without the presence of satellite cells. Methods: Pax7-DTA mice (age 4mo) were subjected to 3, 10 or 20 days of synergist ablation to induce overload of the plantaris muscle, time matched sham surgery mice served as controls. Following overload, the plantaris was removed and either sectioned for immunohistochemistry (IHC) or placed in Trizol for later RNA/protein isolation. Satellite cell depletion was confirmed via IHC to determine Pax7+ cells. VIM expression was also examined via RT-qPCR, western blotting, and IHC. Data were checked for normality via Shapiro-Wilks tests and two-way ANOVAs were performed with Tukey post-hoc tests. Results: In the Pax7-DTA mice, VIM expression revealed a significant Group, Time, and Group x time interaction (all P < 0.001). Further analysis revealed VIM expression was significantly upregulated in satellite cell intact mice after 3, 10, and 20 days of overload (all P < 0.001). VIM expression in the satellite cell depleted mice was non-responsive to 3 and 10 days of MOV (P = 0.964, and P = 0.984, respectively), however VIM expression following 20 days of MOV in satellite cell depleted mice was significantly increased compared to sham mice (P = 0.0047). Conclusion: VIM expression is responsive to hypertrophic stimuli and appears to be satellite cell dependent in the early stages of skeletal muscle hypertrophy.

Funding was provided through discretionary funds for Michael Roberts at Auburn 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.
Dapagliflozin Stimulates Renal Ammonia Excretion in Rats
Authors: Silveira Isabela Borges , Lichtenecker Debora CK , Gomes Guiomar N
Published: May 2024

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are drugs that induce glycosuria and are used to treat type 2 diabetes mellitus, moreover it has also been used in other conditions such as heart failure and atherosclerosis. However, little is known about the effects of these drugs on renal function. Considering that the maintenance of acid-base balance is closely related to renal physiology, in this study we evaluated the influence of chronic use of dapagliflozin on global renal function and urinary excretion of ammonia and titratable acids. Objective: To evaluate global renal function and urinary acid excretion (ammonia and titratable acid) in male Wistar rats chronically treated with dapagliflozin. Methods: 3-month-old male Wistar rats were randomized to control (C) and dapagliflozin (D) groups. Animals in group D received dapagliflozin (3 mg/kg, gavage) for 4 weeks. All animals were given food and water ad libitum throughout the experimental protocol. At 4 months of age, animals were placed in metabolic cages for 24-hour urine collection followed by blood sampling. Plasma concentrations of creatinine, sodium, potassium, urea, pH, pCO2, and bicarbonate were evaluated. The following were also evaluated: body weight, water intake, urine flow, and excretion of ammonia, titratable acids, glucose, and protein. Protocol approved by CEUA-UNIFESP number: 5985180423. Values expressed as mean ± standard error; number of animals per group: 6. Results: No significant changes were observed in blood gas parameters: pH (C: 7.33±0.043; D: 7.36±0.027), pCO2 (C: 53.30±2.40; D: 52.67±3.63 mmHg) and HCO3− (C: 27.07±1.31; D: 29.75±1.72 mEq/L) and no significant changes in plasma creatinine concentration (C: 0.41±0.04; D: 0.40±0.04mg/dl), Na+ (C: 144±0.47; D: 137±2.04 mmol/l) and K+ (C: 4.30±0.21; D: 4.16±0.20 mmol/l). We observed a significant increase in urine flow (C: 0.027±0.006; D: 0.068±0.005 mL/min/kg), possibly associated with intense glycosuria (C: 0.017±0.005; D: 8.97±0.51 g/24h). The significant increase in plasma urea concentration (C: 39.17±2.57; D: 48.83±1.27 mg/dL) and proteinuria (C: 11.04±0.30; D: 15.79±0.56 mg/24h) may indicate some renal impairment. Considering the marked increase in urinary excretion of ammonia (C: 0.65±0.05; D: 3.49±2.31 mEq/24h) and titratable acids (C: 0.180±0.036; D: 0.628±0.078 mEq/24h), we can conclude that the drug-induced glycosuria may lead to biochemical adaptations to maintain blood glucose levels within the normal range, at the expense of increased metabolic acid production. However, further experiments are needed to confirm this hypothesis.

CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior.

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.
Enhanced Functional Ultrasound Imaging for Longitudinal Cerebrovascular Assessment in Aging Mouse Models
Authors: Tarantini Stefano , Negri Sharon , Nyúl-Tóth Ádám , Sanford Madison , Reyff Zeke , Ballard Cade , Yabluchanskiy Andriy
Published: May 2024

This study aims to enhance the visualization of deep cerebrovascular structures and blood flow in the aging brain, a key factor in understanding the pathogenesis of vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD). We hypothesized that functional ultrasound (fUS) imaging through a polymethylpentene window could provide high-resolution insights into cerebral blood flow (CBF) in older mice. Employing this method, we replaced the skull of elderly (24-month-old C57BL/6) mice with a transparent window, allowing for consistent, non-invasive fUS imaging over time. We utilized ultrasound localization mapping (ULM) with a microbubble (approximately 10 micrometers (μm)) suspension for detailed mapping of microvascular vessels and flows. Data were analyzed using a FIJI-based platform to interpret high-quality ULM images. Our results demonstrate this novel method's effcacy in revealing intricate vascular details, proving its utility for longitudinal CBF assessments in physiological research in preclinical murine models and aging.

This study was supported by the following funding sources: NIH R03AG070479, K01AG073614, R21AG080775, American Heart Association, Hevolution/AFAR.

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 Impact of the Estrous Cycle on Abdominal Pain
Authors: Bennett Aidan , Baker Corey , Alward Taylor , Vanner Stephen , Reed David , Lomax Alan
Published: May 2024

Background: Irritable bowel syndrome (IBS) is a chronic abdominal pain disorder that affects women twice as often as men. While luminal mediators of both host and bacterial origin have been implicated in modulating abdominal pain in IBS patients, gonadal hormones have also been shown to influence pain signaling. Estrogen has been identified as a pronociceptive mediator that can modulate central and peripheral neural pathways. Given this, we hypothesized that the estrous cycle modulates sensory neuronal excitability, thereby altering the sensitivity to luminal mediators and this contributes to the female predominance of IBS. Aim: Identify the impact of the estrous cycle on nociceptive signaling and compare the effects of fecal supernatants (FS) from male and female IBS patients on abdominal pain pathways. Methods: Current clamp recordings measured rheobase and voltage clamp measured voltage-gated Na+ current in thoracolumbar dorsal root ganglia (DRG) neurons. FS from male and female IBS patients reporting high levels of abdominal pain were used. FS were perfused through male, female, and ovariectomized murine colonic preparations while performing extracellular colonic afferent nerve recordings to measure changes in action potential frequency during spontaneous firing and in response to colonic distension. Phase of estrous cycle in female mice was determined through analysis of vaginal swabs. Ovariectomies were performed 4 weeks prior to assays. Results: Current clamp recordings revealed an increase in excitability due to a 20% reduction in rheobase in DRG neurons taken from proestrus/estrus female mice compared to males, metestrus/diestrus females and ovariectomized females (p < 0.05). Voltage-gated Na+ current density was increased by 40% in neurons from proestrus/estrus mice compared to metestrus/diestrus female and male mice (p < 0.01). Extracellular afferent nerve recordings revealed that FS from female IBS patients reporting high abdominal pain (N=3) increased afferent nerve discharge (p < 0.05) in proestrus/estrus female mice by 70%. Single unit analysis of nociceptive axons showed that their activation was increased over 50% following FS perfusion. H owever, this excitatory effect was abolished in ovariectomized mice. Interestingly, FS from male IBS patients reporting high abdominal pain (N=4) had no effect in male mice while female IBS patient FS (N = 6) increased afferent nerve discharge (p< 0.05). Conclusion: This work suggests that the estrous cycle impacts abdominal pain signaling, which may contribute to the female predominance of IBS.

This work is funded by CIHR and The Weston Foundation.

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.
Associations Between Grip Strength and Cerebral Hemodynamics in Young and Middle-Aged Adults
Authors: Rosonke Rachel , Frescoln Abby , Reed Krista , Gidley John , Churchill Sydney , Meyer Jacob , Lefferts Wesley
Published: May 2024

Aerobic fitness and aerobic exercise are widely accepted as having protective effects on cognitive function and brain health, with less understood regarding muscular fitness and resistance exercise. Strength is beneficially associated with cognitive function, but the mechanisms underlying this relationship remain understudied and may relate to cerebral hemodynamics. The purpose of this study was to examine the associations between strength and cerebrovascular hemodynamics in young and middle-aged men and women. It was hypothesized that greater strength would be associated with better cerebral hemodynamics (greater mean blood velocity, lower pulsatility, greater pulsatile damping). Ninety-two generally healthy adults between 18-64 years old (36±16 yrs; BMI 25.9±4.0 kg/m2; n=39 women) underwent a hand grip strength assessment and resting cerebrovascular measures. Grip strength was measured via dynamometer and recorded as the highest value of 3 attempts. Middle cerebral artery (MCA) mean velocity and pulsatility index (PI) were measured via transcranial Doppler. Pulsatile damping was calculated as the ratio between the common carotid artery and MCA PI. Mean arterial pressure was assessed via an oscillometric blood pressure cuff. No significant associations were observed between relative grip strength and MCA mean velocity (r=-0.15), MCA PI (r=0.05), or MAP (r=0.07) after adjusting for age. Greater relative grip strength, however, was associated with greater pulsatile damping after adjusting for age (r=0.21; p<0.05). This relationship appeared to be driven by weak associations within each sex (men, r=0.10; women, r=0.02) that were not statistically significant on their own. Our preliminary results suggest there are no strong relations between grip strength and cerebral hemodynamics among generally healthy young and middle-aged adults after accounting for the effects of age and sex. Future studies should examine sex-specific associations with a larger sample, consider disease states related to cerebrovascular health, and include more comprehensive assessments of muscular strength and performance (e.g., power).

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.
Sexual dimorphism in renal metabolism, hemodynamics and diseases
Authors: Xiong Lingyun (Ivy) , Garfinkel Alan , Deeds Eric J.
Published: May 2024

Age-related decline of renal function is faster in males than in age-matched females, manifesting in increased susceptibility to both chronic and acute kidney diseases among males. In the mouse kidney, sexually dimorphic gene activity maps predominantly to proximal tubule (PT) segments, where most reabsorption of water and salt happens, with a high energetic demand. Recent work suggests that male PTs undergo excessive oxidative stress to meet the high energetic demand, while female PTs exhibit an anti-oxidation state. However, it remains elusive how the observed molecular differences relate to sex disparities in renal physiology and pathophysiology. Glomerular filtration rate (GFR) is tightly regulated by tubuloglomerular feedback (TGF) within renal tubules to optimize ultrafiltration of plasma and reabsorption of essential molecules. Importantly, GFR shows a sustained oscillatory pattern over time in rodents, and loss of GFR oscillations is associated with cessation of reabsorption activities and with the occurrence of ischemia-reperfusion injuries in the kidney, as well as with systemic hypertension. To study the relationship between intracellular metabolic events and renal physiology, we developed a mathematical model of TGF linking metabolic regulation within PT cells to fluid handling and salt reabsorption in the nephron, using renal blood flow and intra-vital imaging data. Analysis of this model revealed that dynamical properties of the system differ between male and female kidneys, resulting in male kidneys being more prone to stress-induced damage, thus building towards an explanation for sexual dimorphism in renal aging and diseases. With this mechanistic model, our work also provides insight into how pharmacological interventions can be employed to confer renoprotection.

The authors received no funding for this study.

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.
Alterations in sphingolipid synthesis during training, detraining, and retraining may alter myogenesis in skeletal muscle
Authors: Weidenhamer Clay , Syed Adam , Huang Yi-Heng , Hernancez-Saavedra Diego
Published: May 2024

The benefits of exercise on metabolic health and its effectiveness at reducing morbidity risk are well established. Exercise training enhances skeletal muscle metabolism and function, but whether such adaptations persist through detraining and how they are potentiated with retraining are not well understood. Recent evidence has highlighted the role sphingolipids play on skeletal muscle size and function, but how exercise affects sphingolipid metabolism is not yet known. We hypothesize that alterations in skeletal muscle sphingolipid metabolism with exercise training are necessary to enhance muscle mass with further exercise retraining. Here, mice were SEDentary (SED; static cages) or exercise-TRAINed (TRAIN; voluntary wheel running) and chow-fed. We performed body composition analysis (using EchoMRI) and skeletal muscle collection [tibialis anterior ( TA), extensor digitorum longus ( EDL), gastrocnemius ( Gas), Soleus ( Sol), plantaris ( Plant), and levator ani ( LA)] following training (4wks), detraining (8wk), and retraining (12wk) in three independent cohorts. Sphingolipid and myogenic gene expression was measured in TA muscle by qPCR. Exercise training concomitantly increased lean and decreased fat percentage ( p<0.05), while increasing Sol muscle mass in TRAIN mice ( p<0.05), compared to SED. This was accompanied by higher sphingolipid metabolism ( Acer1, p<0.05; and Cers1, p=0.058) and myogenic gene expression ( MyoD, Myf5; p<0.05). Following detraining, TRAIN mice had an overall increase in lean-to-fat mass ( p<0.05) while maintaining all individual muscle masses ( p<0.05), compared to SED. This was accompanied by a reduction in gene expression of the sphingolipid receptor S1pr1 and myogenic factor Myf5 ( p<0.05), but no differences in sphingolipid metabolism ( Acer1, Cers1). Lastly, retraining increased lean and decreased fat percentage ( p<0.05) and enhanced the masses of TA, Gas, Sol, and Plant muscles in TRAIN mice ( p<0.05), compared to SED. This was accompanied by a reduced expression of rate limiting sphingolipid synthesis genes Sptlc1 and Sptlc2 and the kinase Sphk1 ( p<0.05), but no differences in Cers1 or myogenic gene expression in TRAIN mice, compared to SED. Overall, our data shows that exercise training and retraining potentiate muscle mass accretion and dynamically regulates sphingolipid metabolism adaptations. These data suggest a potential role for sphingolipids to modulate long-lasting improvements to skeletal muscle.

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.
Understanding the Role of Central Parasympathetic Activation in Opioid-Induced Respiratory Depression and Peripheral Airway Constriction
Authors: Burgraff Nicholas , Moreira Thiago , Baertsch Nathan , Ramirez Jan Marino
Published: May 2024

Opioid-induced respiratory depression (OIRD) is a primary cause of mortality resulting from opioid overdose. Numerous mechanisms have been identified as contributors to OIRD, such as the suppression of central respiratory rhythmogenesis. Our recent research revealed that opioids' ability to suppress breathing extends beyond the central suppression of rhythmic activity, notably leading to airway constriction, which can culminate in complete obstruction. The autonomic nervous system plays a pivotal role in regulating the tone of airway smooth muscles with the parasympathetic system being mainly responsible for bronchoconstriction, and the sympathetic system facilitating bronchodilation. In this study, we evaluated the hypothesis that exposure to fentanyl results in the disinhibition of parasympathetic motor output, leading to centrally mediated peripheral airway constriction. After administering fentanyl (500μg/kg i.p.), minute ventilation dropped by nearly 50%, primarily due to a decrease in breathing frequency. Transient airflow obstructions during the inspiratory phase were observed following fentanyl administration, as indicated by an increased latency between diaphragm contraction and the start of inspiratory flow. These airflow obstructions were fully reversed by the sympathomimetics salbutamol or epinephrine. To determine whether the transient obstructions were a result of vagal activation, another group of mice underwent vagotomy prior to fentanyl administration. The vagotomy effectively eliminated the occurrence of airflow obstructions following fentanyl administration. Additionally, using neuronal activity-based fos-dependent labeling and in-vitro patch-clamp recordings, we showed that fentanyl administration led to a pronounced activation of parasympathetic motor neurons within brainstem areas, including the dorsal motor nucleus of the vagus and the nucleus ambiguus. Collectively, our findings suggest that fentanyl induces transient obstructions to airflow that may be attributed to heightened central parasympathetic activity, which in turn drives peripheral airway constriction.

P01 HL090554 (J.M.R.), R01 HL126523 (J.M.R.), R01 HL144801 (J.M.R.), R01 HL151389 (J.M.R.), F32 HL154558 (N.J.B.), R00HL145004 (N.A.B.) and R01HL166317 (N.A.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.
Short-term treatment of Tat-Beclin1 and endurance exercise enhances autophagy and increases grip strength in old male mice but not in female
Authors: Ghiarone Thaysa , Davis Carina , Rahman Shakibur , Murphy Madelyn , Brahmbhatt Dhruti , Silva Kleiton
Published: May 2024

Sarcopenia is a geriatric disease causing loss of muscle mass and function, ultimately declining quality of life and causing death. Despite substantial efforts to prevent sarcopenia, there are no approved drugs for treating this muscle disease. Autophagy, a critical process for maintaining muscle health, offers potential avenues for intervention. However, an integrative therapy comprised of an autophagic-specific compound and endurance exercise in old animals has yet to be tested. We hypothesize that combining Tat-Beclin1 (a potent autophagy-specific inducer) and endurance exercise improves muscle force and autophagy in both male and female old mice. Female and male mice at 23 months of age were divided into four groups: Control, Tat-Beclin1 (TB), endurance exercise (Exe), and TB+Exe. Short-term combined treatment underwent for one month. Exercise training at moderate intensity (70% of running peak test) was performed on Mondays, Wednesdays, and Fridays. Tat-Beclin1 administration (15 mg/kg/day) was conducted on Tuesdays and Thursdays. We assessed muscle function through forelimb grip strength and muscle autophagic markers by western blotting. There was no difference in grip strength in female groups. In contrast, there was an increase in grip strength in treated male mice (p<0.05; TB, Exe, and TB+Exe vs. Control group). Notably, the combination treatment in the TB+Exe group outperformed the individual treatments (TB and Exe groups) in enhancing grip strength (p=0.05). Beclin1 and GLIPR2 (a novel autophagic suppressor) were unchanged in both male and female mice. Sequestosome/p62 was decreased in males only, indicating autophagy cargo degradation. Our findings demonstrate that a short-term treatment of Tat-Beclin1 combined with endurance exercise improves grip strength (muscle force) and autophagy in old male mice. Notably, female mice did not exhibit a similar response to the short-term treatment, suggesting that a more extended therapy duration may be necessary to explore potential benefits for female mice. This synergy of an autophagic-specific agonist with endurance exercise may represent a novel strategy to tackle sarcopenia.

Camden Health Research Initiative - Startup fundings.

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.
Intersection of chronic contractile activity and lysosomal defects in mediating lysosomal adaptations in skeletal muscle cells
Authors: Moradi Neushaw , Hood David A.
Published: May 2024

Mitophagy is the cellular process that serves to degrade mitochondria when these organelles lose their potential for ATP production, generate excessive reactive oxygen species, and exhibit a reduced membrane potential. The terminal step of mitophagy is mediated by the lysosome, the organelle that degrades defective cellular cargos. Electron microscopy evidence shows that lysosomes become defective in aging muscle, as well as in lysosomal storage diseases, ultimately leading to cellular pathology. Recent research has shown that chronic contractile activity can induce rapid increases in lysosomal gene and protein expression in muscle. Our objective is to investigate whether this adaptation leads to greater lysosomal content and function, thus enhancing the capacity to degrade defective mitochondria. This result would suggest that reduced lysosomal function in muscle could be rescued by exercise. However, the underlying mechanisms mediating lysosomal turnover and function are not clear. To study this, we simulated lysosomal dysfunction in C2C12 myotubes using short-interfering RNA targeting the lysosomal calcium channel mucolipin-1 (MCOLN1) or the autophagosome-lysosome fusion protein, lysosomal-associated membrane protein 2 (LAMP2). We achieved a 60-70% knockdown, as well as a 40-50% knockdown, after a 24-hour transfection, in each lysosomal marker, respectively. The cells were then subjected to four days of electrical stimulation-induced chronic contractile activity. Changes in gene expression were measured via qPCR, while protein content was measured via western blotting techniques, in addition to lysosomal content and functional assessments via confocal microscopy and flow cytometry. Silencing of MCOLN1 or LAMP2 both resulted in a compensatory increase in the transcript and protein levels of lysosomal genes, including the lysosomal transcription factors TFEB, TFE3, as well as lysosomal cathepsins B and D. Interestingly, contractile activity superimposed on the MCOLN1 or LAMP2 knockdown did not further enhance these compensatory increases. This suggests that contractile activity and the cellular signaling that arises from lysosomal defects, operate similarly to initiate the biogenesis of lysosomes as a negative feedback mechanism to enhance lysosomal degradation capacity. The nature of these signaling pathways, potentially involving changes in lysosome-derived intracellular calcium driving organelle synthesis, recycling, or degradation represent novel avenues for upcoming research investigating skeletal muscle phenotypic adaptations.

This work is supported by NSERC.

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.
Placental tissues from nonhypertensive black patients demonstrate lower placental leptin expression compared to white patients independent of BMI
Authors: Ives Madison , Cooper Gibson , Bickerstaff Cayman , Stokes Stephanie , Moronge Desmond , Mellott Elisabeth , Ogbi Safia
Published: May 2024

Hypertensive disorders of pregnancy increases risk of maternal and fetal morbidity and mortality. In the US, clinical data indicates that black women are more likely to develop hypertensive pregnancy than white women for reasons largely unknown. The goal of this study was to determine if expression of factors associated with hypertensive pregnancies, in the absence of hypertension milieu, differed between placental tissues from black versus white patient deliveries. We hypothesized that placental tissues from black patient deliveries demonstrate increases in gene expression of these factors compared to white patient deliveries. We collected placentas at time of delivery from healthy, nonhypertensive black (n=13) and white (n=14) patients from AU Medical Center. Snap frozen tissue from maternal side of placenta was processed to isolate RNA, reverse transcriptase for cDNA generation and then subjected to digital droplet PCR analysis of known markers of preeclampsia: leptin (Lep), preproendothelin-1 (PPET1), endothelin converting enzyme-1 (ECE-1) and placental growth factor (PLGF). Data output was recorded for each expression in copies/ul. Body mass index (BMI) at delivery did not differ between black (32.0±2.1 kg/m2) and white patients (31.3±1.4). In addition, correlation analysis (Pearson’s Correlation Coeffcient) was performed for BMI vs expression of Lep, PPET1, ECE-1 and PLGF in all samples from black and white patients and no significant association was found (P>0.05, R2<0.5 for all comparisons). Comparisons of gene expression between white and black patients was performed by 2-tailed t test. Lep expression significantly decreased in black compared to white patient placenta (74±61 vs 590±173 copies/ul, *p<0.05). However, placental expressions of PPET1 (844±185 black vs 626±164 white, copies/ul), ECE-1 (327±117 black vs 626±164 white, copies/ul), and PLGF (305±80 black vs 217±39 white, copies/ul) did not significantly increase or decrease in black compared to white patients. Collectively, these data surprisingly indicate that in nonhypertensive pregnancies, black patients demonstrate lower leptin expression compared to white patients. However, endothelin-1 associated ECE-1 and PPET1 expressions do not increase in nonhypertensive black patient placenta compared to white. As leptin expression is characteristically elevated in hypertensive pregnancy, future studies will determine if placentas collected from hypertensive black and white pregnancies demonstrate a discrepant gene expression in genes associated with increased risk of hypertensive pregnancy.

NIH grants 1R01HL169576, 4R00HL146948.

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.