bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of inspiratory muscle warm-up on perceptual, physiological, and performance outcomes during high-intensity exercise in normoxia and hypoxia
Authors: Gabler Mikaela , Martin Bruce , Johnson Blair , Schlader Zachary , Chapman Robert
Published: May 2024

Some evidence shows that an inspiratory muscle warm-up (IMW) could enhance exercise performance; however, the mechanistic basis is unclear. PURPOSE: To examine how IMW affects the sensory and affective components of dyspnea, exercise performance, and locomotor muscle oxygenation. METHODS: Thirteen recreationally active individuals (23 ± 5 yr, 5 women) performed a cycling time to exhaustion test (~80-85% VȮ2max) preceded by either IMW (2x30 breaths, 40% maximal inspiratory pressure) or SHAM (2x30 breaths, 15% maximal inspiratory pressure) in normoxic (FIO2 = 0.21) and hypoxic (FIO2 = 0.16) conditions (i.e., 4 trials total). NIRS, dyspnea (i.e., breathing intensity and breathing unpleasantness), and cardiorespiratory parameters were measured throughout. Cardiorespiratory variables were analyzed using the individual isotime method. RESULTS: There were no differences in mean dyspnea responses between IMW and SHAM ( p > 0.05). Mean Δ tissue saturation index (TSI) did not reach statistical significance between IMW and SHAM in normoxia ( p = 0.110) or hypoxia ( p = 0.07). Mean performance was not different in normoxia ( p = 0.636) or hypoxia ( p = 0.512). In normoxia, V̇E ( p = 0.059) and fB ( p = 0.056) approached significance with IMW values greater compared to SHAM in the third isotime. CONCLUSION: Group improvements in dyspnea, performance, and ΔTSI were not seen following IMW. However, the degree of select individual responses suggest this intervention has interindividual applicability that should not be overlooked.

No external funding was received for this work.

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.
Physical activity alleviates obesity-associated mesenteric arterial endothelial dysfunction: Role of adiponectin receptor
Authors: Park Yoonjung , Lee Junghoon , Lee Jonghae
Published: May 2024

Introduction: A strong association between cardiovascular disease and obesity has been reported. However, the role of adiponectin in the effect of physical activity on mesenteric circulation and its underlying mechanism has been unknown. We investigated the protective effect of voluntary wheel running (EX) on endothelial function in the mesenteric artery of obese mice and its underlying mechanisms. Methods: C57BL/6J male mice were randomly divided into four groups: (1) control low-fat diet (LF), (2) LF diet with free access to a voluntary running wheel (LF-EX), (3) high-fat diet (HF; 45% of calories from fat), and (4) HF-EX. The protein expressions of total-endothelial nitric oxide synthase (t-eNOS), adiponectin receptors 1 and 2, AMPK, Ob (leptin), inflammatory markers, and proteins regulating apoptosis were quantified by Western blot analysis. Statistical comparisons between groups were performed with two-way ANOVA with Fisher’s LSD test. Results: The protein expressions of t-eNOS, adiponectin receptors 1 and 2, and p-AMPK in HF were lower compared to LF, but EX increased the protein levels ( P < 0.05). Ob in HF was higher compared to LF, but EX decreased it ( P < 0.05). IL-1β, TNF-α, and Caspase-1 in HF were higher compared to LF, but EX decreased the protein levels ( P < 0.05). There was no difference in expressions of AMPK, CHOP, Bcl-2, and GADD153 between groups. Conclusion: Voluntary wheel running alleviates e-NOS-mediated endothelial dysfunction in the mesenteric artery of obese mice possibly via increased adiponectin receptors and decreased inflammation.

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.
Cab39 is the major scaffolding protein for SPAK-mediated NCC activation in the mouse kidney
Authors: Ferdaus Mohammed , Koumangoye Rainelli , Welling Paul , Delpire Eric
Published: May 2024

STE20/SPS1-related proline/alanine-rich kinase (SPAK) phosphorylates the sodium-chloride cotransporter (NCC) to stimulate sodium reabsorption in the Distal Convoluted Tubule (DCT) for K+ homeostasis and blood pressure. The scaffold proteins, Calcium-binding protein 39 (Cab39) and Cab39-like (Cab39l) activate SPAK in a Xenopus oocyte expression system. Still, it has not been determined whether Cab39 or Cab39-like are required for NCC phosphorylation in the DCT. Here, we developed DCT-specific Cab39 knockout (KO), global Cab39l-KO, and Cab39/Cab39l double knockout (DKO) mice to assess the role of the two adaptor proteins in the Kidney. The SPAK-NCC signaling axis was evaluated by Western Blot and immunofluorescence microscopy. Physiological consequences of altered signaling were evaluated with blood and urine electrolyte measurements. Cab39-KO mice had significantly lower total NCC (tNCC) and phosphorylated NCC (pNCC) abundance than wild-type mice. Phospho-activation of NCC with low K+ diet was also blunted in the Cab39 KO mice. By contrast, the Cab39l-KO mice did not show differences in total or phosphorylated NCC signals. However, when Cab39 was eliminated on the Cab39l KO background (DKO), pNCC abundance further decreased to almost undetectable levels. Remarkably, the DKO did not affect the phospho-activation of SPAK. Instead, SPAK failed to move to the apical membrane and accumulated into cytoplasmic puncta in the DKO mice. In summary, these data indicate that Cab39 and Cab39l act as major and minor regulators of SPAK-NCC signaling, providing an adaptor for translocating SPAK to the apical membrane for NCC interaction and phosphorylation.

NIH grant R01DK093501 to Professor Eric Delpire and Professor Paul Welling, The Leducq Foundation grant 17CVD05 to Professor Eric Delpire and Professor Paul Welling, and a Crawford Long Innovation grant to Professor Eric Delpire.

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.
Creatively Reflecting About Human Function
Authors: Petzold Andrew
Published: May 2024

Non-traditional methods of evaluating student knowledge have been gaining traction in non-scientific fields for a number of years. These multi-media based expositions of knowledge, colloquially as the “unessay,” serve to not only showcase a student’s true knowledge of a subject but also a self-awareness that is not commonly examined in science classes. We provided students with various methods of displaying their knowledge in physiology that was coupled with self-reflection. Specifically, students were asked not only to reflect on a topic that struck them as important, exciting or notable, but they were also asked to relay that information to an audience of their choosing. By combining a reflection on their own learning with a review of content knowledge, students could carefully consider information that stuck out to them as being relevant to their own lives and reflect upon that meaning fostering metacognition regarding their own learning.

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.
Effects of Exercise Intensities on Changes in Pro-/Anti-inflammatory Cytokines following 8-weeks of Aerobic Exercise Training
Authors: Beltran Gerardo , Park Kyung-Shin , Arellano Jocelynn , Reyes Sergio , Park Jeffrey , Cho Seong Kwan
Published: May 2024

Inflammatory cytokines are useful biomarkers in predicting the development of metabolic and cardiovascular diseases and may be positively affected by physical activity and weight loss. Despite much interest in chronic low-level inflammation in the obese population, effects of aerobic training intensity on inflammatory cytokines remain elusive. PURPOSE: The purpose of this study was to investigate effects of 8-week aerobic exercise training at high and low intensities on changes in pro-/anti-inflammatory cytokines. Methods: Fifty three inactive obese Hispanic females (mean BMI = 34.5 kg/m2, aged 34-46 years) were divided into one of three groups: low intensity training group (LT: walking at 55% VO2max, n=16), high intensity training group (HT: running at 70% VO2max, n=18), and control group (CON: no intervention, n=19). LT and HT performed aerobic exercises three times per week at the given intensities. Exercise volume for two exercise groups was equated relative to kilograms of body weight by adjusting duration of exercise session (approximately 60 minutes for LT and 40 minutes for HT per session). Blood samples were collected before and after 8 weeks of intervention to measure levels of adiponectin, C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-α). Two-way repeated measures ANOVA and Tukey post hoc tests were used for data analysis. Results: Level of adiponectin showed no significant change in any groups after 8 weeks of aerobic exercise intervention. A significant decrease in CRP was observed in the HT group only (4.12 ±.26mg/L mean±SE → 3.89±.37, P=.041), but levels of TNF-a were significantly decreased in both LT (4.57±.24pg/mL → 4.14±.31, P=.019) and HT (4.54±.25 → 4.02±.41, P=.011). No changes were observed in CON. CONCLUSIONS: Significant decreases in CRP and TNF-a were found following high intensity aerobic exercise training while low intensity training reduced TNF-a only. The greater changes of pro-inflammatory cytokines in HT indicates high intensity aerobic exercise training may be more beneficial than low intensity training. Specifically, for controlling low-grade inflammation and immune function in obese Hispanic females. This study confirmed results of previous studies suggesting that longer period of exercise training with distinct fat loss may be required to induce significant changes in adiponectin in obese adults.

TAMIU university research grant.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Central α2-adrenergic mechanisms differentially affect baroreflex control of sympathetic and cardiovagal outflow
Authors: Spafford Julia , Limberg Jacqueline , Harvey Ronée , Wiggins Chad , Iannarelli Nathan , Senefeld Jonathon , Nicholson Wayne
Published: May 2024

This study aimed to investigate the impact of central α2-adrenergic mechanisms on arterial baroreflex control of sympathetic and cardiovagal outflow in healthy humans. R-R interval (ECG), blood pressure (brachial arterial catheter), and muscle sympathetic nerve activity (MSNA; peroneal microneurography) were measured in eight healthy participants (5 females; 28±7 years). Sympathetic action potentials (AP) were extracted from the filtered MSNA neurogram (continuous wavelet transform) during a 5-minute baseline (BSL) and an intravenous dexmedetomidine infusion consisting of a loading dose (LD; 10 minutes at 0.225 μg/kg/hr) and a maintenance dose (MD; ~0.15 μg/kg/hr). Sympathetic AP baroreflex threshold gain was measured as the slope of the linear relationship between AP discharge probability and diastolic blood pressure. The linear relationship between R-R interval and systolic blood pressure (sequence technique) quantified cardiovagal baroreflex gain. Mixed-effects analyses and post-hoc t-tests were performed. Data are reported as mean ± SD. Dexmedetomidine reset the baroreflex threshold operating points for all sympathetic AP clusters downwards to lower firing probabilities (cluster 4; BSL: 20±6, LD: 13±8, MD: 6±5%, both p<0.01 vs. BSL) and leftwards to lower diastolic pressures (BSL: 72±9, LD: 69±8, MD: 65±10 mmHg, both p<0.01 vs. BSL). Dexmedetomidine reduced baroreflex threshold gain for the subpopulation of medium-sized sympathetic APs (cluster 4; BSL: -6.5±2.0, LD: -2.6±1.6, MD: -2.0±0.7 %/mmHg, both p<0.01 vs. BSL). Dexmedetomidine did not affect baroreflex threshold gain of small (cluster 1; BSL: -1.9±1.1, LD: -1.3±1.6, MD: -1.1±0.8 %/mmHg, both P>0.88 vs. BSL) or large AP clusters (cluster 9; BSL: -0.8±0.4, LD: -0.8±1.0, MD: -0.2±0.7 %/mmHg, both P>0.98 vs. BSL). Dexmedetomidine reset the cardiovagal baroreflex to lower systolic pressures but did not affect R-R interval (BSL: 1035±261, LD: 1025±308, MD: 1005±292ms, Main effect P=0.45) or gain (BSL: 24±11, LD: 30±20, MD: 26±25 ms/mmHg, Main effect P=0.63). These findings suggest that central α2-adrenergic mechanisms differentially affect arterial baroreflex control of sympathetic and cardiovagal outflow in humans by minimally affecting cardiovagal baroreflex gain but strongly affecting the baroreflex gain for the subpopulation of medium-sized sympathetic APs.

This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) and the National Institutes of Health (NIH).

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Presence of XX Sex Chromosome Complement Increases Aortic Circumferential Stiffness in Female Mice
Authors: Kamau Anne , Sakamuri Anil , Sengottaian Divya , O. Ogola Benard
Published: May 2024

Elastin and collagen uniquely adapt to the mechanical demands of high pulsatile pressure in the vascular system in conjunction with the extracellular matrix (ECM). Elastic fiber networks and collagen are affected by component disorganization, leading to an array of vascular diseases and compromised mechanical behavior. It is shown that women than men have accelerated arterial stiffening. Previously, we have shown increased axial and circumferential linearized material stiffness in the carotid arteries of female than male wildtype mice. Whether sex hormones interact with sex chromosomes is unknown. Therefore, we hypothesize that sex hormones interact with sex chromosomes to increase aortic circumferential stiffening in female than male mice. In this study, we used gonadal intact 15-week-old four core genotype mice (n=4-6/group) comprising female (F) and male (M) mice with either XX or XY sex chromosome complement (SCC). Using a tissue puller, we assessed the stress-strain and displacement-force relationship of the abdominal aorta. Briefly, the aorta was cut into 3mm rings and pulled apart to a range of 1300 μm with a velocity of 35 μm/sec. To determine the load-bearing effect of collagen and elastin, collagenase type II (16 units) and elastase (5 units) were used to digest the aortic ring before pulling. Part of the aortic ring was digested for a PCR array of extracellular matrix and adhesion molecules. We observed a leftward shift of stress-strain in XXF than in XXM (P=0.03). A leftward shift of stress-strain was also indicated in XXF than in XYM mice (P=0.004). Displacement-force tests showed a similar effect with a leftward shift in XXF than XXM (P=0.01). A leftward shift of displacement force was also indicated in XXF than in XYM (P=0.004). Aorta digestion with elastase reversed the phenotype, showing a leftward shift of displacement force in XXM than in XXF (P=0.02). Collagenase digestion removed the observed sex differences in stress-strain and displacement force tests. The PCR array comparing XXF and XXM showed increased fold change in Adamts5 (4.2), Emilin (2.2), Icam1 (2.4), and Thbs2 (3). We also observed the downregulation of Cntn1 (0.4), Cntnna1 (0.5), Ecm1 (0.3), and Fbln1 (4). Our data suggested that XX sex chromosome complement, and ECM genes contribute to the structural stiffness of female mice aorta. Our study will contribute to understanding connective tissue diseases, including arterial stiffness, aortic aneurysms, Marfan and Danlos syndrome.

HL105400 and HL155841.

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.
Can the dietary inorganic nitrate supplementation mitigate the vascular dysfunction in elderly with Alzheimer’s disease?
Authors: Venturelli Massimo , Martignon Camilla , Dorelli Gianluigi , Porcelli Simone , Schena Federico , Dalle Carbonare Luca , Giuriato Gaia
Published: May 2024

Aging and Alzheimer disease (AD) are both characterized by progressive reduction in nitric oxide bioavailability and endothelial function impairment. Promising studies on young healthy individuals underly the positive effect of dietary nitrate supplementation on endothelial function. However, the pharmacokinetics of the plasma nitrate and nitrite (PN) and the accompanying endothelial responsiveness following the oral nitrate ingestion in healthy elderly (HE) and patients with AD is not clear. Our hypothesis was that due to the reduction of nitric oxide bioavailability during aging and AD, an equal dose of oral nitrate (ON) would ameliorate the endothelial responsiveness more in the HE and even more in patients with AD in comparison to healthy young subjects (HY). Therefore, with the aim of investigating the pharmacokinetics of PN and the time-course endothelial responsiveness in response to a single dose ON, 10 HY (25±4 YRS), 10 HE (72±8 YRS) and 13 AD (73±7 YRS) were recruited. PN levels and endothelial responsiveness (single-passive leg movement (ΔPLM)) were measured in the recruited individuals prior to (T0) and hourly for 4 hours (T1, T2, T3, and T4) after: a) a single dose of ON; and b) a single dose of placebo. As expected at T0 both PN and ΔPLM were significantly reduced in the HE and even more reduced in the AD in comparison to the HY (all p<0.001). No changes in PN nor ΔPLM were detected in any group following placebo intake. PN increased significantly in all three groups at T1 (p<0.001) and constantly increased up to T4, but no differences were detected between time points T1 to T4 in any group. ΔPLM increased significantly in all three groups at T2, reaching highest values at T4 (p<0.001). However, AD exhibited significantly lower ΔPLM values at any time point compared to HY (p<0.0001) and HE (p<0.001). Significant correlation between PN and ΔPLM was found (p<0.001, R2=0.1654). Contrary to our hypothesis, the results of this study suggest that the PN pharmacokinetics following a single dose of ON is similar in HY, HE and AD. Moreover, the expected time-course amelioration of the endothelial responsiveness was reduced in the HE and even more reduced in the AD, suggesting that other factors, rather than the nitric oxide bioavailability, are playing a role in the age- and AD-related vascular dysfunction.

Ricerca di Base 2017 - RBVR17XRSA - Effectiveness of exercise and nitrate supplementation on progression of dementia in patients with Alzheimer’s disease.

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.
Persistent Skeletal Muscle Overexpression of Inflammatory Lipid Mediators After Disuse Corresponds to Impaired Skeletal Muscle Recovery in Aged Mice
Authors: Bourrant Paul-Emile , J. Ferrara Patrick , M. Yee Elena , NMMP. de hart Naomi , J. Fennel Zachary , J. Petrocelli Jonathan , J. Drummond Micah
Published: May 2024

Aging is associated with impaired recovery of muscle mass and function after a period of disuse, often leading to an increased risk of falls and fractures. The exact mechanisms behind impaired recovery due to aging after disuse are not fully understood. Membrane-derived lipids mediators (LM) in muscle orchestrate inflammatory actions that are critical for restoration of muscle following injury. We tested the hypothesis that muscle LM associated with inflammation would be dysregulated in adult vs older mice during a time course of recovery following disuse atrophy. Therefore, we designed a study in which adult (3-6m/o) and old (23-26m/o) male mice underwent 14 days of hindlimb unloading followed by 2, 4, or 7 days of reloading. The gastrocnemius muscle was collected at each timepoint and between age groups and processed for lipidomic analysis of the eicosanoids. Gastrocnemius muscle mass showed impaired recovery after HU in the old group when compared to adult, at 4 (P=0.0420) and 7 days reload (P=0.0092). We also observed that muscle LM’s associated with acute inflammation (arachidonic acid, prostaglandins, leukotrienes) were significantly overexpressed in old mice during recovery after disuse. Importantly, several of these lipids corresponded with impaired muscle recovery. PGE2 and PGF2a levels showed a correlation (P=0.03 and P=0.02, respectively) with gastrocnemius mass at the 4 days reload. We conclude that recovery from disuse in aged mice are characterized with the upregulation of pro-inflammatory lipids in muscle and this may be related to poor muscle regrowth. Future studies will be considered to determine the role and cell source of these pro-inflammatory LM during muscle recovery in aged mice.

Funding was provided by NIH: R01AG076075 awarded to M.J.D.

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.
Hyperventilation in Patients with Postural Orthostatic Tachycardia Syndrome (POTS): Effects of Tidal Volume versus Hypocapnia on Heart Rate
Authors: Ranada Shaun , Baker Jacquie , Karalasingham Kavithra , Hira Rashmin , Incognito Anthony , Wilson Richard , Phillips Aaron
Published: May 2024

Background: Postural Orthostatic Tachycardia Syndrome (POTS) is a chronic form of orthostatic intolerance that significantly impacts the quality of life and day-to-day functioning of patients. POTS has an estimated prevalence of about 1%, predominantly affecting females of child-bearing age. POTS is characterized by an upright increase in heart rate (HR) of ≥30 bpm, without a drop in blood pressure. POTS is associated with chronic (≥ 3 months) upright symptoms including light-headedness, blurred vision, and cognitive dysfunction. A large proportion of POTS patients also experience hyperventilation when upright. Hyperventilation reduces arterial carbon dioxide (CO2; hypocapnia) and exacerbates tachycardia in POTS. Whether the HR response is due to increased tidal volume (VT) per se or the resulting hypocapnia is unclear. Investigating the independent effects of increased VT versus hypocapnia on HR might identify possible therapeutic targets to reduce HR in patients with POTS. Objective: We aimed to characterize the separate effects of hypocapnia and VT on HR in POTS patients. Hypothesis: We hypothesize that hypocapnia and VT will independently increase HR, with hypocapnia causing the greatest increase in HR in patients with POTS. Methods: Twenty female POTS patients (32±10 years) completed supine normocapnic and hypocapnic breathing tests. To assess the effects of hypocapnia on HR, we compared hypocapnic-hyperventilation versus normocapnic-hyperventilation with constant VT. To assess the effects of VT on HR, we compared increased VT breathing versus normal breathing with constant end-tidal CO2 (ETCO2). Breath-by-breath respiratory (VT, ETCO2) and beat-to-beat hemodynamic parameters (stroke volume [SV], HR) were continuously measured. Data were analyzed with paired t-tests, and are reported as mean ± SD. Results: ETCO2 was lower ( p<0.001) with similar VT during hypocapnia compared to normocapnia. Hypocapnia reduced SV (63.3±11.8 mL vs. 72.4±12.3 mL; p<0.001), and increased HR (99±13 bpm vs. 81±9 bpm; p<0.001). Compared to normal breathing, increased VT ( p<0.001) with constant ETCO2 led to a smaller reduction in SV (72.4±12.3 mL vs. 76.0±14.3 mL; p=0.04), and increase in HR (81±9 bpm vs. 75±9 bpm; p<0.001). Conclusion: Our results suggest that hypocapnia and increased VT independently reduce SV and increase HR in POTS patients. The increase in HR was greater during hypocapnia (+18 bpm) compared to increased VT (+6 bpm). Reducing hypocapnia presents an attractive therapeutic target.

Disclosures: This work was supported by Standing up to POTS.

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.
PVN predisposes microglia to be susceptible to hemodynamic signals and promote sympathetic excitation in hypertension
Authors: Wei Bo , Cheng Guo , Bi Qianqian , Shen Xiao , Shi Peng
Published: May 2024

Hypertension is usually accompanied with an elevated sympathetic tonicity, but how sympathetic hyperactivity is triggered is not fully understood. Recent advances reveal that microglia-centered neuroinflammation contributes to sympathetic excitation in hypertension. In this study, we performed a temporospatial analysis of microglia at both morphological and transcriptomic levels, and found that microglia in the hypothalamic paraventricular nucleus (PVN) were early responders to hypertensive challenges. PVN is the central hub for maintaining cardiovascular function via regulation of fluid balance and sympathetic outflow. Comprehensive vasculature analyses unveiled that PVN was characterized by high capillary density, thin vessel diameter, and complex vascular topology among brain regions. As such, PVN is susceptible to the penetration of ATP released from the vasculature in response to hemodynamic disturbance after blood pressure increase. ATP ligation to microglial P2Y12 receptor is responsible for the microglial accumulation and activation in the PVN. Both pharmacological blockade and genetic ablation of microglial P2Y12 could substantially restrain blood pressure increase under hypertensive challenge. Together, these findings disclose that a unique vasculature pattern results in the vulnerability of PVN pre-sympathetic neurons to hypertension-associated inflammatory insults, which is mediated by microglia.

NSFC82170441.

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.
Exploring Contribution of HMGA2 to the Aggressive Tumor Structure in Urothelial Carcinoma to Identify Prospective Clinical Applications
Authors: Liu Hui-Ying , Luo Hao-Lun
Published: May 2024

For patients with advanced upper tract urothelial carcinoma (UTUC), the five-year survival rate is approximately 20-40%. In previous real-world data analyses, we observed that UTUC patients with a sessile tumor architecture tend to exhibit more aggressive behavior and concurrently have poorer outcomes in terms of metastasis-free and cancer-specific survival. This suggests that tumor architecture may serve as a crucial prognostic factor for predicting outcomes. We utilized various tumor tissue specimens, categorizing them based on tumor architecture into papillary and sessile groups. RNA sequencing was used to analyze the two groups, and significant differences in the expression levels of high mobility group AT-hook 2 (HMGA2) were found. In the more aggressive sessile tumor architecture, HMGA2 exhibited higher expression levels. HMGA2 is currently known to participate in various biological processes, including the cell cycle, DNA damage repair, apoptosis, and epithelial-mesenchymal transition. Additionally, HMGA2 is abnormally regulated in several human cancers, such as lung, breast, ovarian, and bladder cancers. Elevated expression of HMGA2 is associated with a higher risk of tumor recurrence and cancer progression. Hence, we hypothesize that HMGA2 may regulate tumor cell epithelial-mesenchymal transition through the PI3K-Akt cell signaling pathway, influencing tumor architecture and cancer prognosis. Attempting to downregulate HMGA2 should theoretically enhance the effectiveness of chemotherapeutic drugs in achieving an anti-cancer effect. We discovered that inhibiting the expression of HMGA2 using siRNA in UTUC cells, such as BFTC909, significantly reduces cell proliferation and migration. Moreover, the addition of an HMGA2 inhibitor known as suramin enhances cytotoxic effects and decreases cell migration. Our preliminary findings provide evidence indicating a correlation between high levels of HMGA2 expression and aggressive tumor architecture in UTUC. We designed UTUC patient-derived organoids (PDO). The test results revealed that the organoids, as indicated by HE stain and Ki67 immunohistochemical (IHC) staining, closely resembled their corresponding parental tumors. Currently, it appears that the organoids have retained the original tumor structure and protein molecular expression characteristics. The PDO model is hoped to serve as a valuable tool in aiding the selection of suitable therapeutic strategies as clinical applications.

This study was funded by the Chang Gung Medical Foundation, Taiwan (CMRPG8M0131, and CMRPG8M0132) and the Ministry of Science and Technology, Taiwan (MOST 111-2314-B-182A-140).

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.
Obesity and Ventilatory Effciency During Exercise in the Fitness Registry and the Importance of Exercise National Database (FRIEND)
Authors: Bissen Thomas , Arena Ross , Harber Matthew , Kaminsky Leonard , Myers Jonathan , Watso Joseph
Published: May 2024

Background: A high minute ventilation/rate of carbon dioxide production (V̇E/V̇CO2) slope during exercise (i.e., ventilatory ineffciency) is more common in patients with cardiovascular disease and is prognostic of cardiovascular mortality. Interestingly, recent data in adults with obesity suggest that V̇E/V̇CO2 slopes are lower with higher body mass index (BMI) values in the context of adults with and without comorbidities. However, it is unclear whether obesity is associated with V̇E/V̇CO2 slope in adults without comorbidities. Therefore, we used the Fitness Registry and the Importance of Exercise National Database (FRIEND) to test the hypothesis that adults with obesity would have a reduced V̇E/V̇CO2 slope compared with adults without obesity in the context of no known comorbidities. Methods: We used the CDC definition for obesity as a BMI of ≥30 kg/m2. We excluded those with known chronic disease, smoking status, or any medication use. We only included adults with a respiratory exchange ratio >1.00 at peak exercise. All data are presented as median[IQR] because they failed Shapiro-Wilk normality tests ( p>0.05). For our primary analyses, we compared groups using a Mann-Whitney U test (unadjusted) and linear regression adjusted for age, sex, and race (cardiorespiratory fitness was not a significant covariate). We set α a priori to <0.05. Results: The sample (n=3588) characteristics were as follows: 1) age = 40[18] years (range 18-91 years); 2) 20% female; 3) 0.4% American Indian, 3% Asian, 14% Black, 8% Hispanic, 3% Other, 66% White, and 5% Unknown; 4) cardiorespiratory fitness = 27.8[10.8] mLO2·kg−1·min−1; and 5) 17% with obesity. As expected, BMI was different between groups (obese: 32.1[3.0], non-obese: 24.6[4.0] kg/m2, rank biserial correlation[rbc]=1.00, p<0.001). The V̇E/V̇̇CO2 slope was higher in adults with obesity (obese: 25.0[3.5], non-obese: 24.7[3.6], rbc=0.07, p=0.009). Obesity was a significant predictor of the V̇̇E/V̇̇CO2 slope (standard error of the estimate: 0.16 [95% CI 0.09-0.70], p=0.01) after covariate adjustment (model: R2=0.174, F4,3583=188, p<0.001). BMI was also related to the V̇E/V̇̇CO2 slope (ρ=0.07, p<0.001). Finally, the proportion of V̇̇E/V̇̇CO2 slope values >45 was not different between groups (obese: 0.2%, non-obese: 0.3%, X2=0.48, p=0.49). Conclusion: In contrast to our hypothesis, data from the FRIEND indicate that those with obesity exhibit mildly greater ventilatory ineffciency during exercise than those without obesity in the context of no known comorbidities.

Funding: National Institutes of Health K01HL160772 (JCW), American Heart Association 23CDA1037938 (JCW).

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.
Glucocorticoid Resistance Increases PPARγ Activity and Drives Hepatic Lipid Accumulation via Increased Eicosanoid and Monoacylglyceride Synthesis
Authors: Martinez Genesee , Kipp Zachary , Stec David , Hinds Terry
Published: May 2024

A diet high in fat induces adiposity and obesity, and chronic feeding can lead to multiple metabolic complications, including type II diabetes, non-alcoholic fatty liver disease, and cardiovascular disease. The glucocorticoid receptor (GR) regulates genes that control metabolism. The GR has two isoforms (GRα and GRβ) that arise from the GR gene ( NR3C1) due to the alternative splicing of exon 9. The GRα isoform is the classical receptor that binds to glucocorticoids. However, the GRβ isoform has a truncated C-terminus. It cannot bind glucocorticoid steroids, and as a result, this isoform induces a glucocorticoid-resistant state when its expression is increased. We hypothesized that increasing levels of GRβ from long-term excess glucocorticoid exposure or a high-fat diet induces adiposity by affecting lipid metabolism and lipogenesis, causing fat to accumulate in the adipose and liver tissues. We first overexpressed GRβ (GRβ-Ad) or control (Vec-Ad) using adenovirus delivery and fed the mice a normal chow diet. The GRβ-Ad mice had significantly higher lipid accumulation within five days. Western blotting analysis revealed a significant increase (p-value <0.05) in the GRβ-Ad livers for fatty acid synthase (FAS) expression, and there was a remodeling of the hepatic lipid content as measured by mass spectrometry lipidomic analysis. The data indicate an increased level of monoacylglyceride lipid species and some species of long-chain triacylglycerides and diacylglycerides. mRNA analysis revealed a significant increase (p-value <0.05) in Carbohydrate-responsive element-binding protein (ChREBP), PPARγ, and Cyp2j6, indicating an increase in de novo lipogenesis and eicosanoid synthesis. We conclude that glucocorticoid resistance due to increased levels of GRβ drives de novo lipogenesis and increases eicosanoid synthesis, possibly via synergism with PPARγ. A better understanding of the GR isoforms and glucocorticoid resistance could benefit people with obesity and other metabolic disorders to improve obesity-associated comorbidities.

R01DK121797 (T.D.H.J.), R01DA058933 (T.D.H.J.).

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.
Increasing confidence in mentoring strategies for predoctoral and postdoctoral scholars through implementation of a mentoring academy
Authors: Becker Rena , Shacka John , De Miguel Carmen , Mitchell Tanecia , Wyss J. Michael , Hopper Mari , Pollock Jennifer
Published: May 2024

In support of the development of undergraduate researchers and the mentor development of predoctoral and postdoctoral scholars (Near Peers), a targeted near peer mentor training program was developed. Innovative and highly impactful early training experiences in research play a key role to inspire and motivate the next generation of scientists. Predoctoral and postdoctoral trainees are often asked to assist in the training and mentoring of short-term summer undergraduate researchers. Previous studies have shown that the efforts of these “near peers” to educate, train, and develop the summer undergraduate scholars have a positive impact on the undergraduate researchers. However, many near peer mentors have limited mentor training/experience and lack confidence in their ability to mentor undergraduate scholars. Thus, developing avenues and opportunities to train near peers on mentoring is vital to enhancing the experience of both the undergraduate researchers and near peers. The Kidney Undergraduate Research Experience (KURE) at the University of Alabama at Birmingham (UAB) engages undergraduate summer scholars with a wholistic research experience which includes an involved team of near peer mentors. A near peer mentor training program was developed with input from near peer focus groups, based on their interest in expanding their mentoring abilities and developing confidence in their role as a near peer mentor. The aim of this study was to determine whether this mentoring program was effective in increasing near peer mentoring abilities and confidence levels through quantitative and qualitative measures. Evaluations were given to near peers prior to, during, and at the end of the 6-month program (44 scholars started the program in Fall 2022 and 33 scholars completed all activities). We found that 83% of near peers expressed increased confidence in mentoring (n=24). Improvement in specific mentoring abilities were also assessed, such as “confidence in effectively communicating expectations” (pre- 4.02, ±0.82, n=44; post- 4.83 ±0.37, n=24; using a scale from 1 = not at all to 5 = very confident). We also identified the most impactful elements of the program including facilitation, topics, and platforms. Through assessing these aspects of the program, we determined essential and sustainable elements for future near peer mentor training programs. We conclude that a near peer mentor training program builds confidence and enhances the ability of predoctoral and postdoctoral scholars in their roles as near peer mentors.

NIH R25DK115353 — 05S1.

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.
Acute Peripheral Irisin Administration Increases Hippocampal Mass in Young, Healthy Rat Cohort
Authors: White Zachary , Sudasinghe Keshari , Hall Stephanie
Published: May 2024

Introduction: Skeletal muscle-brain crosstalk is highlighted as an important contributor to the beneficial relationship between exercise and the brain. Irisin is a key crosstalk myokine due to the ability of irisin to cross the blood-brain barrier and mediate effects of exercise in the brain. Importantly, the influence of irisin in the brain is often demonstrated through chronic administration or supraphysiological dosing of irisin. The aim of the present study is to determine if an acute, non-supraphysiological dose of exogenous irisin is suffcient to induce previously established effects in the hippocampi of young, healthy rats. Methods: Twenty-four 2–3-month-old male and female F344 rats were divided into two groups of 12 (50% male/female) which either received an irisin (100 μg/kg) or vehicle intraperitoneal injection. Forty-eight hours following irisin injections, brains were sectioned and weighed. Levels of total and phosphorylated hippocampal cyclic-AMP Response Element Binding Protein (CREB), a downstream target of irisin signaling, were quantified with Jess Simple Western automated western blot analysis. Values are mean ± standard deviation. Results: Irisin administration resulted in greater hippocampi mass (relative to brain mass, %) compared to vehicle treated animals (3.65±0.24 vs 3.28±0.32%, p<0.01). Further, pCREB/CREB in the hippocampus of irisin animals (0.58±0.13) was 24.6% greater than vehicle (0.47±0.09, p<0.05). Irisin administration did not influence body mass or whole brain mass relative to body mass. Conclusions: The present study demonstrates that a non-supraphysiological dose of irisin is suffcient to increase hippocampal mass and CREB phosphorylation 48 hours post-injection. This work supports irisin as an important, physiologically relevant mediator of the beneficial relationship between exercise, skeletal muscle, and the brain.

NIH P20GM113109.

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.
Aging Related Changes in Smooth Muscle Contractile and Regulatory Proteins
Authors: Bandi Rishiraj , Han Young , Sieck Gary , Brozovich Frank
Published: May 2024

Aging is a significant risk factor for cardiovascular disease and is known to be associated with an increase in vascular stiffness and decrease in sensitivity to NO mediated vasodilatation. However, the underlying mechanism for these changes in vascular function is unknown. Smooth muscle tone is known to be regulated by the expression and phosphorylation of both nonmuscle (NM) and smooth muscle (SM) myosin. NM and SM phosphorylation is regulated by the activity of myosin light chain kinase (MLCK) and MLC phosphatase. MLC phosphatase is a trimeric enzyme consisting of enzymatic, myosin targeting (MYPT1) and a 20kDa subunit of unknown function. Two isoforms of MYPT1 are produced by alternative mRNA splicing, which differ by the presence or absence of a COOH-terminal leucine zipper (LZ+/-), and the relative expression of LZ+/LZ- MYPT1 determines the sensitivity to NO mediated vasodilatation. We defined NM myosin expression using two-dimensional SDS PAGE and LZ+/LZ- MYPT1 expression using immunoblotting in aortic and tertiary mesenteric smooth muscle from 6mo and 24mo old Fischer344 rats. The data demonstrate that aging is associated with a significant decrease in the expression of both LZ+ MYPT1 and NM myosin. The reduction in LZ+ MYPT1 expression would both decrease the sensitivity to NO mediated smooth muscle dilatation and increase vascular tone, which is a hallmark of the vasculature in aging. On the other hand, the reduction in NM myosin would result in a decrease in vascular tone and could represent a compensatory mechanism to normalize blood pressure during aging. These data demonstrate that there are changes in the expression of smooth muscle regulatory and contractile proteins during aging and these changes in protein expression contribute to molecular mechanism for the decrease in sensitivity to NO mediated vasodilatation as well as the increase in vascular tone or the vascular dysfunction that occurs with aging.

Supported by a Mayo CV Prospective Grant (FVB).

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.
Investigation of social variables affecting the subjective experience of Boston University pre‐health students
Authors: Nessen Evan , Lyons Nicholas , Capuano John Paul , Roberts Lisa , Moreira Jesse
Published: May 2024

Introduction: Students who are pre-health experience higher levels of stress and adopt maladaptive coping behaviors including alcohol and drug use. Additionally, students belonging to sexual and gender minority (SGM) groups are more likely to drop out from science, technology, engineering, and math (STEM) majors. Studies have yet to determine how SGM identities influence self-perceived ability and desire to pursue careers in healthcare. Hypothesis: Pre-health students belonging to SGM groups have lower self confidence in their career trajectory as a function of identity compared to their cisgender, heterosexual peers. Methods: Pre-health students at Boston University were surveyed using quantitative Likert-like items and open response questions. Survey content explored the degree to which students agreed with statements regarding how their sexual orientation and gender has affected their career trajectory as a pre-health student. Responses were grouped by gender and sexual orientation and unpaired Mann-Whitney rank tests were used to assess differences at an alpha of 0.05. Results: Of the 71 respondents, 44 (61.97%) identified as heterosexual women, 14 (19.71%) identified as queer women, 10 (14.08%) identified as heterosexual men and 3 (4.22%) identified as queer men. Queer women, compared to heterosexual women, reported higher perceived effects of sexual orientation (p=0.0228, median 2.0, IQR 1-2 vs. 1.0, IQR 1-2) and gender identity (p=0.0079, median 2.0, IQR 1-3.5, vs. median 1.0, IQR 1-2) on career trajectory. There were no significant differences between responses from queer men and heterosexual men regarding perceived effect of sexual orientation and gender identity on their career trajectories. Conclusion: Queer women in pre-health tracks may benefit most from targeted supportive intervention.

This study was unfunded.

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.