bluuebunny/crossref_metadata_2025 huggingface dataset:
Psoralen mediates BMSCs osteogenic differentiation via cross-talk between Wnt/β-catenin and BMP/smad signaling pathways
Authors: Li Wenxiong , Chen Feifei , Chen Menghan , Zhong Yuan , Yang Feng
Published: May 2024

Background: To explore the mechanism of psoralen mediated Wnt/β-catenin and bone morphogenetic protein (BMP) signaling pathway to induce osteogenesis of BMSC. Methods: Bone marrow mesenchymal stem cells (BMSCs) were treated with psoralen to detect its osteogenic differentiation. In addition, lentivirus and siRNA were used to construct cell models of β-catenin or BMP2 overexpression and knockdown, separately. They may help to clarify the role of β-catenin and BMP2 crosstalk in osteogenic differentiation of BMSCs. What’s more, C57BL/6 mice were selected to be treated psoralen with psoralen to further verify the osteogenic effect. Results: Various in vitro studies on BMSCs showed that psoralen could promote the osteogenic differentiation of BMSCs. Overexpression of β-catenin could promote the expression of BMP2 in BMSCs, and psoralen can enhance the effect of bone differentiation. Knockdown β-catenin decreased the expression of BMP2 and inhibited psoralen in promoting bone differentiation. In addition, it was found that the effect of psoralen on β-catenin level did not change significantly after overexpression or knockdown of BMP2, but the effect of psoralen on promoting bone differentiation was inhibited by knockdown of BMP2. In mice, psoralen intervention regulated the crosstalk of Wnt/β-catenin and BMP signaling pathway to reached to promote osteogenic differentiation of bone tissue. Conclusions: Psoralen can activate β-catenin signaling pathway and up-regulate the expression of BMP signaling pathway to increase the cross talk between β-catenin and BMP, to eventually reach to promote osteogenic differentiation of BMSCs.

This trial was funded by the Program of National Natural Science Foundation of China (81973889 to FY), the Program of Shaanxi Province Natural Science Foundation (2023-YBSF-210 to FY & 2023-JC-QN-0978 to WL), the Program of Shaanxi Education Department (19JC013 to FY & 22JK0346 to WL), the Program of Shaanxi Administration Bureau of Traditional Chinese Medicine (2021-01-22-009 to FY &2022-QCYZH-029 to WL), Youth Innovation Team in Shaanxi universities, and the Program of Health Commission of Shaanxi Province (2022B002 to WL).

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.
Does ungrading promote student engagement and learning in Course-based Undergraduate Research Experiences (CUREs)?
Authors: Beason-Abmayr Beth
Published: May 2024

The goal of assessment should be to encourage learning to drive student engagement and success. However, grades make students focus on the evaluation of their work, often limiting the learning process. In forcing me to rank students, grades promote extrinsic rather than intrinsic motivation and direct attention to how well students are doing rather than engaging them with what they are doing. Ungrading is an alternative approach to grading that increases the focus on feedback and growth and decreases the emphasis on "points." In the Fall 2023 semester, I piloted ungrading in one introductory and in two advanced Course-Based Undergraduate Research Experiences (CUREs). Although students will earn a grade for the course at the end of the semester, they did not get letter or number grades for individual assignments. Student learning was assessed using qualitative, not quantitative, approaches with an emphasis on quality feedback from me, reflections/self-assessments/surveys where students think critically about their own learning, and peer review for certain assignments and activities. In addition to the course learning goals, each student set individual goals for the course at the beginning of the semester, discussed their progress with me, and shared evidence of their learning throughout the semester. At mid-semester and also at the end, students suggested a course grade and explained how they arrived at that grade. Initial analysis of mid-term reflections/self-assessments shows evidence of students making progress towards personal goals as well as course learning goals: they are asking me more questions about the assignments both before submitting them and after receiving feedback, and they are actually reading my feedback; and the grades they suggested for themselves are mostly in agreement with my evaluation of their progress. Overall, students are engaged during class and seem more relaxed and less stressed because they are not worried about earning as many points as possible for each assignment. Further analysis of reflections and self-assessments will highlight student expectations and attitudes towards ungrading and showcase evidence of learning. Student feedback on an end-of-course survey about ungrading will help me refine the approach to improve student learning in future courses. I predict implementation of this ungrading policy in my courses will foster a collaborative and equitable environment where students are encouraged to learn and grow, and I plan to adapt this alternative grading practice in my animal physiology course as well as an additional advanced CURE in the Spring 2024 semester.

All protocols were approved by Rice University IRB (Protocol IRB-FY-2023-239). Rice University Department of Biosciences.

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.
Time-restricted Eating to Improve Metabolic Health: Investigating the Mechanisms Underlying Glycolytic and Lipolytic actions
Authors: Abo Stéphanie , Layton Anita
Published: May 2024

Time-restricted eating (TRE) is a behavioral intervention approach motivated by the emerging role of circadian rhythms in physiology and metabolism. In this approach, all caloric intake is restricted within a regular interval of less than 12 hours, with no overt attempt to reduce calories. We present a whole-body computational model of TRE that incorporates enzyme and substrate reactions as well as hormonal actions during fasting and postprandial states. The model is divided into seven compartments: brain, heart, skeletal muscle, gastrointestinal tract, liver, adipose tissue, and other tissues. We conducted simulations to test the hypothesis that TRE modulates whole-body glucose balance by improving postprandial hyperglycemia and hypertriglyceridemia, keeping these excursions to a minimum. We simulated different TRE schedules with meals varying in fat and carbohydrate content. Our results highlight the importance of chrono-pharmacological considerations in glycemic control: TRE modulates the interplay between glycogenolysis in the liver, lipolysis in adipose tissue and fatty acid oxidation in other organs to improve glucose control. The alternation of eating and fasting, in particular, could be manipulated to balance blood sugar levels. TRE simulations have also shown beneficial effects on the lipid front, such as lower triglyceride levels and improved lipolytic effciency, meaning the body is better able to use fat stores for fuel.

This work was supported by the Canadian Institutes of Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery 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.
Electroacupuncture Rebalances Autonomic Nervous Activities Decreasing Blood Pressure in Salt-Sensitive Hypertensive Rats
Authors: Gong Yiwei , Fu Liang-Wu , Tjen-A-Looi Stephanie , Nguyen Anh , Guo Zhi-Ling , Malik Shaista
Published: May 2024

High blood pressure (BP) associated with sympathetic overactivity is observed in hypertensive animals and patients. We have recently reported that electroacupuncture (EA) at two sets of acupoints ST36-37 and SP6-7 attenuates BP in Dahl salt-sensitive hypertensive (DSSH) rats through a positive interaction between sympathetic nerve activity inhibition (sympathoinhibition, SI-EA) and anti-inflammation (AI-EA). Chronic inflammation is not only influenced by sympathetic (SNA) but also by parasympathetic nerve activity (PNA). However, it remains unclear if combined SI-EA + AI-EA (cEA) rebalances autonomic nerve activity by both inhibiting SNA and exciting PNA that alleviate hypertension (HTN). We hypothesized that cEA decreased SNA and increased PNA in DSSH rats. Dahl salt-sensitive (DSS) rats were fed 4% salt diet and randomly allocated into two groups: cEA or Sham-EA (no electrical stimulation). Another group of DSS rats studied as normotensive (NTNive) controls were fed a standard rat chow throughout the experiment. Systolic/diastolic BP (SBP/DBP) were measured with Tail-cuff via CODA system once a week. Once DSSH rats developed moderate HTN (SBP 160±5 mmHg), cEA or Sham-EA was applied twice weekly for five weeks, while the NTNive control groups received five weeks of similar study procedures (restraining) without the intervention. After five weeks of treatments, rats were anesthetized for the neuronal recording of SNA and PNA. Cervical vagal nerve (CVN) or splanchnic sympathetic nerve (SSN) was isolated from surrounding connective tissue under a dissecting microscope. Multiple-unit nerve activities were recorded and analyzed with Spike2 software. We observed that SBP (189.2±3.5 mmHg) and DBP (138.6±2.2 mmHg) in Sham-EA treated DSSH rats were higher than SBP (140.8±1.8 mmHg) by 25.6% and DBP (105.5±1.4 mmHg) by 23.9% in rats treated with repetitive cEA. Throughout the study, SBP (132.7±1.8 to 135.2±2.1 mmHg) and DBP (74.1±1.7 to 82.9±2.6 mmHg) in NTNive rats remained within normal range. Furthermore, activity of SSN was significantly greater in Sham-EA treated DSSH rats (23.1±1.6 imp/s) compared to cEA treated rats (15.2±2.0 imp/s, P=0.043) and NTNive rats (11.5 ±0.8 imp/s, P=0.004). Activity of CVN was higher in DSSH rats treated with cEA (27.8±2.9 imp/s) than Sham-EA (12.5±2.3 imp/s, P=0.016). Relative to Sham-EA, activity of CVN was higher (42.5±2.9 imp/s, P=0.001) in normal rats. In conclusion, cEA treatment effectively alleviates hypertension by restoring the balance of autonomic nervous functions through sympathoinhibition and parasympathoexcitation.

Funding: NIH 1RO1AT011306-01A1.

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.
Preventing kidney failure in hemolytic anemias with a novel heme and hemoglobin scavenger
Authors: Lucas Daniela , Munoz Carlos , Rodrigues Muller Cynthia , Palmer Andre F. , Cabrales Pedro
Published: May 2024

Chronic hemolytic conditions, seen in genetic and acquired hemolytic diseases, result in increased levels of circulatory hemoglobin (Hb) released from erythrocytes, free heme, and iron. Cell-free Hb's toxicity arises from the Hb dissociation into dimers that can traverse tissue barriers, impacting crucial compartments like arterial smooth muscle cells and renal glomeruli. Chronic hemolysis leads to vasoconstriction, renal injury, and activates pathways via Hb oxidation and heme-ligation of TLR4 on endothelial cells, as well as leukocytes, affecting adhesion pathways. Hb and heme exposure to the immune system causes phagocyte dysfunction, inflammation suppression, and impaired antigen presentation. Kidneys are particularly susceptible to Hb toxicity due to Hb and dimer penetration into glomeruli and tubules, disrupting filtration forces, elevating the glomerular filtration rate (GFR), and causing acute kidney injury (AKI). To combat this issue, our group developed a novel Hb and heme scavenger based on apohemoglobin-haptoglobin (apoHb-Hp), functioning as both a hemopexin (Hpx) and Hp mimetic to scavenge cell-free Hb and heme during hemolytic states. Our study utilized the dorsal window chamber model in Golden Syrian hamsters, employing FITC-Sinistrin for non-invasive GFR measurement, avoiding the need for blood and urine sampling throughout time to estimate GFR. Two experiments were conducted, volumetric exchange groups with 20% of the animal’s blood volume either with Hb at different concentrations or a combination ApoHb-Hp and Hb. Results showed a significant acute decrease of 35% in half-life of the Hb group at 1.2g/dL and 5g/dL after two hours, and further decrease is seen of 45% at 24hrs. In contrast, the ApoHb-Hp group experienced a 30% decrease at 2hrs but reverted back to baseline at 24hrs, signifying Hb's predominant effect on the acute decrease rather than the volume change. Furthermore, the ApoHb-Hp group demonstrated a quicker return to baseline compared to the Hb group after the 24-hour mark, suggesting prolonged Hb exposure's lasting impact on kidney filtration rate, potentially leading to irreversible damage. Further research is required to comprehend these findings fully and explore ApoHb-Hp's protective role in mitigating Hb-induced kidney damage.

Title of the project: Bioengineering a Dual Function Protein Construct to Detoxify Heme and HemoglobinProject number: R01HL159862Title of the project: Bioengineering a novel therapeutic protein complex to minimize the effects of medical device induced hemolysis.Project number: R01HL162120.

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.
Female Sex Protects Cerebral Arteries from Mitochondrial Membrane Potential Depolarization and Cell Death Induced by Reactive Oxygen Species
Authors: Safa  , Norton Charles E.
Published: May 2024

Stroke and traumatic brain injury augment the production of reactive oxygen species (ROS) leading to apoptosis in cerebral arteries, and females are more resilient to vascular damage than males. Depolarization of mitochondrial membrane potential (ΔΨm) is a key event in apoptosis, however, when ΔΨm is suffciently depolarized, ATP synthase can reverse directions and act as a proton pump to limit ΔΨm depolarization. We hypothesized that ATP synthase attenuates depolarization of ΔΨm in cerebral arteries during acute oxidative stress thus limiting cell death. Posterior cerebral arteries (PCA; ~80 μm diameter) from male and female mice (age, 4-6 mo) were isolated, cannulated, and pressurized to 90 cm H2O at 36°C. Cell death was quantified with Hoechst 33342 (1 μM, labels all nuclei) and propidium iodide (2 μM, labels dead nuclei), and ΔΨm was evaluated with tetramethylrhodamine methyl ester (TMRM, 10 nM). Vessels were exposed to H2O2 (200 μM) in the presence/absence of ATP synthase inhibitor oligomycin (2 μM). H2O2 exposure (50 min) led to significantly (p<0.05) greater smooth muscle cell death in males compared to females (30±7.4% vs. 7±3%; n=8); there was a similar trend for endothelial cell death. Oligomycin greatly augmented apoptosis in PCAs from both males and females to ~80% and eliminated differences between sexes. Consistently, H2O2 evoked a more robust depolarization of ΔΨm in males vs. females and oligomycin enhanced ΔΨm depolarization to H2O2 leading to a similar response in both sexes. To directly depolarize ΔΨm, PCAs were treated with the protonophore FCCP (10 μM). Surprisingly, depolarization of ΔΨm to FCCP was greater in males vs. females, and oligomycin augmented depolarization and eliminated differences between sexes. FCCP initiated minimal (<5%) cell death at 50-min or 3-h exposure; oligomycin did not alter cell death to FCCP. We conclude that: 1) cerebral vessels from female mice possess greater resilience to H2O2 -induced apoptosis than males by limiting depolarization of ΔΨm; and 2) oxidative stress triggers cell death through pathways in addition to ΔΨm depolarization.

Support: NIH R01NS134690.

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.
AgRP Neurons Encode Circadian Feeding Time
Authors: Sayar Nilufer , Aklan Iltan , Yavuz Yavuz , Laule Connor , kim Hyojin , rysted Jacob , Alp Muhammed Ikbal
Published: May 2024

Food intake follows a predictable daily pattern and synchronizes metabolic rhythms. Neurons expressing Agouti-related protein (AgRP) read out physiological energetic state and elicit feeding, but the regulation of these neurons across daily timescales is poorly understood. Using a combination of neuron-dynamics measurements and timed optogenetic activation in mice, we show that daily AgRP-neuron activity was not fully consistent with existing models of homeostatic regulation. Instead of operating as deprivation counter, AgRP-neuron activity primarily followed the circadian rest-activity cycle through a process that required an intact suprachiasmatic nucleus (SCN) and synchronization by light. Imposing novel feeding patterns through time-restricted food access or periodic AgRP-neuron stimulation was suffcient to resynchronize the daily AgRP-neuron activity rhythm and drive anticipatory-like behavior through a process that required DMHPDYN neurons. These results indicate that AgRP-neurons integrate time-of-day information of past feeding experience with current metabolic needs to predict circadian feeding time.

This work is supported by NIH to D.A. R01DK126740.

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.
SLAB51 Probiotic Improves Oxygen Saturation and Acute Mountain Sickness Score at High Altitude
Authors: Kaya Kiana , Yu James , Moya Esteban , Cheng Hunter , Ochoa Tim , Simonson Tatum
Published: May 2024

Hypobaric hypoxia imposes various challenges at high altitude that initiate differentphysiological responses as part of the acclimatization process. Current interventions foraccelerating and/or improving acclimatization to high altitude are limited. Preliminarystudies of the multi-strain probiotic SLAB51 (O2booster; Hecto, Seoul, South Korea)have shown its potential to improve oxygenation, a crucial component ofacclimatization, in clinical conditions of hypoxemia. We hypothesized that treatment withSLAB51 at high altitude will lead to improved acclimatization as measured by oxygensaturation (SpO2) and scores from the Acute Mountain Sickness (AMS) survey (2018Lake Louise Questionnaire). A group of 17 (9 males, 8 females) healthy Latino/a adultsfrom the San Diego area, ranging from ages 19-63, were taken from sea-level to WhiteMountain Barcroft Station (3800 m) for up to four days. Participants underwent adouble-blind, placebo-controlled study where nine participants consumed the SLAB51probiotic and eight consumed a placebo up to three times a day. SpO2 was measuredusing a forehead pulse oximeter, and an AMS survey score was attained daily. Ouranalyses revealed that SpO2 was significantly higher in participants who received theSLAB51 probiotic at high altitude versus those who received the placebo (Two-wayANOVA, p-value < 1.12e-05). Furthermore, AMS scores were significantly lower inparticipants treated with SLAB51 than those who received the placebo (Two-wayANOVA, p-value < 0.007). Our results indicate that SLAB51 ingestion at high altitudeimproved SpO2 compared to a placebo and may improve acclimatization to high altitude.

Funding: LEA Altitude Performance Fund.

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.
Carotid body-mediated peripheral chemoreflex drive sets exercise tolerance in adult mice
Authors: Vicencio Sinay , Del Rio Rodrigo
Published: May 2024

Exercise tolerance (EXT) has been primarily explained by individual body/physical features, partly neglecting the complex cardiorespiratory response needed to cope with exercise. While in healthy conditions most people display good EXT, the presence of exercise intolerance (EXINT) has also been documented. More importantly, EXINT increases in several pathological conditions. Despite the precise mechanism underpinning EXINT is not fully understood. It is well known that exaggerated sympathetic outflow to skeletal muscle impairs proper muscle function and that activation of the carotid body (CB) chemoreceptors elicits a robust increase in sympathetic activity. Therefore, it is plausible to hypothesize that an exaggerated CB-chemoreflex drive may impair EXT. Accordingly, we aimed to determine: i) differences in CB-chemoreflex drive between EXT and EXINT mice, and ii) the role played by the CB-chemoreflex on setting EXINT. Male C57/BL6 mice (n=24) were used to study chemoreflex function using whole-body plethysmography. Exercise tolerance/intolerance was determined by a three-day maximal performance exercise test. CB-chemoreflex drive was assessed by allowing the mice to breathe hypoxic gas (FiO2~5%). We found that the incidence of EXINT among healthy mice was ~30%. Notably, compared to EXT mice, animals with EXINT exhibited a heightened CB-mediated chemoreflex drive as evidenced by larger increases in the hypoxic ventilatory responses (HVR). Indeed, HVR was ~1.4-fold larger in EXINT compared to the values obtained in EXT mice (VE: 17 ± 1.6 vs. 12 ± 3.2, mL/min, EXINT vs. EXT, respectively). Then, we tested whether high chemoreflex drive was associated with EXINT. For this, we reduced the chemosensory drive by using the Dejour´s maneuver (FiO2~35%) while EXINT mice continues to exercise. We found that chemoreflex unloading in EXINT markedly improves exercise tolerance. Indeed, exercise tolerance was almost fully restored by reducing chemoreflex drive in EXINT. Our findings underscore the potential role of heightened CB-chemoreflex on setting exercise tolerance.

Supported by Fondecyt 1220950.

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.
Genotypic Variations in Exercise-Induced Hemoglobin Oxygen Desaturation in Sickle Cell Disease: The Role of Hemoglobin Levels
Authors: Antwi-Boasiako Charles , Asare Chamila , Hayfron-Benjamin Charles , Aryee Robert , Boatemaa Gifty , Asare Michael , Afriyie-Mensah Jane
Published: May 2024

Background: Sickle cell disease (SCD) presents abnormal hemoglobin S (HbS) and frequent vaso-occlusive crises. Previous studies reveal exercise intolerance in SCD patients. However, the role of exercise-induced hemoglobin oxygen desaturation (EIHOD) and its predictors remains unclear. This study investigates EIHOD in adult SCD patients, focusing on potential predictors, aligning with the hypothesis that EIHOD is prevalent and varies across genotypes, with hemoglobin as a predictor. Methods: A cross-sectional study was conducted on adult patients with HbSS and HbSC genotypes in a steady state at the Korle-Bu Teaching Hospital, Ghana. Clinical, hematological, and haemolytic markers were assessed. Lung function was evaluated through spirometry, and a six-minute walk test (6MWT) was performed to assess EIHOD. Logistic regression was used to identify predictors of EIHOD. We hypothesis that, EIHOD is common in SCD, varying across genotypes, with hemoglobin predicting its occurrence. Results: The prevalence of EIHOD was 41% in HbSS patients and 36.1% in HbSC patients. No significant differences were observed in age, white blood cell count, platelet count, hemolytic markers, hemoglobin levels, or lung function parameters between SCD patients with and without EIHOD. In the logistic regression model, none of the variables predicted EIHOD in HbSS patients. In HbSC patients, reduced hemoglobin was the only predictor of EIHOD (OR=0.551; 95% CI=0.315-0.964; p-value= 0.037). Discussion: The study highlights a high prevalence of EIHOD within the HbSS genotype, emphasizing the importance of hemoglobin levels as a predictor of EIHOD in SCD. Contrarily, hemolytic markers and lung function were not predictors of EIHOD across either genotype. These results suggest the potentially heightened significance of EIHOD-related complications in patients with the HbSS genotype. Conclusion: EIHOD is common in SCD, more so in HbSS. Reduced hemoglobin predicts EIHOD in HbSC. Lung function and hemolytic markers don't. Understanding the impact of EIHOD in SCD may guide interventions to improve exercise tolerance and reduce complications in this population.

No Funding.

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.
Deletion of irisin exacerbate cardiac dysfunction and increase inflammatory response in hemorrhage
Authors: Kulthinee Supaporn , Wang Lijiang , zhang Ling , zhao Thomas , Slate-Romano John , Zhao Ting
Published: May 2024

Introduction: Irisin plays an important role in regulating tissue stress, cardiac function, and inflammation. The objective of this study is to investigate whether deletion of irisin would exacerbate hemorrhage induced cardiac depression and inflammatory response. Method: Irisin knockout mice was generated by using the CRISPR/Cas-9 genome-editing system. Hemorrhage was induced in mice by achieving a mean arterial blood pressure of 35-45 mmHg for one hour, followed by two hours of resuscitation. Experimental groups were divided as followings: I) WT+Hemorrhage (control, n=6): WT mice were subjected to hemorrhage for 60 minutes followed by resuscitation; II) Irisin −/− +Hemorrhage (n=6): Irisin −/− mice underwent hemorrhage and resuscitation; III) WT +Hemorrhage+Irisin (n=8): The same as the group I except that irisin (50ng/kg) was infused during resuscitation; IV) Irisin −/− +Hemorrhage+ Irisin (n=7): The same as the groups III except that Irisin −/− was used. Cardiac function and hemodynamics were measured using echocardiography and femoral artery catheterization. Systemic cytokine releases were measured using Enzyme-linked immunosorbent assay (ELISA). Histological analyses were used to determine tissue damage in myocardium and skeletal muscles. TUNEL was carried out to assess apoptosis in tissues. Results: As compared to wild type mice, irisin knockout mice attenuated the cardiac function and recovery of hemodynamics, which was associated with the increased release of IL6 and TNF-α in hemorrhage. The infiltration of inflammatory cells and TUNEL positive apoptosis in muscles were increased by deletion of irisin. Irisin treatment demonstrated the profound protection against hemorrhage-induced detrimental effect as compared to control. Furthermore, re-infusion of irisin into irisin-knockout mice rescued mitigated the detrimental effect in hemorrhage by deletion of irisin. Conclusion. Deletion of irisin exacerbate hemorrhage induced cardiac depression and inflammatory response, suggesting critical protection of irisin in modulating hemorrhage.

National Institute of General MedicalSciences (R01GM 141339); National Heart, Lung, andBlood Institute Grants (R01 HL089405).

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Multi-Functional Role of RECK in Metabolic Dysfunction-Associated Steatotic Liver Disease Development: A Mass Spectrometry-Proteomic Approach
Authors: Dashek Ryan , Kelty Taylor , Krause Alexa , Taylor Chris , Meers Grace , Chandrasekar Bysani , Rector R. Scott
Published: May 2024

Metabolic dysfunction-associated steatotic liver disease (MASLD, previously referred to as nonalcoholic fatty liver disease) is characterized by increased fat deposition and inflammation in the liver as well as dysregulation of cellular processes that affect the extracellular matrix (ECM). We previously observed that the expression of Reversion Inducing Cysteine Rich Protein with Kazal motifs (RECK), a key ECM regulatory protein, negatively correlates with MASLD-associated fibrosis and inflammation (metabolic dysfunction-associated steatohepatitis, MASH). However, mechanisms governing this relationship remain unclear. Therefore, we hypothesized that overexpression of RECK is hepatoprotective in the setting of MASH by altering several ECM-linked pathways, as analyzed by proteomics. Accordingly, we generated hepatocyte-specific Reck-overexpressing transgenic mice. Male hepatocyte-specific Reck-overexpressing transgenic mice and littermate controls were fed a Western diet high in fat, carbohydrate, and cholesterol for 24 weeks (n=6/group). Whole liver tissue was submitted for mass spectrometry-proteomic analysis. We identified 370 differentially expressed proteins out of a total of 4693 proteins using a q-value cutoff of ≤0.10; of which 90 proteins were significantly upregulated while 280 significantly downregulated. This included an upregulation of Cyp2b (adjusted p≤0.01) and downregulation of Taok1, C/EBPβ, and Vitronectin (all adjusted p≤0.01), all of which have been shown to be important in liver health and metabolism in the context of MASH. Predictive pathway analysis using Ingenuity Pathway Analysis software (Qiagen) identified several significantly altered pathways, including those involved in ECM regulator pathways (integrin signaling, z-score=6.0; mTOR signaling, z-score=5.3; leukocyte extravasation signaling, z-score=5.1), cell-signaling (chemokine signaling, z-score=5.4; CXCR4 signaling chemokine signaling, z-score=5.0), and inflammatory responses (leukocyte extravasation signaling, z-score=5.1; CXCR4 signaling, z-score=5.0). Interestingly, pathway analysis based on significantly altered proteins predicted the downregulation of critical components of hepatic inflammation and fibrosis, including TGF-β, IL-1β, and TNFα. These novel results reveal the regulatory role of RECK in MASH progression, specifically governing the components of ECM remodeling and inflammation. Our goal is to develop RECK inducers and identify additional therapeutic targets in MASH development and progression.

This work was funded by the NIH award R01DK130243.

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.
Feasibility of remotely supervised home-based high intensity interval training and effects on aerobic fitness and body composition in healthy older adults
Authors: Casella Cameron , Lapierre-Nguyen Stephanie , Kim Jin-Su , Soonhuae Chatchamarn , Sakarya Yasemin , Riesco Eléonor , Robinson Katherine
Published: May 2024

Aging is associated with declines in aerobic fitness and increases in adiposity, both of which increase the risk of cardiovascular disease in older adults. High intensity interval training is an effective strategy for cardiovascular disease risk reduction; however, this promising exercise regimen may be inaccessible to older adults due to weight-bearing limitations or inability to travel to a fitness center. To address these barriers, we have developed a remotely supervised, home-based exercise intervention using high intensity interval training on an all-extremity non-weight-bearing ergometer (HIIT-ANE). The purpose of this study was to investigate the hypotheses that remotely supervised home-based HIIT-ANE would be feasible and lead to improvements in aerobic fitness and body composition in healthy older adults. Twenty sedentary older adults free of major clinical disease (66±1 yrs, mean ± SE) participated in this study. HIIT-ANE was remotely delivered at home under supervision via video conferencing (Zoom) and live heart rate monitoring (Zephyr OmniSense, Medtronic). HIIT-ANE consisted of a 10-min warm-up, 4 × 4-min intervals at 90% HRmax interspersed by 3 × 3-min bouts of active recovery at 70% HRmax, and a 5-min cool down and was performed on 4 days/week. Feasibility was assessed throughout the 8 weeks of HIIT-ANE. Aerobic fitness (maximal oxygen consumption) and body composition (dual-energy x-ray absorptiometry) were assessed at baseline and following an 8-week control period of normal lifestyle and an 8-week HIIT-ANE period. We found that exercise compliance to HIIT-ANE — the number of completed sessions relative to the number of scheduled sessions — was 96±1% and there were no adverse events related to the exercise intervention. Aerobic fitness increased in response to HIIT-ANE (baseline vs. post-HIIT-ANE: 23.7±1.2 vs. 27.0±1.1 ml/kg/min, P=0.001; pre- and post-HIIT-ANE: 22.5±1.2 vs. 27.0±1.1 ml/kg/min, P<0.001), but decreased following the control period (23.7±1.2 vs. 22.5±1.2 ml/kg/min, P=0.04). Body fat % (36±2 vs. 35±2%, P=0.001) and fat mass (28.4±2.0 vs. 27.0±2.0 kg, P=0.003) decreased following HIIT-ANE, but fat free mass did not significantly change ( P=0.05 for time effect; 48.5±1.7 vs. 49.3±1.7 kg). Body weight and body mass index did not change throughout the study duration ( P≥0.8 for time effect). In conclusion, remotely supervised home-based HIIT-ANE was feasible and safe and was associated with improved aerobic fitness and body composition in healthy older adults.

This work was supported by the National Institute of Aging grant AG063143.

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.
Exacerbated cardiac dysfunction after myocardial infarction in offspring from obese parents
Authors: Omoto Ana Carolina Mieko , da Silva Alexandre , Hall John E. , Dai Xuemei , Larson Kylie , Ladnier Emily , Mouton Alan
Published: May 2024

The prevalence of obesity in women of reproductive age is increasing rapidly, and children from obese mothers are at higher risk of developing cardiovascular diseases in adulthood. Acute myocardial infarction (MI) is one of the leading causes of death worldwide with more than one million deaths per year in the U.S. alone. Using a model of parental obesity with male and female Sprague-Dawley rats fed a high fat diet (HFD) prior to mating, and dams maintained on the HFD during gestation and lactation, we found that male and female offspring from these obese parents have multiple metabolic abnormalities early in life (3 weeks old), and that male, but not female, offspring have impaired diastolic function associated with reduced cardiac SIRT3 expression and mitochondrial biogenesis. At 24 weeks of age, male offspring from obese parents exhibit increased blood pressure. To examine if offspring from obese parents are at greater risk of death and worse cardiac function after MI, male and female lean offspring fed a normal diet (ND) born from ND fed lean parents (ND-Offs, n=5-6/sex) and lean offspring fed ND born from HFD fed obese parents (HFD-Offs, n=6-11/sex) were submitted to a permanent left descending coronary artery ligation to induce MI at 12 weeks of age. Twenty-four-hour survival rate post-MI surgery was examined and cardiac function was measured by intraventricular catheterization with a Millar catheter on day 7 post-MI. Compared to ND-Offs, male and female HFD-Off born from obese HFD-fed parents exhibited reduced survival rate (male: 60% vs 100% and female: 55% vs. 83% for HFD-Offs and ND-Offs, respectively) and increased ventricular fibrillation post-MI. At day 7 post-MI, we observed reduced +dP/dtmax in male, but not female, HFD-Offs compared to ND-Offs (6,554±25 vs. 8,253±440 mmHg/sec in males and 7,962±557 vs. 7,668±890 mmHg/sec in females, for HFD-Offs and ND-Offs, respectively) despite similar infarct size in all groups (~40% of the total left ventricle circumference). We found no major differences in -dP/dtmin or tau (indices of diastolic function) between groups. Thus, parental obesity is associated with increased mortality rate in their offspring after induction of MI and worse systolic function in male, but not female, offspring even when offspring are fed a healthy diet after weaning and remain lean.

NIDDK 1R01121411 (do Carmo), HL1630376 (da Silva/do Carmo), NIGMS P20GM104357 (Hall), P30GM149404 (Hall) and U54GM115428 (Hall).

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 increases cardiovascular strain during passive heat stress in middle-aged women
Authors: Wolf S. Tony , Kenney W. Larry
Published: May 2024

Heat waves are becoming more frequent and severe, and cardiovascular events are a contributing cause in most heat-related deaths. Obesity is reported in over 40% of adults over the age of 40 yrs, and is associated with greater heat-related mortality, although the precise mechanisms are not well-understood. To determine whether obesity increases heat-related cardiovascular vulnerability in middle-aged women, this study examined cardiovascular responses to passive whole-body heat stress in four obese (54 ± 11 yr; BMI: 33.1 ± 2.8) and four non-obese (55 ± 5 yr; BMI: 23.6 ± 0.8) middle-aged women. Red cell flux was measured at each site by laser-Doppler flowmetry (LDF) while reflex vasodilation was induced via whole-body heating using a water-perfused suit. After a 1.0°C rise in gastrointestinal temperature (ΔTgi), local skin temperature was increased to 43°C to elicit a maximal vasodilation response. Cutaneous vascular conductance was calculated (CVC = LDF/mean arterial pressure) and expressed as a percentage of maximum (%CVCmax) for each ΔTgi of 0.1°C. Heart rate (HR) was measured continuously and blood pressure (BP) was measured at each ΔTgi of 0.1°C, and rate pressure product (RPP; HR x systolic BP) was calculated as an index of cardiac strain. Percent body fat was measured with dual x-ray absorptiometry (DXA). Time to reach a ΔTgi of 1.0°C was not different between groups (Obese: 65 ± 16 min; Non-obese: 63 ± 13 min; p = 0.85). There was no group difference in CVCmax (Obese: 2.5 ± 0.6; Non-obese: 2.01 ± 0.3; p = 0.19). Likewise, there were no group differences in %CVCmax at baseline or any point throughout local heating (all p ≥ 0.47). RPP was not different between groups at baseline (Obese: 8840 ± 1160; Non-obese: 7492 ± 1081; p > 0.99), but increased to a greater degree in obese women such that there was a significant difference at ΔTgi of 1.0°C (Obese: 14162 ± 1910; Non-obese: 11393 ± 3448; p = 0.05). Further, %BF was directly related to peak RPP (p = 0.03; r = 0.75), but not resting RPP (p = 0.16). Obese women demonstrated an exaggerated RPP response for a given rise in %CVC (p < 0.0001, r = 0.82) relative to non-obese women (p = 0.21, r = 0.19; difference between slopes = 0.002). These data suggest that although thermoregulatory responses are preserved in obese middle-aged women relative to their non-obese counterparts, cardiovascular strain may be exaggerated in obese women for a given magnitude of thermoregulatory response, potentially contributing to increased heat-related mortality.

This work was supported by NIH F32 AG079581 (STW) and a seed grant from the University of Georgia Obesity Research Initiative (STW).

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.
Role of CRF1 and CRF2 Receptors in Stress-induced Increase of Intestinal Epithelial Permeability in the Mouse Colon
Authors: Liu Sumei , Sargent Caroline , Broman Lauren , Yao Daniel
Published: May 2024

Background and Aims: Stress is known to increase intestinal permeability, which may contribute to the development of irritable bowel syndrome (IBS) and other intestinal disorders. Corticotropin releasing factor (CRF) has been proven to mediate stress-induced changes in gut function, such as increased colonic motility, ion secretion, and intestinal permeability. Actions of CRF are mediated by two G-protein coupled receptors, CRF1 and CRF2; both are expressed in the intestine. However, the roles of the CRF1 and CRF2 receptors in stress-induced increase of intestinal epithelial permeability remain unknown. Methods: Adult male and female C57BL/6 mice were restrained (1h/d) for five consecutive days. The selective CRF1 and CRF2 receptor antagonists were injected intraperitoneally 15 min prior to the restraint stress. Control mice were kept in their home cages without restraint. After the last restraint stress/control session, the proximal colon was removed, and the mucosa/submucosa preparations were dissected and mounted onto the Ussing Chamber System for the measurement of intestinal permeability. Transepithelial resistance (TER) and FITC-inulin (4kD) flux across the colonic epithelium were used as indicators of paracellular permeability. Horseradish peroxidase (HRP, 40kD) flux was used to measure transcellular permeability. Results: Restraint stress did not alter TER or FITC-inulin flux in male mice. Pretreatment with the CRF1 receptor antagonist NBI 27914 or the CRF2 receptor antagonist antisauvagine-30 had no effect on TER or FITC-inulin flux in male mice. In female mice, restraint stress significantly reduced TER and increased FITC-inulin flux in the proximal colon, which were blocked by NBI 27914 but not by antisauvagine-30. Restraint stress significantly increased HRP flux in both male and female mice. In male mice, pretreatment with NBI 27914 significantly reduced stress-evoked increase of HRP flux, while antisauvagine-30 had no effect. In female mice, both NBI 27914 and antisauvagine-30 significantly reduced stress-evoked increase of HRP flux. Conclusions: Stress evokes different changes in epithelial permeability in the proximal colon of male and female mice. In male mice, stress does not influence paracellular permeability but increases transcellular permeability, which is mediated by the CRF1 receptor. In female mice, stress increases both transcellular and paracellular permeability. Stress-induced increase of paracellular permeability was mediated by the CRF1 receptor, but the increased transcellular permeability was mediated by both CRF1 and CRF2 receptors.

University of Wisconsin-La Crosse Undergraduate Research Grant (CS and LB).

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.
Embedding undergraduate Research Experience in Human Physiology Labs at Salt Lake Community College
Authors: Taylor Kristen , Mendoza Evelyn , Stosich Feldman Jo
Published: May 2024

We completely overhauled the laboratory portion (BIOL 2425) of our Human Physiology course at Salt Lake Community College. Our objective was to create a laboratory component that allows students to explore Human Physiology more deeply through iterative and connected projects that scaffold into a group Course-based Undergraduate Research Experience (CURE). We report the results from seven semesters of weekly student assessments. Our findings suggest that implementing this CURE increases undergraduate involvement in research and helps students achieve a deeper understanding of Human Physiology concepts.

The Allen Foundation SLCC School of Science, Math, and Engineering.

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.
Fibrotic Fibro-Adipogenic Progenitors Produce an Altered Extracellular Matrix that Impairs Myogenesis
Authors: Loomis Taryn , Wohlgemuth Ross , Smith Lucas
Published: May 2024

Introduction: Fibrosis is the pathological accumulation of extracellular matrix (ECM) components, impairing tissue function. In skeletal muscle, the main source of ECM deposition are fibro-adipogenic progenitors (FAPs). FAPs can signal to muscle satellite cells (MuSCs) through soluble factors and ECM deposition. FAPs are more highly activated into myofibroblasts in fibrotic conditions, but how this affects their signaling to MuSCs is unknown. Cell-derived matrices (CDMs) can be synthesized from FAPs to investigate their ECM deposition. The goal of this study was to understand how FAPs are signaling to MuSCs through their ECM deposition. We hypothesized that FAPs isolated from mdx mice, a model for skeletal muscle fibrosis, would have increased collagen deposition compared to wt FAPs and would produce a matrix that reduces myogenesis. Methods: FAPs were isolated from the lower limb muscles of wt and mdx mice. FAPs were plated in media containing 50μM ascorbic acid to promote collagen deposition for 2 weeks in order to synthesize CDMs. CDMs were imaged using second harmonic generation (SHG) imaging to visualize collagen organization. Some CDMs were solubilized and replated to create a flat protein coating of matrix. MuSCs were then plated on the CDMs, solubilized matrix, in a transwell co-culture with FAPs, and on plastic in differentiation media for 5 days. Results: There was a significant negative correlation between the level of FAP activation into myofibroblasts and the MuSC differentiation index, independent of if the FAPs were isolated from wt or mdx mice. SHG images revealed CDMs derived from mdx FAPs had less aligned collagen fibrils compared to wt CDMs. Conclusions: High activation into myofibroblasts is often an indicator of a fibrotic FAP phenotype. The negative correlation between myofibroblasts and MuSC differentiation found here indicates this phenotype impairs myogenesis. FAPs in transwell co-culture did not have a significant effect on MuSC differentiation, highlighting the importance of ECM deposition rather than soluble signaling is important in FAP signaling to MuSCs. Targeting FAPs activation into myofibroblasts provides a therapeutic target to attenuate fibrosis and improve regeneration in skeletal muscle.

Research reported in this publication was supported by the National Institute Of Arthritis And Musculoskeletal And Skin Diseases of the National Institutes of Health under Award Number F31AR082700. The content is solely the responsibility of the authors and does not necessarily represent the offcial views of the National Institutes of Health.

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.