bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of the Time-Course and Magnitude of Cardiorespiratory Responses to Superimposed Surgical Masks or N95 Respirators during 20-min Treadmill Walking
Authors: Galeos Angela , Isakovich Rodion , Cates Valerie , Marullo Anthony , Strzalkowski Nicholas , Day Trevor
Published: May 2024

Wearing medical barriers has recently expanded from healthcare to public settings, and could increase dead space and facilitate rebreathing of expired air resulting in heat accumulation, hypercapnia, and hypoxia, particularly during physical activity. We recently showed that participants wearing surgical masks (SM) and N95 respirators (N95) over 60-min during seated rest had mild and immediately reversible (a) increases face microclimate temperature, (b) increases in the pressure of end-tidal (PET)CO2, (c) decreases in PETO2, but (d) no differences in peripheral oxygen saturation (SpO2). Previous publications showed conflicting results of superimposed barrier wearing during physical activity, and there are limited studies that assessed face microclimate temperature and end-tidal gases, particularly comparing superimposed SM and N95. We hypothesized that participants wearing SM and N95 will experience mild face microclimate hyperthermia, hypoxia, and hypercapnia during 3mph treadmill walking. Participants (n=18; 8F) randomly wore (a) no barrier (NB), (b) SM or (c) N95 during a 10-min standing baseline, 20-min treadmill walking (3 mph), and a 10-min standing recovery. We continuously measured face microclimate temperature (thermistor), end tidal gases (PETCO2, PETO2; oro-nasal cannula), SpO2 (peripheral pulse oximeter). Average 20-min PETCO2 (higher; p<0.0001, P=0.0001) and PETO2 (lower; P=0.0003, P=0.0178) were significantly from baseline for both SM and N95, respectively. The delta between the 20-min average compared to the baseline data was not statistically significant for PETCO2 or PETO2 in all three conditions, except for ΔPETCO2 NB vs. N95 (higher; P=0.0344). Additionally, there was no difference in SpO2 across all barrier conditions during exercise. These mild physiological effects may account for qualitative reports of shortness of breath and increased perceived exertion while wearing barriers during physical activity. However, these effect-magnitudes are not physiologically-meaningful, and are immediately reversed upon cessation of exercise and/or barrier removal.

NSERC.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
B1AR regulation of the Cav1.2 via the SAP97 complex
Authors: Salemme Victoria , Xu Bing , Bahriz Sherif , Zhu Chaoqun , Zhao Meimi , Wang Ying , Xiang Yang k
Published: May 2024

Beta adrenergic (BAR) signaling is stimulated by the catecholamines norepinephrine (NE) and epinephrine (EPI) to control cardiac contractility. The beta-1-AR (B1AR) is the major cardiac subtype. B1AR signals canonically through the Gas subunit, leading to increases in cAMP and PKA; however, it can also signal via the Gai subunit, leading to increased NOS1, cGMP, and PKG levels. B1AR-NOS1 signaling leads to increased contractility and calcium cycling in cardiomyocytes. We found a novel complex within cardiomyocytes in which the B1AR, Cav1.2, and NOS1 proteins are held in proximity by the membrane scaffolding protein SAP97. In heart failure, there is a decrease in SAP97 expression and impaired B1AR signaling. Cardiac-specific deletion of SAP97 disrupts this complex. In the SAP97-cKO mice, there are minimal changes in B1AR-Gas; however, B1AR-Gai signaling is decreased, with a loss of B1AR-NOS1 signaling. Furthermore, we see a decrease in whole cell calcium currents and cardiac contractility. In mice lacking the NOS1, we see the same decrease in calcium currents. We hypothesize SAP97 is necessary to maintain B1AR modulation of Cav1.2 in cardiomyocytes. Using electrophysiology and biochemical techniques, we aim to elucidate the role of SAP97 in B1AR modulation of Cav1.2 and how this is impacted by the impairment of B1AR-Gai signaling.

T32HL086350 RO1-HL147263.

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.
Myocardial Blood Flow in Newly Diagnosed Breast Cancer Patients at Rest and During Exercise
Authors: Heinonen Ilkka , Koivula Tiia , Uurasmaa Tytti-Maria , Han Chunlei , Maaniitty Teemu , Latifi Shiva , Lempiäinen Salla
Published: May 2024

Heart depends critically on continuous supply of blood, but it is unknown whether cancer, without any treatments, affects myocardial blood flow (MBF) at rest or during exercise. This study therefore aimed at measuring MBF in cancer patients and control subjects and it was hypothesized that MBF is affected by cancer. The study included recently-diagnosed breast cancer patients (n=18) who had not started their oncologic treatments and age-matched female control participants (n=32). Controls were women referred to cardiac diagnostic testing but who were by this testing judged to be free of obstructive coronary artery disease. MBF was quantified with [15O]H2O positron emission tomography (PET) at rest in both groups and additionally during 10-min supine bicycling exercise in the breast cancer patients. Furthermore, cardiac morphological changes were analyzed with a breast cancer mice-model four weeks after the inoculation of 13TC mammary tumor cells. Respective mice without tumors served as controls. Resting heart rate (HR) and rate pressure product (RPP) correlated positively with resting MBF, but were similar in both groups resulting also in similar resting MBF in cancer patients and controls. MBF increased significantly from rest during exercise in breast cancer patients (p<0.0001) and exercising MBF correlated positively with the histologic grade of cancer (r=0.54, p=0.021). However, cancer grade did not associate with exercise intensity measures such as HR, RPP or HR percentage from age-predicted maximal HR. In the mouse model, the breast cancer did not affect heart weight, cardiomyocyte size, myocardial capillary density, or capillary-to-myocyte size ratio. In conclusion, resting MBF in humans or myocardial capillarity in mice appear not to be affected by breast cancer. However, the more severe is the histologic grade of cancer, the higher is the MBF during exercise in patients with breast cancer, independently of the intensity of the exercise suggesting dysregulation of myocardial blood supply with cancer. This novel finding requires further investigations.

This study was financially supported by Academy of Finland and Hospital District of South-West Finland.

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.
Clock and Bmal1 inhibit expression of Sglt1 in mouse Kidneys and glucose reabsorption
Authors: Stevenson Matthew , Mowdawalla Cyrus , Wong Bokey , Chu Alexander , Ragolia Louis , Vallon Volker , Hussain M.Mahmood
Published: May 2024

Aberrantly elevated sodium/glucose cotransporter 1 (Sglt1) expression and increased glucose reabsorption contribute to obesity or lean-associated metabolic complications, however, the precise mechanisms underlying the high expression of Sglt1 and increased glucose absorption are unclear. Clock (circadian locomotor output cycles kaput protein) is known as the master clock gene; Bmal1 (basic helix-loop-helix arnt like 1) is a known heterodimer of Clock that is a critical regulator of circadian metabolism and has the potential for regulating obesity-related diseases. We examined whether circadian clock genes involving Clock/Bmal1 and the orphan nuclear receptor Shp (the small heterodimer partner) regulate the expression of Sglt1 to maintain glucose reabsorption and glucose homeostasis. Renal Sglt1 levels were increased in Clock-mutant or Bmal1-knockout (KO) mice and were decreased by activation of Bmal1 in an SHP-dependent manner. Mechanistically, the transactivation of Sglt1 by HNF1α (hepatic nuclear factor 1 alpha) was inhibited by SHP. In wild-type mice fed a western diet, activation of Shp by Nobiletin reduced Sglt1 levels and improved glucose reabsorption and glucose handling, but these beneficial effects were not seen in Clock−mutant and Bmal1 KO mice. These results demonstrate that normal inhibition of Sglt1 by Clock/Bmal1-SHP is defective in obesity, resulting in increased Sglt1 levels, glucose reabsorption, and renal steatosis. This Clock/Bmal1-SHP-Sglt1 pathway may present novel targets for treating obesity.

This work was supported in part by National Institutes of Health (NIH) grant R56 HL137912 and American Heart Association Scientist Development Grant 2300158 and Grant-in-Aid 16GRNT30960027 to XP; by U.S. NIH grants DK121490, HL137202, HL158054 and HD094778, and VA Merit Award BX004113 to MMH; and NIH grants R01DK112042, R01HL142814, RF1AG061296, the UAB/UCSD O’Brien Center of Acute Kidney Injury NIH-P30DK079337, and the Department of Veterans Affairs to V Vallon.

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.
Examining the Role of the Gut-Brain Axis in Alcohol Use Disorder in Zebrafish
Authors: Ramirez Samuel , Uno Jennifer K.
Published: May 2024

14.5 million people struggle with Alcohol Use Disorder (AUD), characterized by uncontrolled drinking and withdrawal. Both chronic and acute alcohol use are known to disrupt the intestinal microbiome and are associated with mood disorders. The gut-brain axis is a bidirectional communication pathway between the brain and the intestines. Probiotic modulation has already been shown to alter brain chemistry in zebrafish. Recent research indicates the gut-brain axis is involved in the behavior modifications associated with AUD, however the mechanism by which it does so remains unknown. The objective of this study is to examine the impact that alcohol has on the gut-brain axis. We hypothesize that a reduced intestinal diversity will lead to heightened behavioral responses and alter biomarkers associated with chronic alcohol exposure. In order to examine this hypothesis, zebrafish (Danio rerio) were exposed to amoxicillin and erythromycin for fifteen days to clear their microbiome. Following treatment, fish were immersed in 0.50% ethanol for one hour and in escalating dosage up to 0.25% for two weeks to mimic acute and chronic alcohol exposure. Fish were recorded for 10 minutes following treatment to analyze behavioral patterns. Bacterial populations were significantly knocked down following treatment in both groups (n= 6, p < 0.05). Behavioral results from the acute ethanol treatment indicate fish exposed to ethanol displayed reduced vertical and horizontal transitions in both antibiotic and control groups, with more pronounced shifts in antibiotic-ethanol- treated group (n= 6). This reduction was not observed in the chronically treated fish, suggesting an adaptation effect. In order to further assess cognitive function, levels of NMDA Glut1 receptor mRNA were assessed, we observed no significant changes in receptor gene expression in the brains of zebrafish in the treatment groups relative to control groups. Collectively these results indicate that acute alcohol induced behavior correlates to changes in the microbiome, though this correlation is not observed in chronic alcohol exposure. Future studies are needed to better understand what role the gut brain axis plays in alcohol mediated-behavioral observations.

Glen Raven Endowed Grant, Elon University.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Interleukins expression by lymphocytes of rats exposed to chronic intermittent normobaric hypoxia
Authors: Moraga Fernando , Calderon-Jofré Rodrigo , Bernal-Dosseto Giuliano , Moraga Daniel
Published: May 2024

Hypoxia acute and chronic modulates the expression of inflammatory mediators such as cytokines. However, studies in chronic and intermittent hypobaric or normobaric hypoxia similar to described in miner’s population are scares o absent. In regards with this we propose evaluated the effect of chronic intermittent normobaric hypoxia (CINH) on the hematological, cardiovascular response and expression of lymphocyte’s cytokines such as IL-1b, IL-2, IL6 and IL-10 in rats. A total of 20 Sprague-Dawley rats were divided in two groups: a) CINH of FiO2 10% (n=10) and normoxic rats (n=10) were used as controls. Blood samples were obtained from both groups for hematological studies, systolic arterial pressure and heart rate was measured in tail-cuff sensor, and expression of cytokines obtained from lymphocytes was determined by RT-PCR. Hematocrit, hemoglobin, platelet count and hematological constant are elevated however leucocyte count decrease. A significant increase of systolic arterial pressure (over 50%). In vitro expression of cytokines from lymphocytes shown that IL-10, IL-2 and IL6 increase 35%, 64% and 16% respectively, while that of IL-1bdecreases by 18%. CINH could be activate an inflammatory response mediated by IL-2, however this response could be attenuated due to the increase in the expression of IL-10, a known anti-inflammatory cytokine, and the decrease in the expression of IL-1β and IL6 suggesting a mechanism of adaptation to CINH.

Innova-Corfo Project 07CN13ISM-152.

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.
CXCL10 regulates pressure overload-induced heart failure
Authors: Souza-Neto Fernando , Le Preston , Alamgir Ashab , van Berlo Jop H.
Published: May 2024

Rationale: Heart failure involves tissue inflammation with elevated serum levels of CXCL9 and CXCL10, which are CXCR3 receptor ligands. Both chemokines are expressed by cardiac fibroblasts and myeloid cells in mice subjected to pressure overload induced by transverse aortic constriction (TAC) surgery. Although it is known that CXCR3−/− animals are protected from cardiac remodeling induced by TAC, the role of CXCL10 is unknown. The present study was undertaken to test the hypothesis that CXCL10 is crucial in the cardiac remodeling response to pressure overload induced by TAC in mice. Methods: We subjected wild-type and CXCL10−/− mice to TAC surgery, resulting in 4 experimental groups: WT Sham, WT TAC, CXCL10−/− Sham and CXCL10−/− TAC. WGA was used to analyze the cross-sectional area of cardiomyocytes. To analyze total collagen deposition, PicroSirius Red was used. Immunohistochemistry was performed to measure the number of CD64, CD3g and CD45 positive cells. Echocardiography was used to analyze cardiac function. Results are presented as the mean and standard error of the mean. Comparisons between means were made using two-way variance analysis (ANOVA), as well as Tukey's post hoc test for parametric comparisons, or Kruskal-Wallis and Dunn‘s post hoc test for non-parametric data. Differences with p<0.05 were considered significant. Results: After 1 week, the CXCL10−/− mice showed the same level of cardiac hypertrophy and similar changes in echocardiography parameters, when compared to wild-type mice. However, after 6 weeks, we observed that the CXCL10−/− mice showed an attenuation of heart weight with a reduction in the total collagen deposition compared with wild-type TAC mice. At the cellular level, the genetic deletion of CXCL10 prevented the TAC-induced increase in the cross-sectional area of cardiomyocytes. Moreover, we observed that TAC increased the number of CD3+ T-cells in the heart quantified from stained cross sections of both wild type and CXCL10−/− mice, while no differences were observed for the total number of macrophages. Importantly, echocardiographic changes, including dilation and cardiac dysfunction, induced by pressure overload in wild animals were blunted in CXCL10−/− mice. Corroborating this, the genetic deletion of CXCL10 prevented the increase in lung weight induced by TAC. Conclusion: CXCL10 regulates cardiac hypertrophy and fibrosis induced by pressure overload in mice, as well as the functional changes that characterize heart failure. We are currently unraveling the mechanism through which CXCL10 can accelerate the development of heart failure in response to cardiac pressure overload. Interaction between T cells and macrophages are likely mediating these effects.

R01HL155993.

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.
Contractile pericyte-mediated cerebrovascular deficits in a mouse model of CADASIL
Authors: Vigderman Abigail , Hariharan Ashwini , Weir Nick , Xiang Liuruimin , Longden Thomas
Published: May 2024

Small vessel disease (SVD) of the brain underlies 25% of stroke cases and is the most common cause of vascular cognitive impairment. The most common monogenic form of SVD is CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), caused by mutations of the NOTCH3 protein which is widely expressed in mural cells (vascular smooth muscle cells [SMCs] and pericytes). Cerebral blood flow (CBF) deficits present early in CADASIL, attributable in part to NOTCH3-mediated extracellular matrix dysregulation, which alters heparin-binding epidermal growth factor-like (HB-EGF) signaling in SMCs and endothelial cells (ECs). Pericytes also robustly express NOTCH3 and are a relatively underexplored cell type in the context of CADASIL. Pericytes proximal to the penetrating arteriole (PA), known as contractile pericytes, express α-smooth muscle actin (αSMA) and can contract to rapidly regulate capillary diameter and thus blood flow in the downstream capillary tree. We conducted two-photon laser scanning microscopy (2PLSM) of blood flow and pericyte contractile responses with CADASIL Notch3R169C transgenic and control mice. Our data indicates that contractile pericyte-mediated control of blood flow is impaired prior to other known CBF deficits, thus raising the tantalizing possibility that these pericytes could be a target for early clinical intervention in CADASIL. While PA responses to stimulation of capillary electrical signaling remain intact, both blood flow as well as capillary diameter of contractile pericyte-covered vessels are diminished. Taken together, this work will establish pericytes as a novel site of dysfunction and provide a new candidate mechanism by which CBF is diminished early in CADASIL pathogenesis for potential therapeutic intervention.

5T32GM008181-33 (AV), 1DP2OD02944801 (TL), 1R01AG066645 (TL), 5R01NS115401 (TL).

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.
Antigen Presenting Cell activator protein 1 (AP-1) complex contributes to Salt-sensitive Blood Pressure
Authors: Ahmad Taseer , Saleem Mohammad , Pitzer Mutchler Ashley , Ertuglu lale , Kirabo Annet
Published: May 2024

Salt-sensitivity of blood pressure (SSBP) affects 50% of the hypertensive and 25% of the normotensive population and is a major independent risk factor for cardiovascular morbidity and mortality. We previously found that SSBP is associated with activation of the NLRP3 inflammasome in antigen presenting cells (APCs) via increased oxidated stress and isolevuglandin (IsoLG) formation, but the underlying mechanisms are unknown. The activator protein 1 (AP-1) (FOS/JUN) has been implicated in activation of the NLRP3 inflammasome but its role in SSBP is not known. We hypothesized that AP-1 transcription factor in APCs senses elevated sodium and contributes to SSBP. We further hypothesize that antioxidant flavonoid, diosmetin prevents AP-1 activation and SSBP. Using bulk RNA-sequencing in human monocytes, we found elevated sodium increases expression of the AP-1 gene family when compared to normal sodium concentration, including cFOS (2378.18 ± 480.7 vs 6494.09 ± 945.55, p= 0.0009), FOSB (53.63 ± 17. 55 vs 131.06 ± 10.30, p= 0.397), cJUN (7313.90 ± 984.93 vs 11370.09 ± 1286.35, p= 0.2563) JUNB (4218.4.36 ± 199.17 vs 570.45 ± 200.91, p= 0.0445) and JUND (3309. 63 ± 270.64 vs 8057.90 ± 1043.05, p= 0.00006). In additional experiments, we enrolled people with hypertension and phenotype them for SSBP using an established in-patient protocol of salt-loading/depletion and performed single-cell transcriptomic analyses in vivo on peripheral blood mononuclear cells (PBMCs). We found that expression of the FOSB and JUNB genes are more sensitive in concert with blood pressure in salt-sensitive (SS) but not salt-resistant (SR) humans. Moreover, diosmetin attenuated high salt-induced hypertension, 123.5 ± 4.1 vs 146.8 ± 2.5 mm Hg in controls, **p< 0.01). In addition, diosmetin also reduced high salt-induced inflammation including APC production of IsoLG-protein adducts, IL-1β, and NLRP3 inflammasome expression. These findings reveal a role for immune cell AP-1 (FOS/JUN) signaling in salt-sensitive hypertension and diosmetin may provide a potential therapeutic target for treatment of SSBP.

1R01HL144941-01A1.

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.
Time-Dependent Association Between Agonal Respirations and Cardiopulmonary Resuscitation Hemodynamics in a Porcine Model of Cardiac Arrest
Authors: Cucinotta Daniel M , Rolland Tyler J , Weil Brian R
Published: May 2024

Objective: Agonal respirations (AR) are common in patients with cardiac arrest (CA) and are associated with a higher likelihood of successful return of spontaneous circulation (ROSC). Prior preclinical studies suggest that the favorable effects of AR may be mediated by improved coronary perfusion pressure (CPP) during subsequent cardiopulmonary resuscitation (CPR) efforts, but whether this relationship is influenced by the duration of CA has yet to be studied. Accordingly, we measured CPR hemodynamics in swine following 7 minutes or 10 minutes of untreated ventricular fibrillation (VF) to determine if the frequency of AR is associated with CPP after prolonged CA. Methods: Swine (n=71) were subjected to either 7 minutes (n=50) or 10 minutes (n=21) of electrically-induced VF CA, during which the frequency of AR was recorded before the initiation of CPR with chest compressions (100/minute) and mechanical ventilation (16-20 breaths/minute). CPP was assessed during CPR by calculating the difference between aortic pressure and right atrial pressure during decompression. Animals were retrospectively stratified into two groups (high and low frequency of AR) based on the median number of AR in each cohort (7-minute CA median = 6 AR; 10-minute CA median = 9 AR).>Results: In the 7-minute CA cohort, the high AR group (9.7±2.9 AR; n=28) had a significantly longer time from first to last AR (102±6 vs. 34±6 seconds; p<0.001), shorter time from final AR to CPR initiation (208±8 vs. 280±15 seconds; p<0.001), and higher CPP during CPR (14.4±1.0 vs. 9.3±0.6 mmHg; p<0.001) than the low AR group (2.9±0.4 AR; n=22). In contrast, following 10 minutes of CA, the high AR group (12.0±0.4 AR; n=11) did not have a significantly different CPP during CPR (8.7±1.8 vs. 10.4±1.5 mmHg; p=0.48) when compared to the low AR group (6.2±0.5 AR; n=10). A greater number of defibrillation attempts were required to terminate VF after 10 minutes of CA (3.0±0.6) vs. 7 minutes of CA (1.2±0.1; p<0.001), but this was not impacted by the frequency of AR in either cohort. Conclusion: Consistent with prior studies in swine subjected to 5 minutes of untreated CA, a high frequency of AR during a 7-minute episode of CA was associated with higher CPP upon initiation of CPR. However, the favorable effects of AR frequency on CPP during CPR were no longer apparent when the duration of untreated CA was extended to 10 minutes. These results demonstrate that the beneficial effects of AR on CPR hemodynamics are time-dependent and highlight the importance of early initiation of CPR following CA.

Supported by funding from the NIH and US Department of Veteran's Affairs.

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.
Advanced PamGene Coregulator Interactome Analysis of PPARgamma Reveals that Diet Influences Regulatory Protein Interactions and Signaling Mechanisms
Authors: Bates Evelyn , Kipp Zachary , Pauss Sally , Lee Wang-Hsin , Martinez Genesee , Xu Mei , Hinds Terry
Published: May 2024

Studies show a strong correlation with type 2 diabetes mellitus (T2DM) in obese patients developing congestive heart failure (CHF) with rosiglitazone treatment. Rosiglitazone, a thiazolidinedione, treats T2DM by improving insulin resistance. Its use has been halted due to a subset of patients developing CHF through unknown mechanisms. Rosiglitazone targets PPARγ, a nuclear receptor highly expressed in adipose tissue and, to a lesser extent, in cardiac tissue. An important mechanism of PPARγ regulation is through coregulators that can alter transcriptional activity through protein-protein interaction to drive PPARγ toward specific pathways. We hypothesized coregulator interaction with PPARγ may regulate its activity differently in adiposity, inducing CHF through adipose-derived peripheral signaling. To address this, we fed 8-week-old C57BL/6 mice a normal chow (NCD) or high-fat (HFD) diet for 16 weeks. Mice were then injected with rosiglitazone every 48 hours for 4 weeks. In NCD and HFD Rosi mice, we found significantly increased heart weights (p-value<0.05) and various weight changes in five adipose depots. To understand the roles of the PPARγ coregulator interactome in adiposity, we used our state-of-the-art PamGene PamStation Nuclear Hormone Receptor chip to measure the interaction of PPARγ with 155 coregulators in five adipose depots and the liver. In adipose depots increasing in weight due to Rosi treatment, such as retroperitoneal white adipose tissue (WAT) and mesenteric WAT, more coregulators associated with the PPARγ complex. Conversely, depots that did not change in weight with Rosi treatment, such as epididymal WAT and inguinal WAT, showed a reduction of coregulators leaving the PPARγ complex, indicating differential PPARγ regulation. Our data suggests that the coregulator interactome of PPARγ in adipose depots represents potential therapeutic targets, and understanding how PPARγ regulation is different in adiposity is crucial to understanding the negative side effects of rosiglitazone treatment.

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

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.
N-acetyl cysteine (NAC) administration induces behavioral abnormalities in mice experiencing proteotoxic cardiac disease
Authors: Devarajan Asokan , Jarrell Matthew Thomas Cleveland , Natesan Sundaresan , Sunny Sini , Arulmani Ahila , Raveendran Ashvanthi , Might Matthew
Published: May 2024

Background: The co-occurrence of cardiac and neurological complications is becoming increasingly common among individuals diagnosed with either of these disorders. Hypothesis: We tested the hypothesis that elevating glutathione (GSH) levels through N-acetyl cysteine (NAC), a precursor for GSH synthesis, leads to behavioral abnormalities in a mouse model with proteotoxic heart disease. Approach: We used a transgenic mouse model expressing a cardiac-specific human mutant R120G-αB-crystallin (hR120GCryAB-TG), which develops progressive heart failure due to proteotoxicity. Our investigation aimed to understand the effects of NAC on brain redox and behavior in this model. Results: Administering NAC for a period of 12 weeks, we observed an increase in glutathione levels and its redox state (GSH/GSSG) in both heart (1.0 vs. 3.0 Fold in NTG vs. TG; p>0.001) and brain (1.0 vs. 4.0 Fold in NTG vs. TG; p>0.01) tissues. Interestingly, this increase was associated with exacerbated cardiac dysfunction and abnormal behavior. The administration of NAC worsened both structural and functional defects in the hearts of the transgenic (TG) mice, indicating that enhancing antioxidant defense mechanisms could trigger proteotoxic insults through reductive stress (RS). Additionally, the brain of TG mice exhibited enhanced reductive capacity (p>0.01), accompanied by significant alterations in the levels of Tau and α-Synuclein proteins, when compared to non-transgenic (NTG) mice. While NTG mice, with or without NAC treatment, displayed normal behavior, TG mice treated with NAC developed severe behavioral abnormalities, including cognitive impairment (p>0.01). Conclusions: These findings suggest that increased GSH levels (i.e. RS) in progressive heart failure could cause behavioral issues. Thus, further research into the underlying redox mechanisms in other organs, including the brain, is necessary to better understand the use of antioxidant supplements for heart failure treatment. This study will aid in developing personalized therapeutic strategies.

National Institute of Health - NHLBI R01 (R01-2RHL118067; Namakkal-Soorappan) American Heart Assocaition (20POST35200085; Sunny).

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
A potential role for GPR107 in the development of Hypoglycemia Unawareness
Authors: Hagena Lisa , Stafford Joshua , Samson Willis K. , Kolar Grant , Yosten Gina L.C.
Published: May 2024

Diabetes remains one of the largest health burdens in modern society and while an estimated 37.3 million people suffer from either type 1 or type 2 diabetes worldwide, a further 96 million people are currently estimated to be prediabetic. So far, most efforts for diabetic therapies have been focused on insulin-replacement therapies and secretagogues; however, a common risk associated with these therapies is hypoglycemia. Hypoglycemia is defined as low plasma glucose levels (< 70 mg/dl) and can lead to loss of consciousness and death. Recently, it has been established that repeated exposure to bouts of hypoglycemia in diabetic individuals likely impairs sympathoadrenal counter regulation, and shifts the glycemic threshold for symptoms to lower plasma glucose concentrations, close to levels which result in cognitive failure. This pathology has been titled hypoglycemia unawareness (HU) and constitutes a major risk factor for developing severe hypoglycemia. The development of severe hypoglycemia in diabetics accounts for a six-fold increase in mortality, compared to diabetic individuals who do not experience severe hypoglycemia. Thus, it is important to understand how to prevent and reverse its development. We have developed a novel rat model of HU in which rats are exposed to insulin-induced recurrent hypoglycemia for five consecutive days. In this model of HU, we found that GPR107 expression is dramatically increased in the hypothalamus of rats exhibiting loss of hypoglycemia-induced food intake. Our group previously identified GPR107 as a receptor for neuronostatin (NST), a 13 amino acid peptide derived from the somatostatin prepro-hormone, which can exert anorexigenic actions in the hypothalamus. Using a GPR107-flox rat model we are currently evaluating the effect of hypothalamic knock-down of GPR107 on the development of HU and basal feeding behavior. We anticipate that if knock-down of GPR107 reverses HU, the development of NST antagonists could potentially be useful therapeutically for diabetic patients who experience recurrent hypoglycemia. Our GPR107-flox rat model will enable us to identify upstream and downstream interacting partners of GPR107/NST. This could reveal hypothalamic pathways involved in the development of HU that also could serve as potential therapeutic targets for this devastation consequence of iatrogenic hypoglycemia.

Internal Funds St. Louis University.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Investigating the Role of CART/GPR160 Signaling in Stress-Induced Anorexia
Authors: Mirian Niloufarsadat , Stafford Joshua , Samson Willis K. , Yosten Gina L.C.
Published: May 2024

Stress-induced anorexia represents a conserved adaptive response across diverse species. While this response can be crucial for survival in specific situations, it may become detrimental when prolonged stress exposure leads to unhealthy eating patterns, contributing to eating disorders like anorexia nervosa and bulimia. Feeding behavior is intricately connected to the stress response, as stress levels can influence appetite and energy expenditure. Central to the stress response are corticotropin-releasing hormone (CRH)-producing neurons, which secrete CRH, stimulating the production of ACTH in the pituitary gland and subsequently triggering the release of cortisol, a stress hormone, from the adrenal glands. The presence of CRH in the hypothalamus, a brain region involved in controlling feeding, suggests a complex interplay where stress and metabolic signals converge. One such signal is the peptide cocaine- and amphetamine-regulated transcript (CART) which has been shown to regulate feeding behavior, satiety, and metabolic function by signaling through its receptor GPR160 and downstream glucagon-like peptide (GLP)-1 signaling. In this study, we hypothesize that CART/GPR160 signals within CRH-producing neurons to control feeding behavior and stress responses. To test this hypothesis, we used a multifaceted approach, utilizing both wild type and GPR160-floxed rats in which GPR160 was knocked down specifically in CRH neurons using an AAV-Cre under the control of the CRH promoter injected bilaterally into the paraventricular nucleus. We monitored food and water intake, investigated CRH secretion from hypothalamic explants treated with CART, and assessed physiological changes in GPR160, CART, and other related molecules in various brain regions following acute stress. We also examined the effects of GPR160 knockdown in PVN neurons on plasma cortisol levels in response to restraint stress. While further studies are necessary to fully define the roles of CART and GPR160 in stress responses and feeding behavior control, our preliminary findings indicate that this ligand-receptor pair could serve as a novel therapeutic target for treating psychiatric diseases related to eating disorders.

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.
Essential Roles of Mitochondrial Reactive Oxygen Species Signaling in Airway Smooth Muscle from Mice following Nicotine, Pyoverdine, and their Co-exposure Authors: Subika Khatoon, Ed Wilson Santos, Yun-Min Zheng, Yong-Xiao Wang Corresponding Author: Yong-Xiao Wang, wangy@amc.edu
Authors: Khatoon Subika , Wang Yong-Xiao , zheng Yun-Min , SANTOS ED WILSON
Published: May 2024

Consumption of nicotine, a major active component of cigarettes or e-cigarette smoke, is a global health problem, causing a myriad of life-threatening diseases. Pseudomonas aeruginosa is a common cause of lung infections and often exacerbate nicotine-associated lung diseases. However, the underlying cellular and molecular mechanisms remain poorly understood. In this study, we aim to address these important questions by performing a series of experiments. establish a clinical threshold of Pseudomonas Aeruginosa Infection in a COPD animal model and determine the underlying molecular mechanisms underlying the mitochondrial dysfunctions in Airway Smooth Muscle Cells (ASMCs). Utilizing in vitro and in vivo models, our data revealed that mice following inhalation of nicotine showed increased lung resistance, decreased lung compliance, and elevated airway resistance in vivo. In support, nicotine caused airway hyperresponsiveness in isolated mouse tracheal and bronchial smooth muscles. We also found that reactive oxygen species (ROS) production was largely increased in isolated mitochondria from mice after nicotine inhalation. Application of pyoverdine, a primary active component of Pseudomonas aeruginosa, produced a similar effect on ROS production in isolated mouse airway smooth muscle (ASM) mitochondria. Furthermore, mice co-exposed to nicotine inhalation and pyoverdine had a higher increase in ROS production in isolated ASM mitochondria compared with mice following nicotine or pyoverdine exposure alone. In conclusion, our findings for the first time demonstrate mitochondrial ROS signaling plays essential roles in airway dysfunctions following nicotine, pyoverdine, and their co-exposure and may also offer new strategies to treat lung diseases induced by nicotine inhalation and/or Pseudomonas aeruginosa.

Funding: This work was supported by the NIH (R01HL122865, R03AG070784, and R01HL108232, to Yong-Xiao Wang).

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 Piezo2 from renal Foxd1+ stromal progenitors and descendent cells results in abnormal mesangial development and sex-specific differences in kidney function
Authors: McLarnon Sarah , N’Guetta Pierre , O'Brien Lori L
Published: May 2024

Piezo2 is a mechanically activated ion channel recently identified in glomerular mesangial cells and renin+ juxtaglomerular (JG) cells. Despite several studies which confirm this localization of Piezo2 in the kidney, the function of Piezo2 in these cells remains ambiguous. In the current study, we hypothesized that loss of Piezo2 in mesangial and JG cells would result in abnormal glomerular development during nephrogenesis and impaired salt and water balance in adult mice. To test this hypothesis, we generated mutant mice lacking Piezo2 in Foxd1+ stromal progenitors and their cell lineages, which include mesangial and JG cells. Kidney morphology was assessed by immunofluorescent staining and z-stack confocal microscopy during late nephrogenesis (post-natal day 0, P0) and following maturation of the nephron (P20) in wild-type (Piezo2fl/fl, n=3), heterozygous (Foxd1GC/+Piezo2fl/+, n=3), and mutant (Foxd1GC/+Piezo2fl/fl, n=3) mice. In adult male and female mice (n=2/genotype/sex), blood pressure was measured by tail cuff (CODA Systems) between 1-4pm following 3 days of acclimation. In a separate group of control and mutant male and female mice (8-10 weeks, n=3-5/group/sex), a 4-hour saline challenge (i.p. 10% body weight) was performed to assess diuresis and natriuresis. At P0, we found that deletion of Piezo2 from Foxd1+ stromal progenitors and their cell lineages resulted in the abnormal distribution of mesangial cells within glomeruli, such that the mesangial area appears compressed compared to control or heterozygous mice. This phenotype was exacerbated in mutant mice by P20. In adult mice, female mutants had an increase in daytime mean arterial pressure (~10mmHg, mean 79 vs 88) compared to female controls. Cumulative urine excretion (4 hours, percent injected) was decreased in females compared to males, regardless of genotype (p<0.001). Further, female mutant mice had a delayed diuresis response compared to control (2 hour, mean 16% vs 28% cumulative urine volume). However by 4 hours following a saline bolus both groups were similar. Taken together, these data indicate that deletion of Piezo2 in Foxd1+ stromal progenitors results in impairments in mesangial cell development during nephrogenesis and alterations in water and salt balance in adult female mice. Understanding the sex-specific roles of Piezo2 in kidney development and physiology is critical to identify the role of mechanosensation on renal homeostasis.

NIH R01DK121014 to LO.

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.
Characterizing Mitochondrial Maturation in the Heart
Authors: Torniainen Andrea , Mikkila Jennifer , van Berlo Jop
Published: May 2024

Cardiovascular disease is the leading cause of death around the world and the burden is projected to become worse. Because of their ability to supplant the heart’s weak regenerative capabilities, stem cells and their derivatives have been investigated as a potential therapy. However, stem cell-derived cardiomyocytes are less mature than the cells they would be replacing in a clinical setting, causing many functional shortcomings such as unorganized and weak contraction. An in-depth study of how maturation normally occurs is necessary to identify targets to enhance it. As one of the best-known aspects of cardiomyocyte maturation, the mitochondria, and their substrate preferences, dictate the amount of energy a cell produces as well as modulate a cell’s contraction, differentiation, and survival. Similar to the cell itself, the mitochondria mature over time. However, to what extent mitochondrial maturation drives cardiomyocyte maturation is not clear. In this study, we used mass spectrometry to identify the developmental changes across normal cardiac maturation in mitochondria from mice. We detail key shifts in the mitochondrial proteome over time and identify possible regulators of mitochondrial and cardiomyocyte maturation. Pathway and transcription factor analyses highlight transitions over time to more organized, productive mitochondria. Mechanistic evaluation of identified pathways might reveal current bottlenecks for complete maturation of stem cell-derived cardiomyocytes.

This work was supported by RMM091621DS008, NIH155993, and NIH160665.

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.
Stiffer gymnastics floors result in more dorsiflexed ankles, potentially increasing the risk for Achilles tendon ruptures
Authors: Muhlenhaupt Emily , Stauss Harald
Published: May 2024

One in five female collegiate gymnasts suffers an Achilles tendon rupture (ATR), primarily on floor exercise. Training floors are used daily, sometimes for over 10 years, while floors at competition sites are often new. Consequently, training floors feel “soft” and competition floors feel “stiff”. We hypothesized that the ankle joint angle is in a more dorsiflexed position on a “stiff” compared to a “soft” floor during impact, resulting in greater tension of the Achilles tendon and, consequently, a higher incidence of ATRs during competition. Female gymnasts from 78 US collegiate teams were invited to complete a survey, assessing whether ATR occurred at the training or competition sites, among other items. The ankle joint angles during landing from back-tumbling-take-offs on “soft” and “stiff” gymnastics floors were determined using video imaging. Statistical analysis was performed by Pearson’s Chi Square test or t-tests, as appropriate. Twenty-one out of 103 gymnasts (20.4%, 95% CI: 13.6% to 29.4%) experienced an ATR. Relative to time, ATRs occurred only 0.08±0.01 (95% CI: 0.06 to 0.11) times per 1000 hours on training floors, but 1.85±0.11 (95% CI: 1.60 to 2.10) times per 1000 hours (p<0.05) on competition floors. Ankle joint angles were in a more dorsiflexed position on the stiff (103.5±1.1 degree) than the soft floor (117.0±4.1 degree, p<0.05), implying greater tension on the Achilles tendon. We conclude that stiff floors favor more dorsiflexed ankle joints, increasing the tension on the Achilles tendon, and potentially explaining the higher relative incidence of ATRs at competition compared to training sites.

This research was supported by the Offce of Research and Sponsored Programs at Burrell College of Osteopathic Medicine.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.