bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exercise training cycles persistently improve glucose homeostasis and alters hepatic fatty acid oxidation
Authors: Huang Yi-Heng , Weidenhamer Clay , Hernández-Saavedra Diego 
Published: May 2024

Obesity is a metabolic disease associated with a lower capacity for fatty acid oxidation (FAO) that contributes to insulin resistance and reduces metabolic fuel flexibility. Conversely, the long-term consequences of obesity can be reversed through exercise training. While studies suggest that exercise elicits long-lasting and persistent adaptations in muscle akin to an “exercise memory”, how a hepatic memory is established remains unknown. This is key given that beneficial adaptations to the exercised muscle cannot occur without support from the liver. Thus, we hypothesize that exercise training elicits a hepatic “exercise memory” that persists after exercise cessation and is accentuated by retaining to improve metabolic health and FAO. Here, we used male SEDentary (static cages; SED) and exercise-TRAINed (wheel running, TRAIN) chow-fed mice and investigated how exercise impacts whole body glucose homeostasis (glucose tolerance test [GTT], insulin tolerance test [ITT], pyruvate tolerance test [PTT]) and hepatic FAO following training (4wks), detraining (8wk), and retraining (12wk) in three independent cohorts. Exercise training reduced adiposity ( p<0.01) and improved glucose tolerance (GTT) ( p<0.05), compared to SED. Metabolic improvements in TRAIN mice were accompanied by higher gene expression of FAO enzyme Hadha ( p<0.05). Further, improvements to adiposity and glucose handling disappear after detraining. Nevertheless, after detraining, TRAIN mice had a higher expression of lipid uptake ( Lpl, p<0.05), mitochondrial function ( Sdha, Sdhb, p< 0.05), and FAO genes ( Acadvl, p=0.053). Following retraining, we observed a significant enhancement of basal glucose ( p<0.05) and a main effect of exercise training on glucose homeostasis (GTT, ITT, PTT) across timepoints (factorial ANOVA p< 0.001). However, mitochondrial and FAO gene expression ( Sdha, Sdhb, p<0.05, Acadvl, p=0.053) were reduced with retraining in TRAIN mice, compared to SED. In conclusion, we observed that exercise training improves glucose homeostasis, which is further potentiated through exercise retraining. This effect was accompanied by dynamic changes in expression of genes related to mitochondrial function, FAO, and lipid uptake. Our data may suggest a dynamic reprogramming of hepatic fatty acid handling with training, that may persist with detraining, and can be enhanced with retraining. Funding was provided by the University of Illinois Urbana-Champaign. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
The influence of perceived discrimination on aortic hemodynamics in young Black adults
Authors: Griffn Leila , Via Jeremy , Reid Jill , Simulick Summer , Segears Zion , Turley Miranda , Bramble Cole 
Published: May 2024

Black adults experience the greatest prevalence of cardiovascular disease (CVD) risk factors and higher CVD mortality of any racial or ethnic group in the United States. The chronic stress from experiencing racial discrimination may exert a weathering effect that contributes to cardiovascular health inequities observed among Black adults. Prior evidence has suggested that Black adults experience greater aortic stiffness as compared with white adults. However, there is limited information regarding perceived racial discrimination and aortic hemodynamics in young adults. Purpose/Hypothesis: The purpose of this study was to determine whether perceived racial discrimination was associated with worse aortic hemodynamics in young Black adults. Methods: Black adults aged 18-25 (n=18, 44% female) volunteered to participate in this study. Participants arrived at the lab at 7:00AM in a fasted state. Following 30 minutes of rest, central pressure waveforms were derived from the radial artery waveform acquired via applanation tonometry and the use of the generalized transfer function. We report aortic augmentation pressure (AP, mmHg), augmentation index (AIx, %), augmentation index normalized to a heart rate of 75bpm (AIx75), round trip transit time (Tr, ms), and the subendocardial viability ratio (SEVR, %), also known as the Buckberg Index. Peak oxygen consumption (VO2 peak) was measured via Indirect calorimetry during a graded treadmill test. Participants completed a questionnaire that assessed personal-level and group-level discrimination. Partial correlations (Pearson’s r controlled for VO2 peak) were used to assess the association between perceived racial discrimination and aortic hemodynamics. Results: Perceived group-level discrimination was positively associated with AP (r = 0.571, p = 0.026), AIx (r = 0.580, p = 0.023), and AIx75 (r = 0.571, p = 0.026), signifying worse central hemodynamics that are indicative of increased left ventricular systolic load. However, perceived personal-level discrimination was not associated with aortic hemodynamics (ps>0.05). VO2peak was positively associated with Tr (r = 0.511, p = 0.043), signifying a later return of the reflected wave (i.e, better) to the heart to facilitate coronary perfusion during diastole. VO2 peak was also inversely associated with AIx75 (r = -0.657, p = 0.006). Conclusion: These preliminary data indicate that young Black adults who report higher group-level discrimination have an increased left ventricular systolic afterload in the aorta. Future studies investigating coping strategies or the effects of increased fitness to improve central hemodynamics in Black adults are warranted. 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.
Beta cell-derived exosomes from KDM6A KO mice enhances glucose uptake via upregulation of GLUT4 in skeletal muscles and adipocytes
Authors: Zhang Bo , Wang Shirley , Sun Zhongjie 
Published: May 2024

Exosomes are small extracellular vesicles secreted by various cell types which have gained prominence as potent mediators of intercellular communication. Beta cells play a critical role in glucose homeostasis through the production and secretion of insulin. Lysine demethylase 6A (KDM6A) belongs to the KDM6 family of histone H3 lysine 27 (H3K27) demethylases which is important for the development of various organs. Our previous study showed that beta cell-specific knockout of KDM6A increased glucose tolerance and enhanced peripheral insulin sensitivity in mice. The aim of this study is to investigate whether beta cell-derived exosomes, particularly those derived from KDM6A knockout (INS1-KDM6A-KO) beta cells, regulates glucose uptake in skeletal muscles and adipocytes. We found that serum exosome concentrations were increased significantly in the INS1-KDM6A-KO group. Skeletal muscles were isolated from WT and INS1-KDM6A-K mice. GLUT4 protein expression was upregulated in skeletal muscles in INS1-KDM6A-KO mice. Moreover, pancreatic islets isolated from the INS1-KDM6A-KO mice exhibited a notable increase in exosome release. Interestingly, exosomes from beta islets largely enhanced glucose uptake in cultured skeletal muscle cells and 3T3-L1 adipocytes. Meanwhile, beta cell-derived exosomes from KDM6A-KO mice upregulated GLUT4 in NOR-10 cells, especially in the presence of insulin. The findings suggest that beta cell-derived exosomes may play an important role in KDM6A deficiency-induced enhancement in insulin sensitivity likely via upregulation of GLUT4 in skeletal muscle cells and adipocytes. This work was supported by NIH R01 Grants - HL154147 and AG062375. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
The Accelerator and Brake Modulatory System of Carotid Body Sensitivity
Authors: Gold Olivia M.S , Pauza Audrys G , F.R Paton Julian 
Published: May 2024

The carotid body (CB) is the primary sensor of arterial gases in the human body that through reflex pathways maintains cardiovascular homeostasis. It is known that CB chemosensitivity increases upon repeated stimulation as well as disease states; however, the molecular basis for this remains elusive. Objectives: To investigate the effect of excitatory and inhibitory amino acids in mediating CB afferent activity. Hypothesis: We hypothesised that glutamate and γ-aminobutyric acid (GABA) act to modulate CB sensitivity. Methods: Electrophysiological recordings of carotid sinus nerve (CSN) afferent discharge were made from an ex vivo arterially perfused common carotid artery bifurcation preparation. Effects of agents on CB sensitivity were assessed from responses evoked by cyanide (CN−) (1.23 μmol bolus). Results: The CSN response to CN− consisted of a rapid high amplitude discharge that was quenched abruptly, leading to a low amplitude tail. Glutamate administration augmented the CSN response to CN− by 2-fold compared to baseline ( p=0.0005). In contrast, GABA administration suppressed the CN− response by 2-fold ( p = 3.71 x 10−5). An N-methyl-D-aspartic acid (NMDA) receptor antagonist (MK801; 100 μM) increased the response amplitude resulting in one single high amplitude discharge (160% increase from baseline), abolishing the low amplitude tail. Such an effect was also observed following GABAA receptor blockade with bicuculline (500 μM), when an 80% increase was observed. The CN− response was blocked by PPADS (a P2X receptor antagonist; 100 μM) (242 ± 154 vs 4.82 ± 2.23 % change from baseline; p=0.03), suggesting it to be solely mediated by purinergic transmission. Summary of the data: We propose that CN-evoked excitation of CB chemosensory cells leads to the co-release of ATP and glutamate. ATP activates directly P2X receptors on petrosal chemosensory afferents, while glutamate acting via NMDA receptors on chemosensory cells leads to activity-induced potentiation of ATP release and co-release of GABA to quench ATP-mediated CSN discharge in a time-controlled manner. This is supported by our finding that blockade of either excitatory (NMDAR) or inhibitory (GABAA) receptors both heighten the CN− evoked CB response. A statement of the conclusions: Our results suggest an intrinsic ‘accelerator and brake’ paracrine mechanism within the CB involving glutamate and GABA controlling CB afferent sensitivity. Research was supported by the Health Research Council of New Zealand and the Sidney Taylor Trust. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Histamine Receptors Are Altered in Colorectal Cancer
Authors: Edens Rachel , Engevik Kristen , Engevik Mindy , Engevik Amy 
Published: May 2024

Background: Histamine is an endogenous amine that acts on a wide variety of cell types throughout the body. Its activity is mediated by four distinct receptors: HRH1, HRH2, HRH3 and HRH4. Each of these receptors induces a distinct signaling cascade that has diverse output. Histamine has been postulated to influence cancer progression, but little is known about the distribution of histamine receptors in the gut epithelium or its exact role in colorectal cancer. The aim of this study was to define the distribution of histamine receptors in the colonic epithelium in the setting of health and cancer. Methods & Results: We utilized publicly available single cell sequencing databases to examine the distribution of histamine receptors in the normal colon. We found that HRH1 was highly expressed in all colonic epithelial cells. Interestingly, HRH2, HRH3 and HRH4 were not expressed in any cell type in the colon. To confirm these findings, we grew human colonic organoids and found by qPCR analysis that HRH1 was the only receptor present in this epithelial specific system. In the setting of cancer, we found that HRH1 was elevated in colorectal cancer tumors compared to normal controls. Immunostaining of a tissue array confirmed that colon cancer tissue specimens had higher concentrations of immune associated HRH1; suggesting that immune cells were contributing to the higher levels of HRH1 observed in tumors. Single cell RNAseq data demonstrated that macrophages and monocytes had the highest expression of HRH1 among immune cells. Examination of immune infiltration and HRH1 expression in the Cancer Genome Atlas revealed a positive correlation between monocyte and macrophage HRH1 expression. Conclusions: These data suggest that HRH1 is the only receptor expressed in the colonic epithelium and that in cancer, infiltration of monocytes and macrophages harboring HRH1 elevate overall expression levels of this receptor in tumors. DDRC Pilot and Feasibility Award (Amy Engevik) Career Development Award (K01) (Amy Engevik) DK121869-01. 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.
Epigenetic Effects of Finasteride on Dopaminergic Signaling Pathways: A potential contributor to Post-Finasteride Syndrome
Authors: Ihentuge Churchill J , Csoka Antonei B 
Published: May 2024

Dopamine, a widely-distributed neurotransmitter in the brain and elsewhere, is important for regulating reward-motivated behavior, sexual impetus, concentration, pleasure, emotions, and genital arousal. Findings have previously implicated aberrant dopaminergic neurotransmission in mental disorders, as well as sexual and erectile dysfunction. To evaluate the epigenetic effects of finasteride on dopaminergic signaling pathways, we treated human Leydig cells with finasteride and identified several dopaminergic pathways that were altered by differential methylation of component genes. These genes included those involved in the regulation of dopamine secretion and transport (OR56A4, OR13F1 and SYT4), the Phospholipase C-activating dopamine receptor signaling pathway (OR56A4 and OR13F1), the dopaminergic synapse (CALML4, COMT, GNAI2, GNAS, GNG10, GRIA1, GSK3A, GSK3B, KCNJ9, PPP2R2C, PPP2R3B, PPP2R3C, PPP2R5A, PPP2R5E) and the dopamine receptor activity and binding pathway (OR56A4, OR13F1). This alteration of gene methylation suggests a potential role of altered epigenetic regulation of dopaminergic pathways in the etiology and pathophysiology of post-finasteride syndrome (PFS), which should be further investigated. National Institutes of Health (NIH) R25 Resource Grant (1 R25 AG047843-01) to ABC. 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.
Body Position Dependent Participation of Abdominal and Thoracic Breathing Movements During the Breathing Cycle
Authors: Decker Szonja , Takacs Johanna , Deak Darina , Horváth Tamás , Koller Akos 
Published: May 2024

Aims: Both abdominal and thoracic breathing movements play important roles in the mechanics of breathing, participating differently in various body positions with abdominal breathing having a greater role. Recent studies showed that an early proning position of awake, non-intubated patients during the COVID-19 pandemic, even during pregnancy (PMID: 32320506, PMID: 33309507, PMID: 34915799) significantly affected the ventilatory parameters and mortality of SARS-CoV-2 patients. Thus, we hypothesized that in different body positions the participation of abdominal (AB) and thoracic breathing (TB) during the complete respiratory cycle (CRC) is different. To test this, we measured the participation of AB and TB to the CRC in different body positions under resting conditions. Methods: In young participants (N=26) age between 18 and 24 (M=21.3±1.6), changes in abdominal and chest circumferences were measured using plethysmography respiratory belts, during inhalation and exhalation in standing (ST), sitting (SI), supine (SU), prone (PR), and all on fours (AF) body positions. Respiratory frequency was also measured. Results: In different positions, the contribution of AB and TB to CRC were significantly different (F(4,100)=4.999, p=0.004, η2p=0.17). AB was significantly higher than TB in all positions (p<0.001). More specifically, AB gradually increased, while TB gradually decreased in the following order: SU(AB/TB) = 74.8±12.9%/25.2%, ST = 69±16%/31%, PR = 66.8±20.2%/33.2%, SI = 65.5±14.8%/34.5%, AF = 61.1±15.1%/38.9%. A significantly higher value was measured in the SU position compared to AF (p<0.001) and SI (p=0.011) positions; PR and ST positions showed intermediate values, which were not significantly different from those yielded by either of the other positions. Respiratory frequency was similar in different body positions. Conclusions: These data show that different body positions significantly affect the participation of abdominal and thoracic breathing during resting condition, underscoring not only the importance of respiratory distress patients positioning during hospitalization, but its usefulness in developing a respiratory training plan for elite athletes to optimize their physical and mental performance in competitive sports. AK: Ministry of Innovation and Technology (MIT) of Hungary-NRDI TKP2020-NKA-17, TKP2021-EGA-37, and National Research, Development, and Innovation Offce (NKFIH) OTKA K 132596 K_19, and Hungarian Academy of Sciences, Post-Covid 2021-34, and HUN-REN-SU: 02068 of Hungary, JT: ÚNKP-22-4-II-SE-4 (JT), TKP2021-EGA-25. 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.
Antidepressant Treatment Preserves Microvascular Endothelium-Dependent Dilation in Women Who Have Had Preeclampsia
Authors: Lee Ruda , Brustkern Kaila , Pierce Gary , Santillan Mark , Stanhewicz Anna 
Published: May 2024

Women with a history of preeclampsia (hxPE) demonstrate persistent microvascular endothelial dysfunction which may contribute to the progression of cardiovascular disease. Women with hxPE also have higher rates of depression compared to women with a history of healthy pregnancy. Interestingly, accumulating evidence indicates that antidepressant treatment may have vasculoprotective effects and attenuate preeclampsia risk. However, whether antidepressant treatment impacts microvascular function in these women remains unknown. Therefore, we examined the effect of chronic antidepressant use on microvascular function in women with hxPE. We hypothesized that antidepressant-treated women with hxPE would have greater endothelium-mediated microvascular vasodilation than unmedicated women with hxPE. Five women with hxPE who were currently treated with an antidepressant (hxPE+AD; 36±3 years; 26±7 months postpartum), six who were not (hxPE-AD; 34±2 years; 26±5 months postpartum), and six unmedicated women with a history of uncomplicated pregnancy (HC; 37±1 years; 35±7 months postpartum) participated in one study visit. We measured cutaneous vascular conductance (CVC=laser doppler flowmetry flux/MAP) responses to graded perfusion of acetylcholine (10−10-10−1 mM) via microdialysis in a control (lactated Ringer's) site and a site treated with 15 mM NG-nitro-L-arginine methyl ester [L-NAME; nitric oxide (NO) synthase inhibitor]. hxPE-AD had reduced endothelium-dependent dilation compared to HC (acetylcholine ³10−3 mM; P<0.03). hxPE+AD had greater endothelium-dependent dilation compared to hxPE-AD (acetylcholine 10−2 and 10−3 mM; P<0.02) and there were no differences between hxPE+AD and HC (all P>0.05). L-NAME reduced endothelium-dependent dilation in all groups (all P<0.001), and there was no difference between groups in NO-dependent dilation [area under the curve (AUC) at a control site − AUC at a L-NAME treated site; P=0.522]. These data suggest that microvascular endothelium-dependent dilation is preserved in women with a history of preeclampsia treated with an antidepressant, potentially mediated through non-NO-dependent mechanisms. Funding: American Heart Association CDA 937990. 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.
Na/K-ATPase α1/Src Signaling Regulates Mitochondrial Metabolic Function and ROS Production in Human iPSC-derived Cardiomyocytes
Authors: Strause Sidney , Pessoa Marco , Cai Liquan , Gao Yingnyu , Banerjee Moumita , Tian Jiang , Xie Zijian 
Published: May 2024

Through an isoform specific mechanism, the Na/K-ATPase (NKA) α1 polypeptide-mediated regulation of Src kinase has emerged as a novel regulator of mitochondrial function in various cell types. Mitochondrial metabolism ensures adequate myocardial performance and adaptation to physiological demand. It is also a critical cellular determinant of cardiac repair and remodeling. To investigate the importance of the proposed NKA/Src regulatory signaling on cardiac mitochondrial metabolic function independently from the classic Na/K-ATPase enzymatic function, we used a gene targeting approach in cardiomyocytes. Human induced pluripotent stem cells (hiPSC) expressing a Src-signaling null mutant (A420P) form of NKA α1 were generated using CRISPR/Cas9-mediated genome editing. NKA isoform protein expression and enzymatic activity remained unchanged. However, baseline levels of Src and ERK1/2 phosphorylation were decreased by 55% and 80%, respectively in the A420P hiPSC (n=3, p<0.05). Both the WT and A420P hiPSC differentiated into cardiomyocytes (iCM) as assessed by morphology, spontaneous cell contraction, marker gene expression, and subcellular striations. Cell metabolism assessed by Seahorse extracellular flux analysis revealed significant reductions in basal and maximal rates of mitochondrial respiration (50%), spare respiratory capacity (50%), ATP production (60%), and coupling effciency (20%) (n=4, p<0.05). ROS production was monitored in live cells by measuring the oxidation of the CM-H2DCFDA dye using a fluorescence microscope. The slope of the ROS production rate curve was dramatically reduced in A420P iCM (80%, n=3, p<0.05). Protein carbonylation levels, analyzed by ELISA as markers of oxidative damage, were also decreased in A420P iCM (n=4, p<0.05). Taken together, these data provide genetic evidence for a role of NKA α1/Src in the tonic stimulation of basal mitochondrial metabolism and ROS production in human cardiac myocytes. This has potential significance in cardiometabolic diseases and suggests that targeting the NKA α1/Src signaling axis may offer a novel approach to address mitochondrial dysfunction. NIH Grant R15 HL145666, NIH Grant P20GM103434 to the West Virginia IDeA Network of Biomedical Research Excellence, and American Heart Association Postdoctoral Fellowship — 22POST917776 — to Marco T. Pessoa. 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.