bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metabolic regulation of the two-pore domain potassium channel TASK-1
Authors: Yu Yang , Curry John , Hu Keli 
Published: May 2023

TASK-1 is a two-pore potassium ion channel and implicated in the maintenance of cell membrane potential. Little is known about the traffic regulation of TASK-1 under metabolic stress. The present study was designed to explore whether cell surface expression of TASK-1 is modulated by hypoxia. The trafficking of recombinant TASK-1 channels was studied in HEK293T cells under hypoxia induced by sodium cyanide (NaCN). Incubation of cells with NaCN significantly reduced TASK-1 fluorescence intensity at cell periphery, and this effect was inhibited by pretreatment with bisindolylmaleimide (BIM), a specific protein kinase C (PKC) inhibitor. Similar results were confirmed by quantifying extracellular HA-tagged TASK-1 on the cell surface using chemiluminescence assay. NaCN-induced reduction in TASK-1 at cell periphery was also prevented by co-expressing the dominant-negative dynamin 1 (K44E), or cholesterol depletion with MβCD, indicating a potential role of cholesterol and dynamin-dependent endocytosis in PKC-mediated reduction of cell surface TASK-1 by NaCN. Mutagenesis studies further showed that NaCN-induced reduction of TASK-1 at cell periphery was observed in cells expressing wild-type TASK-1 but not mutant TASK-1 with mutation of the dileucine motif (263-264 LL-AA) or the PKC phosphorylation consensus site (T400A). Moreover, Western blot analysis demonstrated that NaCN reduced the amount of wild-type TASK-1 but not the TASK-1 mutants (263-264 LL-AA and T400A) in the membrane fraction. In conclusion, our results demonstrate that cell surface TASK-1 channels are downregulated under metabolic inhibition, possibly through PKC-mediated endocytosis in a cholesterol and dynamin-dependent manner. This is the full abstract presented at the American Physiology Summit 2023 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.
What really matters mobility of middle-aged and older adults: low muscle mass or obesity?
Authors: Chen Chiao-Nan , Hsu Kuo-Jen , Chen Shu-Chen , Chien Kuei-Yu 
Published: May 2023

Study objective: This study explored which body size–adjusted skeletal muscle indices (SMI) has a better correlation with mobility and cardiometabolic health. Additionally, the roles of low muscle mass and obesity in the mobility and cardiometabolic health of individuals were identified. We hypothesized that body mass index (BMI)-or body weight (Wt)-adjusted SMI had a better correlation with mobility in middle-aged and older adults with obesity than did body height (Ht)-adjusted SMI. Methods: 427 community-dwelling middle-aged and older adults (age: 66.0±9.0 years) underwent assessments of body composition (dual-energy X-ray absorptiometry and waist circumference [WC]), grip strength, and mobility (timed up-and-go test and chair stand test). WC was used as a surrogate for obesity. Chi-square test and one-way analysis of variance were used to compare grip strength, mobility, and cardiometabolic health among individuals with normal body composition (N), only low muscle mass (S), only obesity (O), and low muscle mass plus obesity (SO). Pearson’s correlation coefficient was used to examine the correlation between muscle strength/mobility and different body size–adjusted SMI. Regression models were used to examine the factors independently associated with muscle strength, mobility, and cardiometabolic health. The significance level was set at α<0.05. Results: The O group, but not the S group, had poorer mobility than the N group, regardless of the SMI used to define low muscle mass. The O and SO groups had a higher prevalence of cardiometabolic diseases. The relationship between muscle mass and mobility existed in individuals with obesity, but not in individuals without obesity. After adjusting for age, sex, and WC, ASM/BMI was the only SMI that was correlated with grip strength. Similarly, only ASM/BMI was positively correlated with performance on the timed up-and-go test in the population with obesity (p<0.05). When age and sex were controlled, WC, but not SMI (regardless of adjusting for Ht, Wt, or BMI), was associated with mobility and cardiometabolic health. Conclusion: BMI-adjusted SMI had a better correlation with mobility in middle-aged and older adults with obesity than did Ht- and Wt-adjusted SMI. Obesity plays a more independent role in mobility and cardiometabolic health than low muscle mass in middle-aged and older adults. This study was supported by the Ministry of Science and Technology, Taiwan This is the full abstract presented at the American Physiology Summit 2023 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.
Mediators of steatosis in HepG2 cells
Authors: Rida Reem , Rida Reem , Kreydiyyeh Sawsan 
Published: May 2023

Hepatic lipid accumulation or steatosis has become nowadays a major public health problem. The disease can progress into serious liver damage that can lead eventually to hepatic failure and cancer. Fatty liver may result from an increase in lipid acquisition or a decrease in lipid disposal, or both. Although lipid metabolism is known to be under the control of multiple enzymes and signaling molecules, the ones dysregulated in steatosis are still ill defined. The aim of this study was to identify the key molecules altered during hepatic lipid accumulation. Steatosis was induced by incubating HepG2 cells for 24 hrs with 1 mM Oleic and Palmitic acid. Cellular lipid content was quantified using a lipid extraction kit in which lipids were stained with Oil red O, then extracted and quantified colorimetrically. The fatty acids, which are known to activate Gq-linked fatty acid receptors, increased significantly lipid accumulation. This increase was not maintained in presence of specific inhibitors of Gq, PI3K, mTOR, SREBP, and PPARϒ. Gq was found to be upstream of all the other intermediates. It was concluded that saturated fatty acids activate a Gq signaling pathway involving kinases and transcription factors implicated in lipogenesis. The location of the different intermediates with respect to each other needs still to be determined. University Research Board- American University of Beirut This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Effects of home-based high interval inspiratory muscle training on inspiratory muscle strength and exercise capacity in individuals with chronic heart failure
Authors: Wu Yi-Chen , Chen Yung-Hsin , Huang Wei-Ming , Chen Chiao-Nan 
Published: May 2023

Study objective: Heart failure (HF) is a global disease that affects people worldwide. Individuals with HF have symptoms such as dyspnea, fatigue, and exercise intolerance. Inspiratory muscle strength plays an important role in individuals with chronic heart failure (CHF). Recent studies have shown that a long duration (15-30 mins/session) of low-intensity inspiratory muscle training (LI-IMT) improves inspiratory muscle function, exercise capacity, and quality of life in individuals with CHF. However, the long duration of training decreases the compliance of patients. Recently, a short duration (5 mins/session) of high-intensity interval IMT(HI-IMT) was found to improve inspiratory strength and exercise endurance in healthy individuals and individuals with obstructive sleep apnea. To date, the effectiveness of HI-IMT in individuals with HF is unknown. The aim of the study was to examine the effects of HI-IMT in individuals with CHF. The hypothesis of the study was HI-IMT improves inspiratory muscle strength, exercise capacity, and quality of life in individuals with CHF. Methods: This is a randomized control trial. Thirty-six individuals with HF (68% male) were randomly allocated to the HI-IMT group and the control group. Both groups of participants received home-based IMT 6 days/week for 12 weeks. Every session consisted of 30 breaths (5 breaths/set, 6 sets). The intensity of HI-IMT and the control group was 60% and 0% of maximal inspiratory pressure (MIPmax), respectively. Exercise capacity (VO2 peak and 6-minute walking distance, 6MWD), MIPmax, and quality of life (Minnesota living with heart failure questionnaire, MLHFQ) were examined before and after training. Analysis of covariance and paired T-tests were used to examine the training effects. P<0.05 was considered different. Results: Thirty-six individuals with CHF were included in the study. The average age and the left ventricular ejection fraction were 64.7±11.9 years old and 44.5±12.3%, respectively. The improvements of MIPmax, 6MWD, VO2 peak, and MLHFQ were greater in the HI-IMT group than in the control group (p<0.05). The HI-IMT group, but not the control group, showed significant improvements in oxygen uptake efficiency slope after the intervention (p<0.05). Conclusion: 12 weeks of HI-IMT was an effective intervention to improve inspiratory muscle strength, exercise capacity, and quality of life in individuals with CHF. This study was supported by Yen Tjing Ling Medical Foundation, Taiwan. This is the full abstract presented at the American Physiology Summit 2023 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.
Setmelanotide, a melanocortin-4-receptor agonist, increases the hypercapnic ventilatory response and relieves hypoventilation in obese mice
Authors: Aung O T , Ramos Amorim Mateus , Anokye-Danso Frederick , Y Polotsky Vsevolod 
Published: May 2023

Introduction: Obesity leads to high cardiorespiratory morbidity and mortality. Obese individuals can develop obesity hypoventilation syndrome (OHS) characterized by daytime hypercapnia in the absence of alternative underlying causes. OHS leads to daytime sleepiness, cardiovascular complications, and cyanosis. There is no effective pharmacotherapy for OHS. Leptin, an adipose-produced hormone, improves breathing in OHS, but obese individuals and rodents are resistant to the beneficial effects of leptin. The melanocortin axis is a downstream target of leptin but effects of this axis on control of breathing are poorly studied. Setmelanotide is an FDA-approved drug for weight loss that specifically binds to the melanocortin 4 receptor (MC4R). We have previously demonstrated that C57BL/6J mice with diet induced obesity (DIO) hypoventilate during sleep and exhibit all features of OHS. We hypothesized that the activation of MC4R by setmelanotide augments the control of breathing during sleep in DIO mice. Methods: We performed a proof-of-concept single dose randomized trial of intraperitoneal setmelanotide (1.0 mg/kg) vs vehicle in DIO C57BL/6J mice using a cross-over design. The injections were followed by sleep studies, and measurements of the hypercapnic ventilatory response, oxygen consumption (VO2), and carbon dioxide production (VCO2). Results: Activation of MC4R by setmelanotide increased inspiratory flow, respiratory rate, and minute ventilation during NREM and REM sleep compared to vehicle. Activation of MC4R by setmelanotide increased the hypercapnic ventilatory response. Setmelanotide also increased VCO2, and VO2, but the ventilation was increased out of proportion to the upregulation of metabolism, which was evident from increases in the VE/VO2 and VE/VCO2 ratios. Conclusion: Activation of MC4R by setmelanotide relieved hypoventilation during sleep and increased the hypercapnic ventilatory response in obese mice. Our study identified MC4 as a promising therapeutic target in OHS. NIH (R01 HL128970, R01 HL133100, and R01 HL138932), AHA (#915167). This is the full abstract presented at the American Physiology Summit 2023 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.
Activation of Transient Receptor Potential Vanilloid 4 (TRPV4) channels opens Connexin Hemichannels in Lens Epithelial Cells
Authors: Ek-Vitorin Jose , Shahidullah Mohammad , Lopez Rosales Joaquin , Delamere Nicholas 
Published: May 2023

ATP release from the lens via connexin hemichannels has been hypothesized as a response to TRPV4 activation when the lens is subjected to osmotic swelling. To explore the apparent linkage between TRPV4 activation and hemichannel opening we performed patch-clamp recordings on cultured mouse lens epithelial cells exposed to the TRPV4 agonist GSK1016790A (GSK) in the presence or absence of the TRPV4 antagonist HC067047 (HC). GSK was found to cause a fast, variable and generally large non-selective increase of whole cell membrane conductance evident as a larger membrane current (Im) over a wide voltage range. This response was prevented by HC. The GSK-induced Im increase was proportionally larger at negative voltages and coincided with fast depolarization and the simultaneous disappearance of an outward current, likely a K+ current. The initial presence of this outward current in control conditions appeared to be a reliable predictor of a cell’s response to GSK treatment. In some studies, recordings from single cells combining cell-attached and whole-cell patch clamp configurations, were obtained. This novel approach revealed events with a channel conductance 180-270 pS following GSK application through the patch pipette on the cell-attached side. The findings are consistent with TRPV4-dependent opening of connexin hemichannels. Ongoing studies are aimed at confirming the hemichannels identity. NIH: 5R01EY029171-04 and 2R01EY009532-28A1. This is the full abstract presented at the American Physiology Summit 2023 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.
Vitamin D Receptor Attenuates Osteo-sarcopenia by Suppressing the Ferroptosis
Authors: Li Wenxiong , Chen Feifei , Zhang Kuaiqiang , Sun Zhiping , Zhang Yan , Yang Feng 
Published: May 2023

Objective: Vitamin D deficiency is associated with a range of skeleton and muscle disorders, including osteoporosis and sarcopenia, but its functional role and the underlying mechanism in skeleton and muscle physiology remain unclear. We investigated the effect of vitamin D receptor (VDR) deletion on skeleton and muscle using a mice model with dexamethasone-induced osteo-sarcopenia (OS). Methods: The wildtype and VDR(-/-) mice were treated with vehicle and dexamethasone (i.p., once daily) for 14 consecutive days. The murine myoblast cell line C2C12 and bone mesenchymal stem cells (BMSCs) were used as an in vitro model in this study. Results: After challenging to dexamethasone, VDR-null mice exhibited more severe amyotrophy and bone rarefaction compared with wildtype counterparts, manifested by marked weight loss and significant decrease in muscle wet weight coefficient of the tibialis anterior muscle and gastrocnemius, accompanying with a decrease in bone mineral density (BMD). In addition, the limb grip and weight-loading swimming time were also fall off. Similarly, dystrophin fluorescence staining and haematoxylin eosin staining showed the decrease in cross-sectional area of skeletal muscle in the VDR-null mice. Alizarin red staining and TRAP staining showed that the differentiation of osteoblasts was significantly decreased, while the activity of osteoclasts was significantly increased in the VDR-null mice. VDR knockout mice significantly accelerated protein degradation and bone destructions, but inhibited protein synthesis and bone construction in skeleton and muscle tissue. In addition, we further assessed whether increased Fe2+ level and decreased GPX4 in VDR knockout muscle accelerated the muscle injury, since the deletion of VDR activated ferroptosis, giving rise to the accumulated of Fe2+ in mice and Depleting GSH and inhibiting GPX4 expression. Treatment with the inhibitor of ferroptosis Ferrostatin-1 eliminated dexamethasone-induced atrophy and osteoporosis of myotube cells and BMSCs, reflected by alleviating myotube cell atrophy and BMSCs bone rarefaction via MHC fluorescent staining, Alizarin red staining and TRAP staining. It is suggested that ferroptosis may be one of the pathogenesis of OS. Conclusion: These results provided evidence that VDR attenuated dexamethasone-induced OS at least in part by suppressing the ferroptosis. This work was sponsored by the Program of Natural Science Foundation of China (81973889), the Program of Shaanxi Education Department (19JC013 to FY & 22JK0346 to WL), Youth Innovation Team in Shaanxi universities, and the Program of Health Commission of Shaanxi Province (2022B002). This is the full abstract presented at the American Physiology Summit 2023 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.
HDAC and p300/CBP activities regulate Reactive Oxygen species dependent increase in Histone 3 acetylation in response to intermittent hypoxia
Authors: Nanduri Jayasri , Wang Ning , Prabhakar Nanduri 
Published: May 2023

Histone3 (H3) lysine acetylation levels regulate transcriptional activation through a dynamic process involving equilibrium between histone acetylases (KATs) and histone deacetylases (KDACs). We have previously shown that lysine acetylation of H3 is an early epigenetic mechanism associated with Hypoxia inducible transcription factor (HIF-1) activation and sympathetic excitation in rodent models of intermittent hypoxia (IH), a hallmark feature of sleep apnea (Wang et al, Front Physiol 2021). The goal of the present study was to determine the molecular mechanisms underlying IH increased H3 acetylation. We tested the hypothesis that IH decreased KDAC activity leads to increased KAT activity, thereby increasing H3 acetylation. Pheochromocytoma (PC)-12 cells exposed to IH (1.5% O2 for 30 sec followed by 20% O2 for 5 min) exhibited reduced KDAC and increased KAT enzyme activity along with increased global acetylation of H3 in a stimulus-dependent and reversible manner. Increased H3 acetylation by IH was blocked by an antioxidant. Conversely, reactive oxygen species (ROS) mimetics, like IH, increased H3 acetylated protein expression. Treating cells with Trichostatin A (TSA), an inhibitor of KDACs mimicked IH-increased H3 acetylation under normoxic conditions. Pharmacological blockade p300/CBP (KAT) with CTK7A abolished IH-induced increased H3 acetylation. Similar to PC12 cells, decreased KDAC activity lead to augmented p300/CBP mediated H3 acetylation in both rats exposed to IH and heme-oxygnease null mice (HO-2-/-) which exhibit high incidence of apneas. In summary, interplay between KATs and KDACs regulate ROS-dependent H3 acetylation and the ensuing IH induced transcriptional activity leading to sympathetic activation. NIH-PO1-HL90554 This is the full abstract presented at the American Physiology Summit 2023 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 reduction in Homeodomain Interacting Protein Kinase-2 in lung fibroblasts ameliorates lung fibrosis
Authors: Hewawasam Sankha , Liang Yurong , Hang Chaoqun , Dang Quanjin , Liu Lin 
Published: May 2023

Idiopathic pulmonary fibrosis is a chronic, progressive, and scarring lung disease with an unknown etiology. Homeodomain Interacting Protein Kinase 2 ( HIPK2) is a co-transcriptional regulator involved in kidney fibrosis. We hypothesize that a decrease in HIPK2 expression attenuates the activation and proliferation of lung fibroblasts through inhibition of TGF-β1 and Wnt 3a pathways. HIPK2 knockdown using a lentiviral shRNA in human pulmonary fibroblasts (HPFs) reduced TGF-β1- and WNT3a-induced expression of fibrotic markers including α-smooth actin, fibronectin, and collagen 1A1 and 3A1 as determined by Western blots and real-time PCR. Immunostaining of α-smooth actin showed that HIPK2 knockdown inhibited fiber formation in HPFs. Furthermore, HIPK2 knockdown suppressed fibroblast proliferation. HIPK2 knockdown in HPFs also resulted in a reduction in TGF-β1-induced SMAD 2/3 phosphorylation and WNT3a-induced activated β-Catenin expression, suggesting the involvement of HIPK2 regulation on above pathways. To investigate the effects of HIPK2 knockdown on lung fibrosis in mice, HIPK2 was knocked down (KD) in the lungs of mice using an adenovirus expressing 4 shRNAs targeting HIPK2 and lung fibrosis was induced by an intratracheal instillation of bleomycin (1U/kg body weight) for 14 days. HIPK2 KD mice lost less body weight compared to the control mice. Analysis of bronchoalveolar lavage (BAL) indicated a significant reduction in total infiltrated immune cells in Hipk2 KD mice. Lung fibrosis was reduced in Hipk2 KD mice as demonstrated by fibrotic score, Sirius red staining, fibronectin mRNA level, and collagen content as measured by hydroxyproline assay. Lung functions including elastance, compliance, resistance, and inspiratory capacity, as determined by Flexivent, were improved in Hipk2 KD mice. Real-time PCR and ELISA revealed a significantly reduced mRNA expression of Tgf-β1 in the lung tissues and a decreased TGF-β1 level in BAL fluids of Hipk2 KD mice. Immunofluorescence indicated reduced SMAD-3 and activated β-Catenin levels in the fibrotic regions of Hipk2 KD mice. These findings clearly suggest that reduced HIPK2 expression in the lung attenuates lung fibrosis through the suppression of TGF-β1 and WNT3a signaling pathways. R01 HL157450, R01HL135152 and P20GM103648 This is the full abstract presented at the American Physiology Summit 2023 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.