bluuebunny/crossref_metadata_2025_split huggingface dataset:
Processing body accumulation in aged muscle stem cells contributes to impaired self-renewal
Authors: Hettinger Zachary , Hu Sophia , Xing Jianhua , Ambrosio Fabrisia 
Published: May 2023

Stem cell exhaustion is a pillar of aging hallmarks, mediated by an inability of the body’s stem cells to self-renew. In skeletal muscle, impaired self-renewal of muscle stem cells (MuSCs) manifests as a progressive decline in muscle regenerative capacities, leading to functional dependence in the aged. Self-renewal depends on preventing degradation of factors mediating pluripotency during division, thereby averting differentiation, however, mechanisms underlying the inability of MuSCs to self-renew in the aged are unknown. Here, we show processing bodies (p-bodies) accumulate in MuSCs isolated from old mice. As p-bodies canonically represent cellular depots for RNA degradation, our findings suggest age-related changes to RNA degradation may contribute to impaired self-renewal of old MuSCs. To investigate the consequence of p-body enrichment in old MuSCs on self-renewal, we utilized a computational-based lineage analysis termed Dynamo following single cell RNA-sequencing of MuSCs isolated from young and old mice. Dynamo incorporates the velocity of RNA to generate transcriptional vector fields, allowing for inference of lineage specification. Moreover, through characterization of each cell’s transcriptome, this framework also allows for investigation of changes to lineage specification as a result of genetic perturbation. We found that manipulation of scaffold proteins mediating p-body formation resulted in a pronounced effect on lineage specification. Specifically, our results showed that upregulation of LSM14a mRNA processing body assembly factor ( LSM14a) in young MuSCs resulted in a loss of cycling-related gene expression, and subsequently promoted differentiation. Moreover, we found that downregulation of LSM14a in old MuSCs oriented transcriptional vector fields towards a self-renewing phenotype and away from differentiation, mediated by increased expression of cycling-related genes and decreases in differentiation-related genes. Together, the accumulation of p-bodies in old MuSCs coupled with the ability of p-bodies to facilitate self-renewal, suggests that targeted interventions focusing on p-body assembly may be therapeutic in restoring old MuSC self-renewal, and thereby regenerative capacities in the aged. This study was supported by NIA R01 AG061005 (FA), NIA R01 AG052978 (FA), and NIEHS R01 ES025529 (FA). Postdoctoral fellowship funding provided by P30AG024827 (ZH). 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.
Alpha 1-adrenergic-mediated vasoconstriction and functional sympatholysis in patients with heart failure with preserved ejection fraction
Authors: Alpenglow Jeremy , Bunsawat Kanokwan , Fancisco Michael , Broxterman Ryan , Craig Jesse , Iacovelli Jarred , Harrison Jonathan , Morgan David , Silverton Natalie , Ryan John , Ma Chisty , Wray D. 
Published: May 2023

Heart failure with preserved ejection fraction (HFpEF) is characterized by peripheral vascular dysregulation at both rest and during exercise. Prior studies have demonstrated that blood flow to skeletal muscle is closely regulated by sympathetic (α-adrenergic) vasoconstriction and the interaction of vasoactive substances released locally during exercise that counteract α-adrenergic vasoconstriction. This phenomenon, known as “functional sympatholysis” helps facilitate exercise hyperemia and has been shown to decline via aging and disease-related changes in α1-adrenergic function but this has not been studied in HFpEF. Thus, the overall objective of this study was to characterize peripheral α1-adrenergic vasoconstriction in HFpEF. We hypothesized that both resting α1-mediated vasoconstriction and the magnitude of functional sympatholysis would be diminished in HFpEF compared to healthy, age-matched control (CON) subjects.Six patients with HFpEF (3 male, 70±3 yrs) and six CON (3 male, 67±1 yrs) completed this study. Leg blood flow (LBF, ultrasound Doppler) was evaluated at rest and during dynamic single leg knee-extension exercise (0, 5 and 10 Watts) before and after local, intra-arterial administration of Phenylephrine (PE, α1-adrenergic agonist). PE-mediated changes in LBF (%Δ) at rest and during exercise were compared between groups. The magnitude of functional sympatholysis was calculated as the difference between PE-induced %Δ LBF from rest to exercise.At rest, the PE-induced %Δ LBF was smaller in HFpEF (HFpEF: -17±2% vs. CON: -31±8%, P=0.01). While PE-induced %Δ LBF were similar between groups during exercise, when these responses were compared to %Δ LBF at rest, the calculated magnitude of sympatholysis was significantly reduced in HFpEF (0W: -4±3%, 5W: -5±4%, 10W: -8±3%) compared to CON (0W: -17±7%, 5W: -20±8%, 10W: -25±6%). These data demonstrate a marked diminution in both α1-adrenergic responsiveness at rest and the ability to attenuate α1-adrenergic mediated vasoconstriction during exercise (functional sympatholysis) in patients with HFpEF. Diminished α1-adrenergic signaling and impaired functional sympatholysis may represent an important aspect of HFpEF pathophysiology that likely contribute to vascular dysregulation in this patient group. Funded in part by grants from the National Institutes of Health (T32HL139451) and the Veterans Health Administration (I01RX001311, IK2RX003670, IK2CX002114). 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.
Pompe mice have improved respiration during hypercapnic challenge following acute intermittent hypoxia
Authors: Roger Angela , Huston Meredith , Kehoe Sean , Smith Jennifer , Le Davina , ElMallah Mai 
Published: May 2023

Pompe disease results in cardiorespiratory distress secondary to glycogen accumulation in the lysosomes of all muscle types and motor neurons. The only approved treatment is enzyme replacement therapy (ERT), which improves survival, however, it cannot completely correct skeletal muscle or motor neuron pathology, therefore respiratory failure persists. To prevent respiratory distress effectively in Pompe patients, there is a need to develop novel approaches that can improve respiratory muscle and motor neuron function. Acute intermittent hypoxia (AIH) is a non-invasive therapy capable of improving respiratory motor function and has has been successful in studies of spinal cord injury and ALS. The hypothesis of this study is that AIH will promote plasticity in skeletal muscle and motor neurons to improve respiration in Pompe mice.2-month-old Pompe and wildtype (WT) mice were exposed to 10 cycles of alternating room air (21% O2) and hypoxia (10% O2) for 5 minutes each, once per day for 7 consecutive days. After the initial week of exposures, mice were given a reminder dose twice per week. An additional group of Pompe and WT mice were only exposed to room air to serve as untreated controls. Mice underwent whole body plethysmography (WBP) immediately before and after the initial week of AIH exposure and again at 6 months of age. During WBP, unanesthetized mice were placed in a Plexiglas chamber and exposed to room air (21% O2) for 2 hours, during which a 5-minute baseline period of quiet breathing was recorded, then the mice were exposed to 3, 10-minute respiratory challenges, first hypoxic air (10% O2), then hypercapnic air (7% CO2), and finally hypoxic and hypercapnic air together. At 6 months of age, respiration (frequency, tidal volume, minute ventilation, and peak inspiratory flow) was slightly improved in Pompe mice receiving AIH during the hypercapnia and hypercapnia + hypoxia challenges compared to untreated Pompe mice. The next steps of this study include evaluating glycogen accumulation and subsequent pathology in the carotid bodies, characterizing proteins associated with hypoxia induced plasticity in the medulla and spinal cord, and analyzing the health and integrity of diaphragm neuromuscular junctions. Our conclusion is that AIH improved respiration under hypercapnia conditions in Pompe mice. NIH/NHLBI K99HL161420 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.
Response patterns of NTS neurons during electrical stimulation of the superior laryngeal nerve: Influence of codeine
Authors: Bolser Donald , Rose Melanie , Wang Wei , Morris Kendall , Segers Lauren , Nuding Sarah , Valarezo Ashley , Shen Tabitha 
Published: May 2023

Electrical or mechanical activation of laryngeal afferents elicits the laryngeal adductor reflex (LAR), an airway defensive behavior that adducts the vocal folds to protect the airway from aspiration. This behavior is mediated, in part, by neurons in the NTS (nucleus of the solitary tract) and is sensitive to suppression by codeine. We hypothesized that NTS neuron responses to electrical stimulation of the superior laryngeal nerve (SLN) would be reduced by codeine, consistent with an action of the drug at this level of the brainstem to suppress the LAR. We recorded extracellular activity of multiple NTS neurons simultaneously in three anesthetized, spontaneously breathing cats using multiple microelectrode arrays. We also recorded bilateral EMG activity of upper airway and chest wall muscles. The neurons were tested with electrical stimulation of the SLN (2 Hz, 0.1 ms pulse duration, 1.5X threshold for inducing the LAR) during vehicle and a cumulative dose response to codeine (0.1-10.0 mg/kg iv). A total of 35 NTS neurons were recorded; some were identified as premotor to laryngeal or upper airway motoneuron pools by spike triggered averaging. Prior to codeine administration, approximately 30% of cells had short latency excitatory responses to electrical stimulation of the SLN; no inhibitory responses were observed. After codeine doses, changes in spontaneous activity were observed in most neurons (~80%). In response to codeine, both enhancement and suppression of short latency excitatory responses were observed in cells that were excited by SLN stimulation during vehicle. The data support complex actions of codeine on NTS neurons that do not easily account for opioid-suppression of the LAR. T32 HL134621, and NIH HL155721 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.
Inflammatory biomarkers throughout influenza infection associate with changes in cardiovascular measurements
Authors: Martin Brigitte , Martin Brigitte , Attipoe Esinam , Wu Wenji , Challagundla Lavanya , Showmaker Kurt , Garrett Michael 
Published: May 2023

For better infectious disease surveillance, there is growing interest in the detection of subtle changes in cardiovascular physiology in response to viral infection. This is not only important for earlier diagnosis and better prognosis of symptomatic carriers, but also useful to diagnose asymptomatic carriers of the virus. In our previous study, we found changes in cardiovascular physiology induced in A/Puerto Rico/8/34 (PR8) influenza infections in female and male C57BL/6J mice. Reduction in activity, blood pressure (BP) and heart rate (HR) for females was observed approximately 3-13 days post infection (dpi) and males approximately 5-12 dpi. Additionally, we found sex differences in inflammatory maker expression in lungs at 7dpi with bulk RNA sequencing (RNA-seq) data of lungs and Bio-plex cytokine assay for blood. In this study, we aim to associate changes in cardiovascular measurements with biomarkers throughout infection. Blood, brain, heart, lung, kidney, and nasal septum were collected at 1, 3, 5, and 9 dpi from influenza infected and naïve C57BL/6J female and male mice (n=6 for each time point and experimental group). Using body weight loss as a marker for disease in mice, we found both females and males had significant decrease in body weight at 9 dpi, yet infected females had a significant increase in brain, lung, and kidney weight at 9 dpi compared to naïve females. We are currently in process of analyzing pathological impacts of each tissue with histology and differing patterns of inflammatory maker expression in lungs throughout infection by analyzing bulk RNA sequencing (RNA-seq) data of lungs and Bio-plex cytokine assay for blood. Both cardiovascular measurements and molecular markers throughout influenza infection help to distinguish sex differences caused by influenza virus infection for better, earlier disease diagnosis. Hypertension and Cardiorenal Diseases Research Training Program T32HL105324 (NIH) 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.
Early life stress (ELS) induces aortic stiffening and increased cytokine production in mice
Authors: Kelly Gillian , Kellum Cailin , Washington LaTimberly , Pollock Jennifer 
Published: May 2023

ELS exposure (childhood adversity such as household dysfunction, abuse, or neglect) is an independent risk factor for adult-onset cardiovascular disease (CVD). ELS exposure is associated with increased circulating inflammatory markers in humans, as well as elevated aortic inflammatory monocytes in mice. The cellular sources and mechanisms of excessive cytokine production behind these findings are still poorly understood. We hypothesized that mice exposed to ELS, maternal separation with early weaning (MSEW), will have greater arterial stiffening and greater reactive aortic macrophages leading to a larger cytokine response when activated with LPS than normally reared (NR) mice. The MSEW model includes pups separated from the dam 4h/day (postnatal day (PD) 2 to PD5), 8h/day (PD6 to 16), and weaned at PD17. NR pups remain with the dams until weaning at PD21. Pulse wave velocity (PWV), a measure of aortic stiffness, determined at 6 wks of age found that MSEW mice had elevated PWV as compared to NR (NR: 1.2±0.08 mm/sec, MSEW: 2.1±0.04 mm/sec, p<0.0001, n=4,6). In the aorta, total F4/80+ macrophages as well as cells expressing activation markers CD86 and MHCII were elevated in 14 wk old MSEW mice (%F4/80+: NR:2.73±0.34, MSEW 5.04±0.56, p=0.004, n=7,5; %CD86: NR: 0.12±0.03, MSEW: 0.52±0.09, p=0.004, n=7,5; %MHCII: NR: 1.14±0.09, MSEW: 1.92±0.22, p=0.001, n=7,5). MSEW mice showed significantly elevated levels of macrophages (%CD11c-CD11b+F4/80+ of CD45+) in the spleen red pulp (NR: 1.09±0.04, MSEW: 1.28±0.07, P=0.03, n=14,10). However, expression of activation markers CD86 and MHCII as well as TNFα, IL-1b and IL6 in splenic macrophages from 14 wk old MSEW mice did not significantly differ between the MSEW and NR cohorts. Finally, we isolated splenic macrophages, stimulated with LPS (100 ng/mL) for 24 hrs and cytokine secretion measured by cytokine array. The qualitative array showed that the total supernatant of macrophage cultures from MSEW sample had greater IL1-ra, IL-16, G-CSF, CXCL10, macrophage inflammatory protein 1B and 2, and TNFα compared to cultures from NR samples. These results suggest that macrophages of MSEW mice are primed for inflammatory responses and may secrete intracellular cytokines compared to macrophages from NR mice. Elevated PWV is an early indicator for the development of CVD, seen as early as 6 wks in MSEW mice. Taken together these findings suggest a greater propensity for those who have experienced ELS to develop CVD. Future studies will aim to elucidate the role of the elevated macrophage derived cytokines in arterial stiffening. NIH R25 DK 112731, NIH R25 DK 115353, NIH T32 DK 116672 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.
Pharmacological inhibition of the endocannabinoid anandamide metabolism alleviates cisplatin-induced acute kidney injury
Authors: Chen Chaoling , Wang Weili , Poklis Justin , Em Brandon , Lichtman Aron , Gewirtz David , Li Ningjun 
Published: May 2023

Fatty acid amide hydrolase (FAAH) is the primary enzyme that degrades the endocannabinoid anandamide (AEA). Inhibition of FAAH by pharmacology or genetic approach has been shown to reduce inflammation in the brain, colon, heart and kidneys. Kidney medullary infusion of a FAAH inhibitor exerts diuretic and natriuretic effects. Faah knockout mice are protected from both post ischemia reperfusion injury and cisplatin-induced acute kidney injury (AKI) but through distinct mechanisms. The presented study tested the hypothesis that pharmacological inhibition of FAAH activity mitigates cisplatin-induced AKI and explored the potential renoprotective mechanism. Male wild type C57BL/6 (WT) were treated with oral gavage of a FAAH inhibitor (PF-04457845, PF, 5mg/kg) or vehicle (10% PEG200+5% Tween80+normal saline) at 72, 48, 24, 2-hr before and 24, 48-hr after a single dose of intraperitoneal injection of cisplatin (Cis, 25 mg/kg). Mice were euthanatized 72 hours after cisplatin treatment. PF-treated mice showed a decrease of cisplatin-induced plasma creatinine levels compared with vehicle (Veh)-treated mice (mean: 0.23±0.17, 1.98± 1.09, 0.31±0.16 and 1.11±0.56 mg/dL in Veh, Veh+Cis, PF and PF+Cis, respectively, p=0.02). Western blot analysis revealed that increased kidney injury molecule-1 (KIM-1) levels in kidney tissue of Veh-mice by cisplatin were reduced in PF-treated mice (2-fold increase vs. 1.1-fold in Veh+Cis vs. PF+Cis compared to the Veh-mice, respectively, p=0.04). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay showed that PF+Cis mice displayed enhanced AEA tone compared with Veh+Cis mice (1.3-fold increase vs. 2.9-fold in Veh+Cis vs. PF+Cis compared to the Veh-mice, respectively, p=0.03). These results suggest that the renal protection from oral gavage of the FAAH inhibitor against cisplatin nephrotoxicity may be associated with enhanced tone of AEA and that pharmacological inactivation of FAAH could be a novel strategy to prevent cisplatin-induced AKI. NIH grant R01HL145163 and P30DA033934 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.
Acceleration of artery stiffness during childhood obesity in mice lacking lysosomal acid ceramidase
Authors: Zhang Fan , Zhang Fan , Yuan Xinxu , Li Guangbi , Zou Yao , Bhat Owais , Li Pin-Lan 
Published: May 2023

Childhood obesity imposes significant risks of cardiovascular diseases in adulthood and the late life. Our previous studies found that the arterial calcification was developed in Asah1fl/fl/SMcre mice, a mouse model whose lysosomal acid ceramidase was tissue-specifically knocked out in smooth muscle cells. The present study was designed to investigate whether there occurred arterial stiffness, an early pathological event prior to the arterial calcification, and explore the underling mechanism in Asah1fl/fl/SMcre mice at their young age. The young obesity mice were generated by starting with feeding mother mice with high fat diet (HFD) during their gestation and lactation, followed by putting pups on HFD for 6 weeks after weaning. The arterial stiffness was assessed in vivo by pulse wave velocity (PWV) method using the ultrasound to measure velocity of arterial waveform traveling along the aorta. It was found that PWV was significantly increased, an indication of elevated arterial stiffness, in young obese Asah1fl/fl/SMcre mice than wild type mice. In the isolated aorta using wire and pressure myography, young obese Asah1fl/fl/SMcre mice were found to have much steeper force-diameter curve from wire myography, but much smaller maximal increases in aorta diameter compared to WT controls in pressure myography. To explore the mechanisms accelerating arterial stiffness in young obese Asah1fl/fl/SMcre, integrins level and their adhesion to fibronectin were examined. Immunohistochemistry showed that the aortic integrin staining significantly increased in the aorta from young obese Asah1fl/fl/SMcre mice. Confocal microscopy demonstrated that the colocalization coefficient of integrin with fibronectin was also markedly enhanced in the aorta from young obese Asah1fl/fl/SMcre mice. This increased integrin staining and integrin-fibronectin interactions were markedly attenuated when young obese Asah1fl/fl/SMcre mice were treated with amitriptyline (a lysosomal function enhancer), rapamycin (a lysosomal function enhancer) or ML-SA5 (a lysosomal TRP-ML1 channel agonist). In primary cultures of aortic smooth muscle cells (ASMCs) from Asah1fl/fl/SMcre mice, the recycling rates of integrin (labeled with Alexa 488 integrin antibody) to the cell membrane (stained with Alexa 594-wheat germ agglutinin) was shown markedly elevated in response to visfatin, compared to those ASMCs from WT mice. These results strongly suggest that the deficiency of lysosomal acid ceramidase accelerates arterial stiffness in young obese mice, which may be associated with enhanced integrin recycling back to cell membrane of ASMCs. Supported by NIH grants HL057244 and HL075316 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.