Physiology最新文献

{"title":"Mosaic Loss of Y Chromosome in White Blood Cells: Its Impact on Men's Health.","authors":"Soichi Sano, Mark C Thel, Kenneth Walsh","doi":"10.1152/physiol.00008.2023","DOIUrl":"10.1152/physiol.00008.2023","url":null,"abstract":"<p><p>We present a brief introduction of loss of Y chromosome (LOY) in blood and describe the known risk factors for this condition. We then overview the associations between LOY and age-related disease traits. Finally, we discuss murine models and the potential mechanisms by which LOY contributes to disease.</p>","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"38 4","pages":"0"},"PeriodicalIF":5.3,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10281780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9705887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systemic Reprogramming of Endothelial Cell Signaling in Metastasis and Cachexia.","authors":"Stephanie F Preuss,&nbsp;Denise Grieshober,&nbsp;Hellmut G Augustin","doi":"10.1152/physiol.00001.2023","DOIUrl":"https://doi.org/10.1152/physiol.00001.2023","url":null,"abstract":"<p><p>Proliferating cancer cells secrete a multitude of factors impacting metabolism, interorgan communication, and tumor progression. The distribution of tumor-derived factors to distant organs occurs via the circulation, which provides an extensive reactive surface lined by endothelial cells. Primary tumor-derived proteins impact cancer progression by modulating endothelial cell activation at the (pre-)metastatic niche, which affects tumor cell dissemination as well as the outgrowth of seeded metastatic cells into overt tumors. In addition, new insight indicates that endothelial cell signaling contributes to metabolic symptoms of cancer, including cancer-associated cachexia, opening a new field of vascular metabolism research. This review addresses how tumor-derived factors systemically affect endothelial cell signaling and activation and impact distant organs as well as tumor progression.</p>","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"38 4","pages":"0"},"PeriodicalIF":8.4,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10281790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9710402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exertional heart stroke causes long-term obesity and cardiac hypertrophy in mice","authors":"Jamal M. Alzahrani, Bryce J Gambino, C. Delgado, Michael T. Rua, Iris Young, Kevin J. Cusack, T. Clanton","doi":"10.1152/physiol.2023.38.s1.5733420","DOIUrl":"https://doi.org/10.1152/physiol.2023.38.s1.5733420","url":null,"abstract":"Exertional heat stroke (EHS) is a life-threatening illness that can lead to short- and long-term adverse health outcomes. Several human epidemiology studies have shown that heat stroke exposure is highly associated with the development of cardiovascular disease later in life. However, whether EHS causes heart disease or individuals with predispositions to heart disease are more susceptible to EHS is unknown. Previously, our laboratory demonstrated metabolic abnormalities in the myocardium of mice, two weeks after EHS, characterized by lipid accumulation. In this study, we hypothesized that EHS exposure in mice leads to long-term susceptibilities to cardiovascular disease that is accelerated by co-exposure to a Western diet. METHODS: Sixty-four male (n=32) and female (n=32) C57BL/6 mice were exposed to either EHS (forced wheel running in 34.5°C for males and 37.5°C for females) or sham exercise controls (EXC, forced wheel running in ~22.5°C). Fourteen days later, mice were placed on either a Western diet (WD) or a standard diet (SD) and then followed for 9 additional weeks. At week 12, post interventions (EHS or EXC), animals were euthanized and samples collected for analysis. RESULTS: Male mice exposed to EHS with either WD ( P = 0.0001) or SD ( P = 0.0001) gained more body mass over the 9-week diet period compared to diet matched EXC controls. Also, regardless of diet, male mice exposed to EHS consumed more food compared to matched EXC (WD: P < 0.005 and SD: P < 0.04). However, only female mice exposed to EHS with WD gained more body mass compared to female EXC mice with WD ( P < 0.04). At the end of the study, and regardless of diet, male mice exposed to EHS showed enlarged hearts in terms of absolute mass (WD: P=0.0241, SD: P=0.0069) and relative mass/tibia length (WD: P=0.013, SD P=0.03). On the other hand, EHS female mice exposed to WD showed enlarged heart mass compared to EHS on SD ( P=0.0005). CONCLUSIONS: These results demonstrate that EHS exposure in mice leads to a long-term metabolic disorder characterized by greatly accelerated weight gain, greater appetite and cardiac hypertrophy. Effects were more evident and consistent in males. Such a response is typical of early stages of metabolic syndrome and would likely contribute to eventual cardiac disease. Therefore, the data is consistent with EHS exposure being a risk factor for long term heart disease. U.S. Army Grant BA180078 and from King Saud University, Saudi Arabia 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.","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"16 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90243300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improved workflow for analysis of smooth muscle calcium signals from intact arterial preparations","authors":"Madison Boskind, Nikitha Nelapudi, Grace Williamson, Rucha Juarez, Bobby Mendez, Lubo Zhang, A. Blood, Christopher Wilson, S. Wilson","doi":"10.1152/physiol.2023.38.s1.5732992","DOIUrl":"https://doi.org/10.1152/physiol.2023.38.s1.5732992","url":null,"abstract":"Intracellular Ca2+ signals are well regarded for their regulation of cellular processes ranging from myocyte contraction, hormonal secretion, neural transmission, cellular metabolism, transcriptional regulation, and cell proliferation. Measurement of cellular Ca2+ is routinely performed using fluorescent microscopy techniques with biological indicators. Analysis of deterministic signals is relatively straightforward as relevant data can be discriminated based on the timing of cellular responses. However, analysis of stochastic events in complex tissues takes considerable time and effort that often includes visual analysis by trained investigators. The purpose of the current study was to determine if the image analysis workflow could be automated without introducing errors. This evaluation was addressed by re-analyzing a published “gold standard” dataset through visual analysis of Ca2+ signals from recordings made in pulmonary arterial myocytes of en face arterial preparations. We applied a combination of data-driven and statistical approaches with comparisons to our published data to assess the fidelity of the various approaches. Regions of interest with Ca2+ oscillations were detected automatically post-hoc using the LC Pro plug-in for ImageJ. Oscillatory signals were separated based on event durations between 4 and 40 seconds. These data were filtered based on cutoffs obtained from multiple methods and compared to the published manually curated “gold standard” dataset. After filtering, the number of true positives, false positives, and false negatives were calculated through comparisons to the gold standard dataset. Positive predictive value, sensitivity and false discovery rates were calculated. There were very few significant differences between the quality of the events and no systematic biases based on the data curation or filtering techniques. The lack of difference between manual data curation and statistically derived critical cutoff techniques leads us to question the importance of manually curating stochastic Ca2+ event datasets using labor-intensive visual observation techniques. NIH R01HL155295, R01HL149608 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.","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"4 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90284859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell-free hemoglobin-mediated oxidation of low-density lipoprotein (oxLDL) contributes to lung microvascular endothelial dysfunction during sepsis","authors":"J. Meegan, L. Ware, J. Bastarache","doi":"10.1152/physiol.2023.38.s1.5728289","DOIUrl":"https://doi.org/10.1152/physiol.2023.38.s1.5728289","url":null,"abstract":"Introduction: Disruption of the microvascular endothelial barrier is a critical pathological feature of sepsis-induced acute lung injury. Plasma cell-free hemoglobin (CFH) is elevated in approximately 80% of patients with sepsis and is independently associated with development of acute respiratory distress syndrome (ARDS) and mortality. Oxidized CFH (ferric, 3+) can oxidize low-density lipoprotein (oxLDL), which signals through its major endothelial receptor, the lectin-like oxidized LDL receptor 1 (LOX-1), to cause endothelial dysfunction through several pro-inflammatory pathways including activation of mitogen-activated protein kinases (MAPKs). However, little is known regarding whether LOX-1 receptor signaling leads to microvascular endothelial hyperpermeability or acute lung injury, especially in the context of sepsis. We hypothesized that oxidation of LDL by CFH contributes to lung microvascular endothelial barrier dysfunction and worse outcomes during sepsis through LOX-1 and downstream p38 MAPK. Methods: To test whether generation of oxLDL by CFH is associated with endothelial injury in clinical sepsis, circulating levels of CFH, oxLDL, and vascular injury marker sVE-cadherin were measured in 24 sepsis patients via ELISA and tested for association with development of ARDS. LDL was oxidized by combining LDL with CFH in a test tube overnight at 37°C and oxLDL was quantified by TBARS assay. In primary human lung microvascular endothelial cells (HLMVEC) transendothelial electrical resistance (TER), a measure of barrier dysfunction, was assessed by Electric Cell-substrate Impedance Sensing (ECIS). LOX-1 receptor was blocked using BI-0115 (Boehringer Ingelheim, 20 μM) and p38 MAPK was inhibited using NiPp (100 μM). Results: In sepsis patients, plasma oxLDL levels correlated with CFH (r=0.686, p=0.016) and sVE-cadherin (r=0.603, p=0.012), and tended to be higher in those who developed ARDS (38 U/L [IQR 27, 45] vs. 27 U/L [IQR 19, 35], p=0.1). Oxidation of LDL by CFH exacerbated HLMVEC barrier dysfunction compared to control, LDL, or CFH. Barrier dysfunction induced by CFH or oxLDL was attenuated by blocking the LOX-1 receptor or p38 MAPK. Conclusions: Increased plasma CFH and oxLDL are associated with vascular injury during clinical sepsis; one mechanism by which CFH may cause vascular hyperpermeability and sepsis-mediated lung injury is through oxidation of LDL which can drive signaling through the endothelial LOX-1 receptor and activation of p38 MAPK. NIH R35HL150783, R21GM144915, R01HL158906, R01HL164937, T32HL094296; Parker B. Francis Fellowship 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.","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"78 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90360074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Arterial and Intracranial Hypotension During and Following Exercise","authors":"L. Petersen","doi":"10.1152/physiol.2023.38.s1.5793685","DOIUrl":"https://doi.org/10.1152/physiol.2023.38.s1.5793685","url":null,"abstract":"Exercise induced arterial hypertension and post-exercise arterial hypotension (PEH) are well-described phenomena with direct impact on cerebral blood flow. Cerebral perfusion pressure is given by the difference between mean arterial pressure at brain-level (MAPbrain) and intracranial pressure (ICP), however, little is known about effects of moderate aerobic exercise on ICP. We hypothesize that moderate exercise does not increase ICP thereby facilitating the augmented cerebral blood flow and that a post-exercise decrease in ICP is a contributing mechanism to maintained cerebral blood flow during PEH.Non-invasive (N=14) and invasive (N=3) ICP recordings and cardiovascular parameters were measured upright and supine before, during, and after 30 minutes of seated moderate aerobic bicycle exercise. Exercise elevated MAPbrain from 68±4 to 82±7 mmHg (mean±SEM, P<0.05) without elevating ICP, thus increasing CPP (72±3 to 87±6 mmHg, P<0.05). Compared to before exercise, we found significant PEH with a decrease in MAPbrain of 5±3% (5 mmHg; P<0.05), predominantly driven by a 26±5% (P<0.0001) decrease in total peripheral resistance (TPR). Because post-exercise ICP decreased concomitantly by 58±20% (P<0.0001) CPP remained unchanged. Recovery of ICP towards baseline was similarly correlated to TPR-recovery (R2=0.92, P<0.001), all variables returned to baseline within one hour.Here, we show for the first time ICP during and following aerobic exercise and consequences for cerebral perfusion. Periodic PEH is cardio-vascular protective and has long-term benefits for hypertensive patients, here we suggest that post-exercise decreases in ICP could similarly be cerebo-protective and in part explain the long-term beneficial effects of exercise for cerebral health and cognition. This work was supported by NASA grant no 80NSSC19K0020 and the Novo Nordic Foundation grant no NNF15OC0019196 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.","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"20 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90371064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KNDy innervation of MCH neurons modulates sleep in an estradiol-dependent manner","authors":"Bethany G Beekly, Katherine Furman, C. Burgess, C. Elias","doi":"10.1152/physiol.2023.38.s1.5732862","DOIUrl":"https://doi.org/10.1152/physiol.2023.38.s1.5732862","url":null,"abstract":"Levels of circulating gonadal hormones, including estrogens, affect both subjective and objective measures of sleep quality. However, the mechanisms linking sex variables to sleep architecture are incompletely understood. One brain region known to be potently regulated by circulating levels of estradiol is the arcuate nucleus of the hypothalamus (ARH). In particular, ARH neurons containing the trio of neuropeptides kisspeptin, neurokinin B (NKB), and dynorphin (“KNDy neurons”) express ERα and are well-known to respond to estradiol. We sought to determine whether ARH KNDy neurons are implicated in estrogenic effects on sleep.Melanin-concentrating hormone (MCH) neurons of the lateral hypothalamus are established regulators of sleep. A subset of MCH neurons also express the NKB receptor, NK3R, and are innervated by NKB immunoreactive fibers. Thus, we hypothesized that ARH KNDy neurons modulate sleep architecture in an estradiol-dependent manner via NKB signaling to NK3R-expressing MCH neurons. To test this hypothesis, we employed optogenetic stimulation in the LHA of female Kiss1-Cre;ChR2-eYFP transgenic mice, which express channelrhodopsin in kisspeptin-expressing neurons, to activate KNDy neuron terminals apposing MCH-expressing cells.We recorded sleep via electroencephalogram (EEG) with and without optogenetic stimulation in a randomized-crossover design. Adult ovariectomized female mice with and without estradiol replacement were used (“OVX and OVX+E2 mice”). Each mouse was recorded under both conditions to minimize the effects of individual variation, with the first condition (i.e., with vs without estradiol implant) randomly assigned. EEG data were first evaluated using a semiautomated scoring algorithm and then manually checked. These steps were performed by at least two different researchers to ensure accurate, reproducible scoring.During the light phase, when sleep pressure is highest for mice, stimulation of KNDy terminals in the LHA caused OVX females to spend more time awake, primarily at the expense of rapid-eye movement (REM) sleep. Conversely, OVX+E2 females exhibited reduced wakefulness when KNDy neuron terminals were stimulated. This corresponded to increases to both REM and non-REM sleep. During the dark phase, the reverse phenotype was observed. Optogenetic stimulation caused OVX females to spend less time awake and more time in both REM and non-REM sleep during the dark phase, while it resulted in OVX+E2 females spending more time awake at the expense of both REM and non-REM sleep. Taken together, these data suggest that the activation of KNDy neuron terminals in the LHA affects sleep in manner determined by both circulating estrogens and circadian rhythms. (NIH) Grants R01HD069702, R01HD096324; T32HD079342, F31HD102160; 1R01DK129366-01, the Michigan Diabetes Research Center Pilot and Feasibility Award, and the Whitehall Foundation New Investigator Grant #2018-08-50 This is the full abstract presented at the American Physiology S","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"57 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90883904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex differences in central airway luminal area among people with interstitial lung disease","authors":"A. Miller, Erik A. Ovrom, J. Senefeld, C. Wiggins, P. Dominelli, Michael J. Joyner, B. Welch, A. Ramsook","doi":"10.1152/physiol.2023.38.s1.5731276","DOIUrl":"https://doi.org/10.1152/physiol.2023.38.s1.5731276","url":null,"abstract":"Background: Interstitial lung disease (ILD) encompasses several pulmonary disorders associated with scarring and fibrosis of pulmonary tissue. People with idiopathic pulmonary fibrosis, a subset of ILD, have greater central airway luminal area compared to age- and sex-matched healthy controls when evaluated using microcomputed tomography, a process examining the luminal area of ex-vivo lung tissue. In this study we aimed to confirm these findings using a different method of airway assessment, three-dimensional (3D) reconstruction of computed tomography (CT) scans. Moreover, in health, males have larger central airways than height-matched females, but it remains unknown if there are sex differences in airway area among people with ILD. We hypothesized that sex differences observed in healthy people would persist among people with ILD. Methods: A cohort of 399 patients with lung CT scans were screened, of which 19 people (7 females) with ILD were included in analyses after exclusions. People with ILD were matched based on sex, age, and height to 19 healthy controls. We assessed cross-sectional luminal area at the midpoint of seven conducting airways (trachea, left and right main bronchus, intermediate bronchus, left and right upper lobe, and left lower lobe). Results from pulmonary function tests were also abstracted, as available. To examine sex differences, we compared airway luminal area, normalized to participant height, between males and females with ILD. Sex differences were analyzed using a univariate ANOVA test. Results: People with ILD had a preserved ratio of forced expiratory volume in the first second to forced vital capacity (101 ±12%predicted) and decreased diffusing capacity for carbon monoxide (55 ±23%predicted). People with ILD had airways that were between 19.6%-45.0% larger than controls (p&lt;0.05). Composite physiologic index, a marker of ILD severity, was not different between sexes (p=0.07). Males with ILD had significantly larger, luminal areas than females in two central airways - right main bronchus (1.46±0.41 vs. 1.07±0.22 mm2/cm, p=0.04) and left upper lobe (0.54±0.10 vs. 0.43±0.08 mm2/cm, p=0.02). However, luminal area of other central airways, including: trachea (2.15±0.57 vs. 1.65±0.32 mm2/cm, p=0.051), bronchus intermediate (0.77±0.23 vs. 0.61±0.13 mm2/cm, p=0.12), right upper lobe (0.47±0.15 vs. 0.40±0.06 mm2/cm, p=0.26), left main bronchus (0.93±0.33 vs. 0.69±0.16 mm2/cm, p=0.09), and left lower lobe (0.41±0.13 vs. 0.40±0.08 mm2 /cm, p=0.79) were not different between sexes in people with ILD. Conclusion: Sex differences observed in healthy people are potentially preserved in ILD, but a more robust sample is required to fully elucidate these findings. Illuminating any sex differences in ILD pathophysiology may provide knowledge to treat and improve clinical outcomes in ILD. Funding: National Heart, Lung, and Blood Institute (F32HL154320 to JWS; 5R35HL139854 to MJJ). This is the full abstract presented at the American ","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"82 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90884049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vitamin D Receptor Attenuates Osteo-sarcopenia by Suppressing the Ferroptosis","authors":"Wenxiong Li, Fei-Fei Chen, Kuaiqiang Zhang, Zhiping Sun, Yan Zhang, Feng Yang","doi":"10.1152/physiol.2023.38.s1.5731132","DOIUrl":"https://doi.org/10.1152/physiol.2023.38.s1.5731132","url":null,"abstract":"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.","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"111 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91004508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dietary vitamin D supplementation partially rescues heart rate in Ts65Dn mice, a model of Down syndrome","authors":"K. Deruisseau, Silas Derfel, J. MacDonald, L. DeRuisseau","doi":"10.1152/physiol.2023.38.s1.5735207","DOIUrl":"https://doi.org/10.1152/physiol.2023.38.s1.5735207","url":null,"abstract":"Down syndrome is the most common developmental and intellectual disability that leads to co-morbidities including lower heart rate and blood pressure. We previously showed that Ts65Dn mice also display reduced heart rate and blood pressure compared to wild-type (WT) colony controls. Lower serum Vitamin D (VitD) levels have been reported among individuals with Ds. In other populations, VitD is a regulator of nitric oxide synthase and a known modulator of cardiovascular outcomes. VitD effects on cardiovascular physiology in Ds is unknown. In this preliminary study, we hypothesized that Ts65Dn mice supplemented with VitD would display improved heart rate compared to Ts65Dn mice on a control diet. Two-month old male Ts65Dn mice were placed onto a control diet (1IU VitD/g; n=4) or VitD supplemented diet (50IU/g; n=5) for two weeks and subsequently tested for resting heart rate. Mice were fitted with a MouseOx neck collar to monitor heart rate while freely moving within the cage. After habituation to the collar, heart rate was recorded for 30 minutes in the light cycle. Heart rate in Ts65Dn on the control diet was 510±67 bpm vs. 636±78 on the VitD diet (p=.038; t-test). As expected, WT (n=5; control diet) displayed a higher heart rate of 729±62 bpm. These preliminary data reveal a partial rescue of resting heart rate in Ts65Dn following VitD supplementation. Future studies can evaluate serum VitD levels, nitric oxide synthase, and cardiovascular metrics including blood pressure, heart rate, and pulse wave velocity in Ts65Dn and WT mice supplemented with dietary VitD. This work was supported by NIH R21HD099573 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.","PeriodicalId":49694,"journal":{"name":"Physiology","volume":"1 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91036295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}