Pub Date : 2024-05-01DOI: 10.1152/physiol.2024.39.s1.1245
Clay Weidenhamer, Adam Syed, Yi-Heng Huang, Diego Hernancez-Saavedra
The benefits of exercise on metabolic health and its effectiveness at reducing morbidity risk are well established. Exercise training enhances skeletal muscle metabolism and function, but whether such adaptations persist through detraining and how they are potentiated with retraining are not well understood. Recent evidence has highlighted the role sphingolipids play on skeletal muscle size and function, but how exercise affects sphingolipid metabolism is not yet known. We hypothesize that alterations in skeletal muscle sphingolipid metabolism with exercise training are necessary to enhance muscle mass with further exercise retraining. Here, mice were SEDentary (SED; static cages) or exercise-TRAINed (TRAIN; voluntary wheel running) and chow-fed. We performed body composition analysis (using EchoMRI) and skeletal muscle collection [tibialis anterior ( TA), extensor digitorum longus ( EDL), gastrocnemius ( Gas), Soleus ( Sol), plantaris ( Plant), and levator ani ( LA)] following training (4wks), detraining (8wk), and retraining (12wk) in three independent cohorts. Sphingolipid and myogenic gene expression was measured in TA muscle by qPCR. Exercise training concomitantly increased lean and decreased fat percentage ( p<0.05), while increasing Sol muscle mass in TRAIN mice ( p<0.05), compared to SED. This was accompanied by higher sphingolipid metabolism ( Acer1, p<0.05; and Cers1, p=0.058) and myogenic gene expression ( MyoD, Myf5; p<0.05). Following detraining, TRAIN mice had an overall increase in lean-to-fat mass ( p<0.05) while maintaining all individual muscle masses ( p<0.05), compared to SED. This was accompanied by a reduction in gene expression of the sphingolipid receptor S1pr1 and myogenic factor Myf5 ( p<0.05), but no differences in sphingolipid metabolism ( Acer1, Cers1). Lastly, retraining increased lean and decreased fat percentage ( p<0.05) and enhanced the masses of TA, Gas, Sol, and Plant muscles in TRAIN mice ( p<0.05), compared to SED. This was accompanied by a reduced expression of rate limiting sphingolipid synthesis genes Sptlc1 and Sptlc2 and the kinase Sphk1 ( p<0.05), but no differences in Cers1 or myogenic gene expression in TRAIN mice, compared to SED. Overall, our data shows that exercise training and retraining potentiate muscle mass accretion and dynamically regulates sphingolipid metabolism adaptations. These data suggest a potential role for sphingolipids to modulate long-lasting improvements to skeletal muscle. 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.
运动对新陈代谢健康的益处及其降低发病风险的功效已得到公认。运动训练能增强骨骼肌的新陈代谢和功能，但这种适应性是否会在脱离训练后持续存在，以及如何通过再训练增强这种适应性，目前尚不十分清楚。最近的证据强调了鞘脂对骨骼肌大小和功能的作用，但运动如何影响鞘脂代谢尚不清楚。我们假设，骨骼肌鞘脂代谢在运动训练中的改变是进一步运动再训练增强肌肉质量所必需的。在此，我们对小鼠进行了静止（SED；静态笼养）或运动训练（TRAIN；自愿轮跑），并喂食饲料。在训练（4 周）、脱离训练（8 周）和再训练（12 周）后，我们对三个独立队列的小鼠进行了身体成分分析（使用 EchoMRI）和骨骼肌收集[胫骨前肌（TA）、伸肌（EDL）、腓肠肌（Gas）、Soleus（Sol）、足底肌（Plant）和提肌（LA）]。通过 qPCR 测量了 TA 肌肉中鞘脂类和肌源性基因的表达。与 SED 相比，运动训练同时增加了瘦肉率，降低了脂肪率（p<0.05），同时增加了 TRAIN 小鼠的肌肉质量（p<0.05）。与此同时，鞘脂代谢（Acer1，p<0.05；Cers1，p=0.058）和生肌基因表达（MyoD、Myf5；p<0.05）也有所提高。与 SED 小鼠相比，脱训练后，TRAIN 小鼠的瘦肉-脂肪质量总体增加（p<0.05），而所有单个肌肉质量保持不变（p<0.05）。与此同时，鞘脂受体 S1pr1 和肌生成因子 Myf5 的基因表达量减少（p<0.05），但鞘脂代谢（Acer1、Cers1）没有差异。最后，与 SED 相比，再训练提高了 TRAIN 小鼠的瘦肉率，降低了脂肪率（p<0.05），并提高了 TA、Gas、Sol 和 Plant 肌肉的质量（p<0.05）。同时，与 SED 相比，TRAIN 小鼠中限制鞘脂合成速率的基因 Sptlc1 和 Sptlc2 以及激酶 Sphk1 的表达量减少（p<0.05），但 Cers1 或肌源性基因的表达量没有差异。总之，我们的数据表明，运动训练和再训练可促进肌肉质量的增加，并动态调节鞘脂代谢的适应性。这些数据表明，鞘脂具有调节骨骼肌长期改善的潜在作用。经费由伊利诺伊大学香槟分校提供。本文是在 2024 年美国生理学峰会上发表的摘要全文，仅提供 HTML 格式。本摘要没有附加版本或附加内容。生理学》未参与同行评审过程。
{"title":"Alterations in sphingolipid synthesis during training, detraining, and retraining may alter myogenesis in skeletal muscle","authors":"Clay Weidenhamer, Adam Syed, Yi-Heng Huang, Diego Hernancez-Saavedra","doi":"10.1152/physiol.2024.39.s1.1245","DOIUrl":"https://doi.org/10.1152/physiol.2024.39.s1.1245","url":null,"abstract":"The benefits of exercise on metabolic health and its effectiveness at reducing morbidity risk are well established. Exercise training enhances skeletal muscle metabolism and function, but whether such adaptations persist through detraining and how they are potentiated with retraining are not well understood. Recent evidence has highlighted the role sphingolipids play on skeletal muscle size and function, but how exercise affects sphingolipid metabolism is not yet known. We hypothesize that alterations in skeletal muscle sphingolipid metabolism with exercise training are necessary to enhance muscle mass with further exercise retraining. Here, mice were SEDentary (SED; static cages) or exercise-TRAINed (TRAIN; voluntary wheel running) and chow-fed. We performed body composition analysis (using EchoMRI) and skeletal muscle collection [tibialis anterior ( TA), extensor digitorum longus ( EDL), gastrocnemius ( Gas), Soleus ( Sol), plantaris ( Plant), and levator ani ( LA)] following training (4wks), detraining (8wk), and retraining (12wk) in three independent cohorts. Sphingolipid and myogenic gene expression was measured in TA muscle by qPCR. Exercise training concomitantly increased lean and decreased fat percentage ( p<0.05), while increasing Sol muscle mass in TRAIN mice ( p<0.05), compared to SED. This was accompanied by higher sphingolipid metabolism ( Acer1, p<0.05; and Cers1, p=0.058) and myogenic gene expression ( MyoD, Myf5; p<0.05). Following detraining, TRAIN mice had an overall increase in lean-to-fat mass ( p<0.05) while maintaining all individual muscle masses ( p<0.05), compared to SED. This was accompanied by a reduction in gene expression of the sphingolipid receptor S1pr1 and myogenic factor Myf5 ( p<0.05), but no differences in sphingolipid metabolism ( Acer1, Cers1). Lastly, retraining increased lean and decreased fat percentage ( p<0.05) and enhanced the masses of TA, Gas, Sol, and Plant muscles in TRAIN mice ( p<0.05), compared to SED. This was accompanied by a reduced expression of rate limiting sphingolipid synthesis genes Sptlc1 and Sptlc2 and the kinase Sphk1 ( p<0.05), but no differences in Cers1 or myogenic gene expression in TRAIN mice, compared to SED. Overall, our data shows that exercise training and retraining potentiate muscle mass accretion and dynamically regulates sphingolipid metabolism adaptations. These data suggest a potential role for sphingolipids to modulate long-lasting improvements to skeletal muscle. 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.","PeriodicalId":49694,"journal":{"name":"Physiology","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141134363","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}
Pub Date : 2024-05-01DOI: 10.1152/physiol.2024.39.s1.1384
Eduardo Freitas, Lori Roust, Eleanna Defilippis, Christos Katsanos
Changes in circulating insulin-like growth factor 1 (IGF-1) implicate regulation of skeletal muscle metabolism, including protein and glucose metabolism. Previous studies have shown that an acute bout of exercise increases serum IGF-1 concentrations in healthy, lean humans. However, exercise-induced changes in serum IGF-1 concentrations in humans with obesity remain unknown. We compared changes in plasma IGF-1 during and after an acute bout of endurance exercise between humans with and without obesity. Eight subjects with obesity (i.e., OB: BMI = 34.48 ± 2.96) and eight subjects without obesity (i.e., LN: BMI = 24.45 ± 2.43 kg/m2) exercised for 45 min in a cycle ergometer at 65% of their maximum oxygen uptake, after an overnight 10-h fast. Blood draws were taken immediately before exercise, at 15 and 30 minutes (i.e., during exercise), and at 55, 75, 95, and 115 minutes after the start of the exercise. Serum concentrations of total IGF-1 and insulin were determined using commercially available ELISA assays (Alpco 22-IGFHU-E01 and 80-INSHU-E10.1, respectively). Plasma glucose concentrations were determined using an automatic analyzer (YSI glucose analyzer). One-way repeated measures analyses of variance were carried out to detect significant changes over time within each group. Independent t tests were used to determine group differences at each time point. Alpha level was set at p ≤ 0.05 and data are reported as mean ± SD. There were no significant ( p > 0.05) differences between groups for IGF-1 serum concentrations at baseline (LN = 205.61 ± 40.07 ng/mL, OB = 200.89 ± 80.40 ng/mL) nor during or after exercise. Significant increases from baseline in serum IGF-1 concentrations were detected in the LN group at 15 min (231.30 ± 50.47 ng/mL, p = 0.007) and 30 min (227.94 ± 49.02 ng/mL, p = 0.04) during exercise, followed by significant decreases from baseline at 95 min (189.99 ± 34.73 ng/mL, p = 0.052) and 115 min (196.42 ± 40.39 ng/mL, p = 0.023). No significant ( p > 0.05) differences from baseline were observed in the obese group neither during nor after exercise. Higher serum insulin concentrations were observed in the OB group at baseline (LN = 5.55 ± 2.62 μIU/mL, OB = 11.07 ± 5.76 μIU/mL, p = 0.027) but significant group differences no longer existed ( p > 0.05) during exercise and up to 55 min after exercise; however, insulin concentrations for the OB group were significantly greater than those measured in the LN group at 75 min ( p = 0.028), 95 min ( p = 0.008), and 115 min ( p = 0.007) after exercise. Moreover, a significant increase from baseline was measured 55 min after exercise in the lean group (8.22 ± 3.13 μIU/mL, p = 0.005), whereas no significant changes were observed in the OB groups at any time point ( p > 0.05). No significant ( p > 0.05) group differences were detected for plasma glucose concentrations at any time point, and despite a significant decrease from baseline observed in the LN group at 115 min after exercise (baseline
{"title":"Impaired exercise-induced increase in serum IGF-1 in humans with obesity","authors":"Eduardo Freitas, Lori Roust, Eleanna Defilippis, Christos Katsanos","doi":"10.1152/physiol.2024.39.s1.1384","DOIUrl":"https://doi.org/10.1152/physiol.2024.39.s1.1384","url":null,"abstract":"Changes in circulating insulin-like growth factor 1 (IGF-1) implicate regulation of skeletal muscle metabolism, including protein and glucose metabolism. Previous studies have shown that an acute bout of exercise increases serum IGF-1 concentrations in healthy, lean humans. However, exercise-induced changes in serum IGF-1 concentrations in humans with obesity remain unknown. We compared changes in plasma IGF-1 during and after an acute bout of endurance exercise between humans with and without obesity. Eight subjects with obesity (i.e., OB: BMI = 34.48 ± 2.96) and eight subjects without obesity (i.e., LN: BMI = 24.45 ± 2.43 kg/m2) exercised for 45 min in a cycle ergometer at 65% of their maximum oxygen uptake, after an overnight 10-h fast. Blood draws were taken immediately before exercise, at 15 and 30 minutes (i.e., during exercise), and at 55, 75, 95, and 115 minutes after the start of the exercise. Serum concentrations of total IGF-1 and insulin were determined using commercially available ELISA assays (Alpco 22-IGFHU-E01 and 80-INSHU-E10.1, respectively). Plasma glucose concentrations were determined using an automatic analyzer (YSI glucose analyzer). One-way repeated measures analyses of variance were carried out to detect significant changes over time within each group. Independent t tests were used to determine group differences at each time point. Alpha level was set at p ≤ 0.05 and data are reported as mean ± SD. There were no significant ( p > 0.05) differences between groups for IGF-1 serum concentrations at baseline (LN = 205.61 ± 40.07 ng/mL, OB = 200.89 ± 80.40 ng/mL) nor during or after exercise. Significant increases from baseline in serum IGF-1 concentrations were detected in the LN group at 15 min (231.30 ± 50.47 ng/mL, p = 0.007) and 30 min (227.94 ± 49.02 ng/mL, p = 0.04) during exercise, followed by significant decreases from baseline at 95 min (189.99 ± 34.73 ng/mL, p = 0.052) and 115 min (196.42 ± 40.39 ng/mL, p = 0.023). No significant ( p > 0.05) differences from baseline were observed in the obese group neither during nor after exercise. Higher serum insulin concentrations were observed in the OB group at baseline (LN = 5.55 ± 2.62 μIU/mL, OB = 11.07 ± 5.76 μIU/mL, p = 0.027) but significant group differences no longer existed ( p > 0.05) during exercise and up to 55 min after exercise; however, insulin concentrations for the OB group were significantly greater than those measured in the LN group at 75 min ( p = 0.028), 95 min ( p = 0.008), and 115 min ( p = 0.007) after exercise. Moreover, a significant increase from baseline was measured 55 min after exercise in the lean group (8.22 ± 3.13 μIU/mL, p = 0.005), whereas no significant changes were observed in the OB groups at any time point ( p > 0.05). No significant ( p > 0.05) group differences were detected for plasma glucose concentrations at any time point, and despite a significant decrease from baseline observed in the LN group at 115 min after exercise (baseline","PeriodicalId":49694,"journal":{"name":"Physiology","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141137977","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}
Pub Date : 2024-05-01DOI: 10.1152/physiol.2024.39.s1.1983
Breland F. Crudup, Jordan H Mallette, Harley S. Nabors, Alex Willis, Kathy L. Cockrell, Alexandre A da Silva, Licy L Yanes Cardozo
Transgender females (TGF) are individuals who are born biologically male, but identify as female. Gender-Affrming Hormone Therapy (GAHT), consisting of 17β-Estradiol (E2) supplementation with androgen suppression [i.e. castration (CTX)], is used in TGFs to match their physical characteristics with their perceived gender. Previously, we reported that E2+CTX in the normotensive male Sprague-Dawley (SD) rat is associated with a significant increase in E2 and decrease in testosterone, body weight, and lean mass. Whether GAHT enhances cardiac morbidity and mortality in the transgender population on GAHT relative to cisgender individuals is still unclear. Moreover, the sustained effect of high E2 coupled to androgen suppression in male rats on their cardiac morphology and function is unknown. Thus, this study tested the hypothesis that GAHT in the adult male SD rat is associated with impaired cardiac function under baseline conditions. Methods: Adult male SDs (13 weeks of age) were randomly assigned to either: Control or E2+CTX therapy (E2 at 5 mg/day, pellet sc, replaced every 3 weeks, with CTX performed at 15 weeks of age) (n=8/grp). Baseline cardiac function was measured via echocardiogram (VEVO 3100), body composition via EchoMRI. Results: at 28 weeks of age, total lean mass and body weight were significantly decreased in the E2+CTX group, as previously observed; total fat mass did not differ between groups. Heart rate was significantly decreased; yet, other indices of cardiac function were not altered at baseline. Although no major differences in baseline cardiac function were observed, the long-term impact of GAHT on CV health and the ability of the heart to respond to secondary challenges are unknown. This study is ongoing and further studies will determine the ability of the heart to recover from secondary insults in order to determine if GAHT in males is associated with increased CV risk. [Formula: see text] Funding sources: HL143459, P20-GM-104357, P20-GM121334, T32-HL105324. 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.
{"title":"Cross Sex Steroid Therapy and Baseline Cardiac Function in a Rodent Model of Gender Affrming Hormone Therapy in the Male Rat","authors":"Breland F. Crudup, Jordan H Mallette, Harley S. Nabors, Alex Willis, Kathy L. Cockrell, Alexandre A da Silva, Licy L Yanes Cardozo","doi":"10.1152/physiol.2024.39.s1.1983","DOIUrl":"https://doi.org/10.1152/physiol.2024.39.s1.1983","url":null,"abstract":"Transgender females (TGF) are individuals who are born biologically male, but identify as female. Gender-Affrming Hormone Therapy (GAHT), consisting of 17β-Estradiol (E2) supplementation with androgen suppression [i.e. castration (CTX)], is used in TGFs to match their physical characteristics with their perceived gender. Previously, we reported that E2+CTX in the normotensive male Sprague-Dawley (SD) rat is associated with a significant increase in E2 and decrease in testosterone, body weight, and lean mass. Whether GAHT enhances cardiac morbidity and mortality in the transgender population on GAHT relative to cisgender individuals is still unclear. Moreover, the sustained effect of high E2 coupled to androgen suppression in male rats on their cardiac morphology and function is unknown. Thus, this study tested the hypothesis that GAHT in the adult male SD rat is associated with impaired cardiac function under baseline conditions. Methods: Adult male SDs (13 weeks of age) were randomly assigned to either: Control or E2+CTX therapy (E2 at 5 mg/day, pellet sc, replaced every 3 weeks, with CTX performed at 15 weeks of age) (n=8/grp). Baseline cardiac function was measured via echocardiogram (VEVO 3100), body composition via EchoMRI. Results: at 28 weeks of age, total lean mass and body weight were significantly decreased in the E2+CTX group, as previously observed; total fat mass did not differ between groups. Heart rate was significantly decreased; yet, other indices of cardiac function were not altered at baseline. Although no major differences in baseline cardiac function were observed, the long-term impact of GAHT on CV health and the ability of the heart to respond to secondary challenges are unknown. This study is ongoing and further studies will determine the ability of the heart to recover from secondary insults in order to determine if GAHT in males is associated with increased CV risk. [Formula: see text] Funding sources: HL143459, P20-GM-104357, P20-GM121334, T32-HL105324. 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.","PeriodicalId":49694,"journal":{"name":"Physiology","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141138194","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}
Pub Date : 2024-05-01DOI: 10.1152/physiol.2024.39.s1.1795
Eunice Oribamise, An Xie, Johannes Bjorge, Satyabrata Das, Qinglu Li, Mary Garry
Introduction and rationale: The Exercise pressor reflex (EPR) is a physiological mechanism in which the contraction of skeletal muscle results in a rise in heart rate (HR) and mean arterial pressure (MAP). In patients with Peripheral Artery Disease (PAD), this reflex is exaggerated, leading to abnormally high elevations in blood pressure during exercise. These cardiovascular responses in patients with PAD have been linked to increased morbidity and mortality, thus limiting the prescription of exercise for these patients. Using a novel murine model of the EPR, our laboratory has demonstrated that mice with femoral artery ligation (a well-established model of PAD), exhibit augmented increases in MAP which is mediated by PIEZO2 positive, mechanosensitive afferent neurons. We have demonstrated that inhibition of PIEZO2 expressing channels normalizes the MAP response to exercise. Patients with PAD also display increased macrophage infiltration in their ischemia-injured limbs, indicating a pro-inflammatory environment. Sensory neurons have been reported to detect various signals produced by immune cells including IL-1β and TNFα. The immune-derived signals can sensitize the peripheral terminals of the sensory neurons, thereby reducing their firing threshold and increasing their responsiveness. Previous studies have also reported the enhancement of Piezo2-mediated mechanosensitive currents in the presence of inflammatory signals. Hypothesis: We, therefore, hypothesize that in mice with femoral artery ligation, muscle inflammation increases the expression and activation of resident ion channels (e.g., Piezo2) in mechanosensitive afferent neurons to mediate the exaggerated EPR in PAD.Study objective: To mechanistically investigate the interaction between muscle inflammation and Piezo2 in mechanosensitive afferent neurons.Methods: We performed sham surgery or ligation of the femoral artery ipsilaterally in C57BL/6 mice. After 72 hours, we harvested the gastrocnemius muscle for histological and molecular analyses.Data and summary and results: Our preliminary findings reveal that there is significantly increased expression of pro-inflammatory genes and infiltrating immune cells in the ischemic muscle when compared to non-ischemic muscle.Specifically, H&E staining revealed the presence and accumulation of inflammatory cells, including macrophages, in the ischemic muscle compared to control, along with observed necrosis. Transcript analysis of the ischemic gastrocnemius muscle showed significantly increased IL-1β and TNFα, two pan-proinflammatory genes that encode cytokines released by macrophages. TNFα is known to induce the synthesis of adhesion molecules (E-selectin and ICAM-1) on endothelial cells, allowing leukocytes to adhere and cross the endothelial wall into the injured tissue. Indeed, we observed significantly increased ICAM-1 and E-selectin transcripts in the ischemic muscle compared to controls. MCP1, a well-established chemokine, was also significa
{"title":"Neuro-inflammatory interactions as a mediator of the Exaggerated Exercise Pressor Reflex (EPR) in a mouse model of Peripheral Artery Disease","authors":"Eunice Oribamise, An Xie, Johannes Bjorge, Satyabrata Das, Qinglu Li, Mary Garry","doi":"10.1152/physiol.2024.39.s1.1795","DOIUrl":"https://doi.org/10.1152/physiol.2024.39.s1.1795","url":null,"abstract":"Introduction and rationale: The Exercise pressor reflex (EPR) is a physiological mechanism in which the contraction of skeletal muscle results in a rise in heart rate (HR) and mean arterial pressure (MAP). In patients with Peripheral Artery Disease (PAD), this reflex is exaggerated, leading to abnormally high elevations in blood pressure during exercise. These cardiovascular responses in patients with PAD have been linked to increased morbidity and mortality, thus limiting the prescription of exercise for these patients. Using a novel murine model of the EPR, our laboratory has demonstrated that mice with femoral artery ligation (a well-established model of PAD), exhibit augmented increases in MAP which is mediated by PIEZO2 positive, mechanosensitive afferent neurons. We have demonstrated that inhibition of PIEZO2 expressing channels normalizes the MAP response to exercise. Patients with PAD also display increased macrophage infiltration in their ischemia-injured limbs, indicating a pro-inflammatory environment. Sensory neurons have been reported to detect various signals produced by immune cells including IL-1β and TNFα. The immune-derived signals can sensitize the peripheral terminals of the sensory neurons, thereby reducing their firing threshold and increasing their responsiveness. Previous studies have also reported the enhancement of Piezo2-mediated mechanosensitive currents in the presence of inflammatory signals. Hypothesis: We, therefore, hypothesize that in mice with femoral artery ligation, muscle inflammation increases the expression and activation of resident ion channels (e.g., Piezo2) in mechanosensitive afferent neurons to mediate the exaggerated EPR in PAD.Study objective: To mechanistically investigate the interaction between muscle inflammation and Piezo2 in mechanosensitive afferent neurons.Methods: We performed sham surgery or ligation of the femoral artery ipsilaterally in C57BL/6 mice. After 72 hours, we harvested the gastrocnemius muscle for histological and molecular analyses.Data and summary and results: Our preliminary findings reveal that there is significantly increased expression of pro-inflammatory genes and infiltrating immune cells in the ischemic muscle when compared to non-ischemic muscle.Specifically, H&E staining revealed the presence and accumulation of inflammatory cells, including macrophages, in the ischemic muscle compared to control, along with observed necrosis. Transcript analysis of the ischemic gastrocnemius muscle showed significantly increased IL-1β and TNFα, two pan-proinflammatory genes that encode cytokines released by macrophages. TNFα is known to induce the synthesis of adhesion molecules (E-selectin and ICAM-1) on endothelial cells, allowing leukocytes to adhere and cross the endothelial wall into the injured tissue. Indeed, we observed significantly increased ICAM-1 and E-selectin transcripts in the ischemic muscle compared to controls. MCP1, a well-established chemokine, was also significa","PeriodicalId":49694,"journal":{"name":"Physiology","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141140605","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}
Pub Date : 2024-05-01DOI: 10.1152/physiol.2024.39.s1.1994
Alan de Araujo, Guillaume deLartigue, J. Zubcevic
Hypertension is associated with gut dysbiosis and autonomic dysfunction in humans and rodent models. While hypertension-associated gut dysbiosis elevates blood pressure in rodents, the precise mechanisms are unknown. In our model gut dysbiosis-induced hypertension, fecal matter transplant from hypertensive SHR reduced colonic serotonin and relative expression of serotonergic 5ht3a receptors (5ht3aRs) on vagal afferents in the control WKY rats. To investigate the role of serotonergic gut vagal axis in regulation of blood pressure, in a cre-dependent manner we first overexpressed channelrhodopsin 2 in the 5ht3aR-expressing gut-projecting vagal afferents (NG5ht3Ar) in 5ht3aR Cre rats. Acute bilateral optic stimulation of NG5ht3Ar produced an immediate decrease in blood pressure and heart rate. Conversely, chronic ablation of NG5ht3Ar by cre-dependent expression of caspase elevated blood pressure in 5ht3aR Cre rats. This effect was potentiated both by the infusion of low dose of angiotensin II and exposure to acute restraint stress separately. On the other hand, overexpression of 5ht3aRs in NG5ht3Ar reduced blood pressure in the SHR, the effect that was further potentiated by dietary tryptophan supplementation. Altogether, these data propose that hypertension-associated microbiota contribute to rodent hypertension via modulation of colonic serotonin and gut vagal 5ht3aRs. NIHR01HL152162. 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.
{"title":"Gut bacteria contribute to rodent hypertension via modulation of colonic serotonin and gut vagal 5ht3aRs","authors":"Alan de Araujo, Guillaume deLartigue, J. Zubcevic","doi":"10.1152/physiol.2024.39.s1.1994","DOIUrl":"https://doi.org/10.1152/physiol.2024.39.s1.1994","url":null,"abstract":"Hypertension is associated with gut dysbiosis and autonomic dysfunction in humans and rodent models. While hypertension-associated gut dysbiosis elevates blood pressure in rodents, the precise mechanisms are unknown. In our model gut dysbiosis-induced hypertension, fecal matter transplant from hypertensive SHR reduced colonic serotonin and relative expression of serotonergic 5ht3a receptors (5ht3aRs) on vagal afferents in the control WKY rats. To investigate the role of serotonergic gut vagal axis in regulation of blood pressure, in a cre-dependent manner we first overexpressed channelrhodopsin 2 in the 5ht3aR-expressing gut-projecting vagal afferents (NG5ht3Ar) in 5ht3aR Cre rats. Acute bilateral optic stimulation of NG5ht3Ar produced an immediate decrease in blood pressure and heart rate. Conversely, chronic ablation of NG5ht3Ar by cre-dependent expression of caspase elevated blood pressure in 5ht3aR Cre rats. This effect was potentiated both by the infusion of low dose of angiotensin II and exposure to acute restraint stress separately. On the other hand, overexpression of 5ht3aRs in NG5ht3Ar reduced blood pressure in the SHR, the effect that was further potentiated by dietary tryptophan supplementation. Altogether, these data propose that hypertension-associated microbiota contribute to rodent hypertension via modulation of colonic serotonin and gut vagal 5ht3aRs. NIHR01HL152162. 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.","PeriodicalId":49694,"journal":{"name":"Physiology","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141143519","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}
Pub Date : 2024-05-01DOI: 10.1152/physiol.2024.39.s1.2212
Kevin Volk, I. Baranovskaya, Alena Cherezova, V. Buncha, Sati Alexander, Nichole Mumuney, M. Mamenko
INTRODUCTION. Lithium (Li+) is an effective mood stabilizer that continues to be widely used in modern psychiatric practice. One of the most common adverse effects of Li+ therapy is nephrogenic diabetes insipidus manifesting in reduced urinary concentrating ability due to impaired vasopressin (AVP) signaling in the collecting duct principal cells. While distal tubular acidosis has also been reported in patients receiving Li+, molecular determinants underlying the pathophysiological effects of Li+ on the collecting duct intercalated cells and renal acid-base transport remain to be fully elucidated. Activation of Gq-coupled vasopressin 1a receptors (V1aR) in A-intercalated cells reportedly induces intracellular Ca2+ ([Ca2+]i) mobilization and stimulates luminal H+ secretion, resulting in urine acidification. OBJECTIVE. The objective of this study was to test if Li+ impaired V1aR-induced [Ca2+]i response in the intercalated cells of murine collecting ducts. HYPOTHESIS. We hypothesized that Li+ markedly impaired V1aR-dependent [Ca2+]i signaling in A-intercalated cells causing the reduction of luminal proton secretion in the collecting duct. METHODS. We combined immunofluorescent imaging in freshly isolated collecting duct segments with metabolic cage studies in C57BL/6NJ (Jackson Labotatory) mice receiving a regular Teklad 2918 chow (control) or a Teklad 2918-based diet containing 0.3% lithium carbonate (Li+-treated) to evaluate how Li+ affects V1aR-mediated [Ca2+]i signal, H+ transport by intercalated cells, as well as urinary pH and ammonia excretion. RESULTS. We found that AVP elicited a transient [Ca2+]i response in the aquaporin-2 (AQP2) negative cells from collecting duct segments isolated from control mice. The response was mediated by Ca2+ release from the endoplasmic reticulum (ER), as it was inhibited by pretreatment of collecting duct segments with thapsigargin, a SERCA pump inhibitor. The amplitude of the AVP-induced calcium transient was 4 times lower in the AQP2-negative cells isolated from Li+-treated mice. Li+ intake remarkably facilitated store-operated calcium entry (SOCE) in the collecting duct cells, indicating chronic ER depletion and stress. At the systemic level Li+-treated mice exhibited urine alkalinization (by 0.8 pH units) and a 6-fold elevation in urinary ammonium excretion, when compared to controls. CONCLUSIONS. Intracellular Ca2+ signaling in the intercalated cells is an essential determinant of acid-base handling in the collecting duct. Our findings reveal that Li+ markedly alters [Ca2+]i signaling in the intercalated cells, causing urine alkalinization and elevated ammonium excretion, likely, to compensate for ensuing metabolic acidosis. NIDDK R01DK125464. 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.
{"title":"Lithium-Induced Disruption of Intracellular Ca2+ Balance in the Collecting Duct Intercalated Cells Contributes to Metabolic Acidosis in Mice","authors":"Kevin Volk, I. Baranovskaya, Alena Cherezova, V. Buncha, Sati Alexander, Nichole Mumuney, M. Mamenko","doi":"10.1152/physiol.2024.39.s1.2212","DOIUrl":"https://doi.org/10.1152/physiol.2024.39.s1.2212","url":null,"abstract":"INTRODUCTION. Lithium (Li+) is an effective mood stabilizer that continues to be widely used in modern psychiatric practice. One of the most common adverse effects of Li+ therapy is nephrogenic diabetes insipidus manifesting in reduced urinary concentrating ability due to impaired vasopressin (AVP) signaling in the collecting duct principal cells. While distal tubular acidosis has also been reported in patients receiving Li+, molecular determinants underlying the pathophysiological effects of Li+ on the collecting duct intercalated cells and renal acid-base transport remain to be fully elucidated. Activation of Gq-coupled vasopressin 1a receptors (V1aR) in A-intercalated cells reportedly induces intracellular Ca2+ ([Ca2+]i) mobilization and stimulates luminal H+ secretion, resulting in urine acidification. OBJECTIVE. The objective of this study was to test if Li+ impaired V1aR-induced [Ca2+]i response in the intercalated cells of murine collecting ducts. HYPOTHESIS. We hypothesized that Li+ markedly impaired V1aR-dependent [Ca2+]i signaling in A-intercalated cells causing the reduction of luminal proton secretion in the collecting duct. METHODS. We combined immunofluorescent imaging in freshly isolated collecting duct segments with metabolic cage studies in C57BL/6NJ (Jackson Labotatory) mice receiving a regular Teklad 2918 chow (control) or a Teklad 2918-based diet containing 0.3% lithium carbonate (Li+-treated) to evaluate how Li+ affects V1aR-mediated [Ca2+]i signal, H+ transport by intercalated cells, as well as urinary pH and ammonia excretion. RESULTS. We found that AVP elicited a transient [Ca2+]i response in the aquaporin-2 (AQP2) negative cells from collecting duct segments isolated from control mice. The response was mediated by Ca2+ release from the endoplasmic reticulum (ER), as it was inhibited by pretreatment of collecting duct segments with thapsigargin, a SERCA pump inhibitor. The amplitude of the AVP-induced calcium transient was 4 times lower in the AQP2-negative cells isolated from Li+-treated mice. Li+ intake remarkably facilitated store-operated calcium entry (SOCE) in the collecting duct cells, indicating chronic ER depletion and stress. At the systemic level Li+-treated mice exhibited urine alkalinization (by 0.8 pH units) and a 6-fold elevation in urinary ammonium excretion, when compared to controls. CONCLUSIONS. Intracellular Ca2+ signaling in the intercalated cells is an essential determinant of acid-base handling in the collecting duct. Our findings reveal that Li+ markedly alters [Ca2+]i signaling in the intercalated cells, causing urine alkalinization and elevated ammonium excretion, likely, to compensate for ensuing metabolic acidosis. NIDDK R01DK125464. 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.","PeriodicalId":49694,"journal":{"name":"Physiology","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141144041","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}
Pub Date : 2024-05-01DOI: 10.1152/physiol.2024.39.s1.914
Alexander Rawlings, Michael Kozlin, Johnathan Przybysz, Lora Cavuoto, Zachary Schlader, Riana Pryor
Hydration practices across consecutive days of heavy-intensity work in heat when fluid is freely available is unknown. Without this information it remains unknown whether hydration modifies heat strain under hot working conditions and whether worker recommendations adequately maintain hydration status. We hypothesized that participants would maintain hydration status including daily percent change in body mass across workdays. Fifteen healthy, unacclimated participants (7 Females, Age: 27±6 y, Body mass: 75.0±14.4 kg, Body fat: 26.6±5.8%) completed three consecutive days (Day 1, Day 2, Day 3) of 4 h of 395±10 W work to a work/rest cycle of 45/15 min in a 36.3±0.8°C, 21±5% relative humidity environment. Participants were offered 237 mL of a sport drink every 20 min to consume ad libitum. Urine flow rate (UFR) was measured before work. Urine specific gravity (USG) and nude body mass were measured before and after work. Thirst and fluid consumption were measured throughout work. USG before work was not different between Day 1 (1.013±0.010) and Day 2 (1.013±0.010, p=0.822), but was greater before work on Day 3 (1.015±0.010, p=0.046) compared to Day 2. Change in USG from before to after work was not different between Day 1 (+0.003±0.008) and Day 2 (+0.000±0.006, p=0.123), but was lower on Day 3 (-0.002±0.006, p=0.021) compared to Day 1, with no difference between Day 2 and Day 3 (p=0.058). Before work body mass was not different across days (p=0.103). Daily percent change in body mass was not different across days (p=0.366, Day 1: 0.53±1.11%, Day 2: 0.18±0.95%, Day 3: 0.18±0.81%), indicating weight gain each day. Sweat rate (p=0.790) and UFR (p=0.469) were not different among days. Participants consumed 77±18% (Day 1), 82±19% (Day 2), and 82±16% (Day 3) of fluid offered (p=0.401), equaling 31±10 mL/kg (Day 1), 33±11 mL/kg (Day 2), 33±10 mL/kg (Day 3) (p=0.370). Maximum thirst was greater on Day 1 (3.5±1.1) compared to Day 3 (2.9±1.0, p=0.045) with no difference between Day 1 and Day 2 (3.4±1.4, p=0.648) or between Day 2 and Day 3 (p=0.121). This study demonstrates consistent hydration practices and no differences in hydration status across three consecutive days of high-intensity work in heat when fluid is freely available. Under these conditions, workers can consume fluids ad libitum and worker recommendations for hydration during heat stress should be revisited. This project was funded my the National Institute for Occupational Safety and Health (1K01OH012016-01A1). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
{"title":"Ad Libitum Drinking Prevents Body Mass Loss Across Consecutive Workdays in Heat","authors":"Alexander Rawlings, Michael Kozlin, Johnathan Przybysz, Lora Cavuoto, Zachary Schlader, Riana Pryor","doi":"10.1152/physiol.2024.39.s1.914","DOIUrl":"https://doi.org/10.1152/physiol.2024.39.s1.914","url":null,"abstract":"Hydration practices across consecutive days of heavy-intensity work in heat when fluid is freely available is unknown. Without this information it remains unknown whether hydration modifies heat strain under hot working conditions and whether worker recommendations adequately maintain hydration status. We hypothesized that participants would maintain hydration status including daily percent change in body mass across workdays. Fifteen healthy, unacclimated participants (7 Females, Age: 27±6 y, Body mass: 75.0±14.4 kg, Body fat: 26.6±5.8%) completed three consecutive days (Day 1, Day 2, Day 3) of 4 h of 395±10 W work to a work/rest cycle of 45/15 min in a 36.3±0.8°C, 21±5% relative humidity environment. Participants were offered 237 mL of a sport drink every 20 min to consume ad libitum. Urine flow rate (UFR) was measured before work. Urine specific gravity (USG) and nude body mass were measured before and after work. Thirst and fluid consumption were measured throughout work. USG before work was not different between Day 1 (1.013±0.010) and Day 2 (1.013±0.010, p=0.822), but was greater before work on Day 3 (1.015±0.010, p=0.046) compared to Day 2. Change in USG from before to after work was not different between Day 1 (+0.003±0.008) and Day 2 (+0.000±0.006, p=0.123), but was lower on Day 3 (-0.002±0.006, p=0.021) compared to Day 1, with no difference between Day 2 and Day 3 (p=0.058). Before work body mass was not different across days (p=0.103). Daily percent change in body mass was not different across days (p=0.366, Day 1: 0.53±1.11%, Day 2: 0.18±0.95%, Day 3: 0.18±0.81%), indicating weight gain each day. Sweat rate (p=0.790) and UFR (p=0.469) were not different among days. Participants consumed 77±18% (Day 1), 82±19% (Day 2), and 82±16% (Day 3) of fluid offered (p=0.401), equaling 31±10 mL/kg (Day 1), 33±11 mL/kg (Day 2), 33±10 mL/kg (Day 3) (p=0.370). Maximum thirst was greater on Day 1 (3.5±1.1) compared to Day 3 (2.9±1.0, p=0.045) with no difference between Day 1 and Day 2 (3.4±1.4, p=0.648) or between Day 2 and Day 3 (p=0.121). This study demonstrates consistent hydration practices and no differences in hydration status across three consecutive days of high-intensity work in heat when fluid is freely available. Under these conditions, workers can consume fluids ad libitum and worker recommendations for hydration during heat stress should be revisited. This project was funded my the National Institute for Occupational Safety and Health (1K01OH012016-01A1). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.","PeriodicalId":49694,"journal":{"name":"Physiology","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141142473","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}
Pub Date : 2024-05-01DOI: 10.1152/physiol.2024.39.s1.784
Prerna Kumar, Gabriel Adams-Sherrod, H. Brooks
Elucidation of epigenetic mechanism associated with aging renal physiology may reveal potential biomarkers and therapeutic targets for reversing aging renal pathologies. There is a sex difference in the age of onset of renal and cardiac disease, where females are protected against age related changes, including hypertension and fibrosis, until menopause. We hypothesized that sex and age would differentially regulate epigenetic modifications and renal physiology. To test this hypothesis, we examined kidney tissue and serum from 4-month (4M), 12-month (12M), and 24-month (24M)-old male and female C57BL/6JN mice (National Institute of Aging). Renal histone deacetylase (HDAC) and histone acetyltransferase (HAT) activities (ELISA) were significantly higher in all male mice groups compared with age-matched females. However, HAT activity decreased significantly in 24M males compared with 4M males and exhibited sex differences with 24M males having higher (p < 0.05) activity that 24M females. Levels of histone 3 (H3) acetylation at lysine (K) 9 and 27 and methylation at K9 were comparable in all male and female groups. Nonetheless, age and sex differences were observed in H3K27 methylation levels with 24M males having significantly higher (p < 0.05) levels as compared with 24M female mice. Serum creatinine (sCr) levels exhibited significant interaction between age and sex (p < 0.0001). Aging significantly increased sCr levels in 24M mice compared with 4M mice in both sexes. However, sex-differences were evident in sCr levels with 24M female mice having higher levels compared with their age matched male counterparts. Of note, serum levels of kidney injury molecule-1 (KIM-1), a tubule injury biomarker were significantly higher in 24M mice compared with 4M and 12M sex-matched mice (male 24M, 410.1 ± 94.6 vs. 12M, 53.6 ± 17.2 and 4M, 27.9 ± 2.0; pg/ml, p < 0.001; female 24M, 358.3 ± 56.1 vs. 12M, 63.8 ± 13.3 and 4M, 28.2 ± 5.0; pg/ml, p < 0.001). Histones are released in the extracellular space during disease state, act as damage-associated molecular pattern molecules and activate inflammatory pathways. In the serum, circulating histone H3 levels showed significant interaction with age and sex (p < 0.05) and increased significantly with age in both sexes. The data demonstrate that aged female mice exhibited higher levels of serum Cr and KIM-1 whereas aged males have higher KIM-1 levels as compared to sex matched young mice. Sex differences were observed in HDAC and HAT activity with males having higher enzymatic activity as compared to females. These findings will have important implications in age-related renal injury as aging is a primary risk factor for hypertension and related renal disease in men and women. Supported by the NIH grant R03AG075396. 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. Physi
{"title":"Sex and Age Differentially Regulate Epigenetic Modifications and Renal Injury Markers in Mice","authors":"Prerna Kumar, Gabriel Adams-Sherrod, H. Brooks","doi":"10.1152/physiol.2024.39.s1.784","DOIUrl":"https://doi.org/10.1152/physiol.2024.39.s1.784","url":null,"abstract":"Elucidation of epigenetic mechanism associated with aging renal physiology may reveal potential biomarkers and therapeutic targets for reversing aging renal pathologies. There is a sex difference in the age of onset of renal and cardiac disease, where females are protected against age related changes, including hypertension and fibrosis, until menopause. We hypothesized that sex and age would differentially regulate epigenetic modifications and renal physiology. To test this hypothesis, we examined kidney tissue and serum from 4-month (4M), 12-month (12M), and 24-month (24M)-old male and female C57BL/6JN mice (National Institute of Aging). Renal histone deacetylase (HDAC) and histone acetyltransferase (HAT) activities (ELISA) were significantly higher in all male mice groups compared with age-matched females. However, HAT activity decreased significantly in 24M males compared with 4M males and exhibited sex differences with 24M males having higher (p < 0.05) activity that 24M females. Levels of histone 3 (H3) acetylation at lysine (K) 9 and 27 and methylation at K9 were comparable in all male and female groups. Nonetheless, age and sex differences were observed in H3K27 methylation levels with 24M males having significantly higher (p < 0.05) levels as compared with 24M female mice. Serum creatinine (sCr) levels exhibited significant interaction between age and sex (p < 0.0001). Aging significantly increased sCr levels in 24M mice compared with 4M mice in both sexes. However, sex-differences were evident in sCr levels with 24M female mice having higher levels compared with their age matched male counterparts. Of note, serum levels of kidney injury molecule-1 (KIM-1), a tubule injury biomarker were significantly higher in 24M mice compared with 4M and 12M sex-matched mice (male 24M, 410.1 ± 94.6 vs. 12M, 53.6 ± 17.2 and 4M, 27.9 ± 2.0; pg/ml, p < 0.001; female 24M, 358.3 ± 56.1 vs. 12M, 63.8 ± 13.3 and 4M, 28.2 ± 5.0; pg/ml, p < 0.001). Histones are released in the extracellular space during disease state, act as damage-associated molecular pattern molecules and activate inflammatory pathways. In the serum, circulating histone H3 levels showed significant interaction with age and sex (p < 0.05) and increased significantly with age in both sexes. The data demonstrate that aged female mice exhibited higher levels of serum Cr and KIM-1 whereas aged males have higher KIM-1 levels as compared to sex matched young mice. Sex differences were observed in HDAC and HAT activity with males having higher enzymatic activity as compared to females. These findings will have important implications in age-related renal injury as aging is a primary risk factor for hypertension and related renal disease in men and women. Supported by the NIH grant R03AG075396. 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. Physi","PeriodicalId":49694,"journal":{"name":"Physiology","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141145518","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}
Pub Date : 2024-05-01DOI: 10.1152/physiol.2024.39.s1.818
Kayla A. Burrowes, Alexandria B. Marciante, Raphael R. Perim, Mohamed El-Chami, Gordon S. Mitchell
Acute intermittent hypoxia (AIH) elicits a form of respiratory motor plasticity known as phrenic long-term facilitation (pLTF). Both moderate and severe AIH elicit phenotypically similar pLTF but do so via completely distinct cellular mechanisms. With moderate AIH (mAIH), pLTF arises from a serotonin-dominant, adenosine-constrained mechanism. In aged rats, mAIH-induced pLTF is impaired due to increased basal spinal adenosine levels, which constrain serotonin-dependent pLTF. With severe AIH (sAIH), pLTF arises from an adenosine-dominant, serotonin-constrained mechanism. Since spinal adenosine levels are elevated in aged male rats, we hypothesized that age would actually enhance sAIH-induced- pLTF. Young (~3.5 month) and aged (~20 month) male Sprague Dawley rats were urethane anesthetized, artificially ventilated, vagotomized, paralyzed, and exposed to sAIH (3, 5-minute episodes; arterial Po2 = 25-30 mmHg). Integrated phrenic nerve burst activity was measured before (baseline), during hypoxic episodes and 60 minutes after sAIH. Neither baseline phrenic burst amplitude, the short-term hypoxic phrenic response nor pLTF magnitude (assessed as % change in phrenic burst amplitude from baseline to 60 minutes post-sAIH) were different in aged versus young rats (120 ± 22% vs. 98 ± 17%, respectively). Thus, aged male rats preserve the capacity for adenosine driven phrenic motor plasticity. Although we cannot conclude that sAIH-induced pLTF is actually increased, age effects on adenosine versus serotonin-driven plasticity are clearly different. NIH HL148030. 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.
{"title":"Phrenic Long-term Facilitation Following Severe Acute Intermittent Hypoxia Is Preserved in Geriatric Male Rats","authors":"Kayla A. Burrowes, Alexandria B. Marciante, Raphael R. Perim, Mohamed El-Chami, Gordon S. Mitchell","doi":"10.1152/physiol.2024.39.s1.818","DOIUrl":"https://doi.org/10.1152/physiol.2024.39.s1.818","url":null,"abstract":"Acute intermittent hypoxia (AIH) elicits a form of respiratory motor plasticity known as phrenic long-term facilitation (pLTF). Both moderate and severe AIH elicit phenotypically similar pLTF but do so via completely distinct cellular mechanisms. With moderate AIH (mAIH), pLTF arises from a serotonin-dominant, adenosine-constrained mechanism. In aged rats, mAIH-induced pLTF is impaired due to increased basal spinal adenosine levels, which constrain serotonin-dependent pLTF. With severe AIH (sAIH), pLTF arises from an adenosine-dominant, serotonin-constrained mechanism. Since spinal adenosine levels are elevated in aged male rats, we hypothesized that age would actually enhance sAIH-induced- pLTF. Young (~3.5 month) and aged (~20 month) male Sprague Dawley rats were urethane anesthetized, artificially ventilated, vagotomized, paralyzed, and exposed to sAIH (3, 5-minute episodes; arterial Po2 = 25-30 mmHg). Integrated phrenic nerve burst activity was measured before (baseline), during hypoxic episodes and 60 minutes after sAIH. Neither baseline phrenic burst amplitude, the short-term hypoxic phrenic response nor pLTF magnitude (assessed as % change in phrenic burst amplitude from baseline to 60 minutes post-sAIH) were different in aged versus young rats (120 ± 22% vs. 98 ± 17%, respectively). Thus, aged male rats preserve the capacity for adenosine driven phrenic motor plasticity. Although we cannot conclude that sAIH-induced pLTF is actually increased, age effects on adenosine versus serotonin-driven plasticity are clearly different. NIH HL148030. 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.","PeriodicalId":49694,"journal":{"name":"Physiology","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141130643","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}
Pub Date : 2024-05-01DOI: 10.1152/physiol.2024.39.s1.1856
Amanda Zhong, Irene C Solomon
Acute intermittent hypoxia (AIH) induces spinal neural plasticity in both respiratory and non-respiratory somatic motor systems. AIH-induced neural plasticity has been best studied in the respiratory neural control system, where exposure to moderate AIH (9-15% inspired O2), typically composed of 3,5-min hypoxic episodes (AIH3x5min), has been shown to consistently elicit a robust increase in phrenic motor activity due to a serotonin-dependent mechanism that promotes de novo synthesis of BDNF and activation of high affnity BDNF-TrkB receptors to initiate ERK MAP kinase signaling in phrenic motoneurons. Whether other protocols that use a total duration of 15 min of hypoxic exposure, but with an increased number of shorter duration hypoxic episodes ( e.g, AIH5x3min) similarly elicit serotonin-dependent BDNF pathway-mediated neural plasticity mechanisms in this region remains to be determined. To begin to assess this possibility, we evaluated BDNF expression in C4-C5 spinal cord segments containing the phrenic motor nucleus following single exposure to AIH5x3min (12% O2) in urethane-anesthetized spontaneously breathing adult female rats at 4-weeks after mid-thoracic SCI. Experiments using AIH3x5min (12% O2) exposure and intermittent normoxia (Nx, 21% O2) exposure served as controls. At ~60-90 min after the AIH or Nx exposure protocol, the rats were transcardially perfused with saline followed by 4% PFA, and various regions of the CNS, including the C3-C5 spinal cord were removed, post-fixed, and cryoprotected. 20 μm thick transverse sections were then cut to obtain sets of slides for single- or double-label fluorescence IHC staining to localize BDNF protein expression in the C4-C5 spinal cord, including the region containing the phrenic motor nucleus. Preliminary analyses show that both AIH5x3min and AIH3x5min exposures elicit increased BDNF expression when compared to Nx exposure, with both diffuse cytosolic and punctate immunofluorescence labeling in and around neurons within the phrenic motor nucleus region, including labeling of presumptive phrenic motoneurons. No labeling was seen in adjacent tissue sections that were incubated without the primary antibody. Immunofluorescence labeling was also seen in the more medial regions of lamina VIII in the ventral horn, the medial regions of laminae VI and VII, and throughout lamina X; these regions have been reported to contain the V0-V3 classes of spinal interneurons (SpINs) albeit we did not verify BDNF labeling of specific classes of presumptive SpINs. These preliminary observations suggest that AIH5x3min exposure likely recruits a serotonin-dependent BDNF pathway-mediated mechanism for neural plasticity in a manner similar to that seen for AIH3x5min exposure. APS Summer Undergraduate Research Fellowship; DOD CDMRP W81XWH-17-1-0260; NYS DOH SCIRB C37711GG. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional ver
{"title":"Brain Derived Neurotrophic Factor (BDNF) Immunolabeling in C4-C5 Spinal Cord of Adult Female Rats Following Acute Intermittent Hypoxia (AIH) Exposure Composed of 5,3-min Hypoxic Episodes (AIH5x3min) at 4-weeks After mid-thoracic SCI","authors":"Amanda Zhong, Irene C Solomon","doi":"10.1152/physiol.2024.39.s1.1856","DOIUrl":"https://doi.org/10.1152/physiol.2024.39.s1.1856","url":null,"abstract":"Acute intermittent hypoxia (AIH) induces spinal neural plasticity in both respiratory and non-respiratory somatic motor systems. AIH-induced neural plasticity has been best studied in the respiratory neural control system, where exposure to moderate AIH (9-15% inspired O2), typically composed of 3,5-min hypoxic episodes (AIH3x5min), has been shown to consistently elicit a robust increase in phrenic motor activity due to a serotonin-dependent mechanism that promotes de novo synthesis of BDNF and activation of high affnity BDNF-TrkB receptors to initiate ERK MAP kinase signaling in phrenic motoneurons. Whether other protocols that use a total duration of 15 min of hypoxic exposure, but with an increased number of shorter duration hypoxic episodes ( e.g, AIH5x3min) similarly elicit serotonin-dependent BDNF pathway-mediated neural plasticity mechanisms in this region remains to be determined. To begin to assess this possibility, we evaluated BDNF expression in C4-C5 spinal cord segments containing the phrenic motor nucleus following single exposure to AIH5x3min (12% O2) in urethane-anesthetized spontaneously breathing adult female rats at 4-weeks after mid-thoracic SCI. Experiments using AIH3x5min (12% O2) exposure and intermittent normoxia (Nx, 21% O2) exposure served as controls. At ~60-90 min after the AIH or Nx exposure protocol, the rats were transcardially perfused with saline followed by 4% PFA, and various regions of the CNS, including the C3-C5 spinal cord were removed, post-fixed, and cryoprotected. 20 μm thick transverse sections were then cut to obtain sets of slides for single- or double-label fluorescence IHC staining to localize BDNF protein expression in the C4-C5 spinal cord, including the region containing the phrenic motor nucleus. Preliminary analyses show that both AIH5x3min and AIH3x5min exposures elicit increased BDNF expression when compared to Nx exposure, with both diffuse cytosolic and punctate immunofluorescence labeling in and around neurons within the phrenic motor nucleus region, including labeling of presumptive phrenic motoneurons. No labeling was seen in adjacent tissue sections that were incubated without the primary antibody. Immunofluorescence labeling was also seen in the more medial regions of lamina VIII in the ventral horn, the medial regions of laminae VI and VII, and throughout lamina X; these regions have been reported to contain the V0-V3 classes of spinal interneurons (SpINs) albeit we did not verify BDNF labeling of specific classes of presumptive SpINs. These preliminary observations suggest that AIH5x3min exposure likely recruits a serotonin-dependent BDNF pathway-mediated mechanism for neural plasticity in a manner similar to that seen for AIH3x5min exposure. APS Summer Undergraduate Research Fellowship; DOD CDMRP W81XWH-17-1-0260; NYS DOH SCIRB C37711GG. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional ver","PeriodicalId":49694,"journal":{"name":"Physiology","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141139545","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}
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