Pub Date : 2024-05-01DOI: 10.1152/physiol.2024.39.s1.999
Jeffrey R. Moore, Jochen Kressler
Glycemic markers, including postprandial glucose, insulin, and insulin sensitivity, are strong predictors of morbidity and mortality in individuals with and without diabetes. Stair-climbing and -descending (SCD) at a comfortable pace for as little as 1 to 3 minutes after a sugary beverage (300 kilocalories; 100% carbohydrate) improves glucose and insulin, with insulin sensitivity improving with as little as 10 minutes. Objective: To determine if benefits to glucose, insulin, and insulin sensitivity are seen with SCD following consumption of a meal with mixed macronutrients. Hypothesis: SCD will improve to glucose, insulin, and insulin sensitivity in a dose response manner following a mixed meal. Methods: In a randomized, controlled, crossover trial, young adults (N=31) in apparent good health performed SCD for 0, 1, 3, and 10 minutes after a mixed meal (650 kilocalories; 53% carbohydrates, 33% fat, and 14% protein). Differences in glucose, insulin, and insulin sensitivity (ISI) from baseline to 30 minutes were analyzed using a mixed-effects ANOVA. Results: A significant fixed-effect was found for change in glucose [F(2.551,67.17)=4.724, p=.0071)], insulin [F(2.692,74.49)=11.28, p<.0001)], and ISI [F(2.127,56.00)=5.848, p=.0042)]. Compared to control, changes in glucose (mean (95%CI)) were significantly lower after 1 min (-14 (-7 to -21) mg/dL, p=.0006), 3 min (-18 (-9 to -28) mg/dL, p=.0007), and 10 min (-10.0 (-1 to -20) mg/dL, p=.0387); changes in insulin were significantly lower after 1 min (-1.8 (-0.8 to -2.8) μIU/mL, p=.0011), 3 min (-2.8 (-1.7 to -4.0) μIU/mL, p<.0001), and 10 min (-1.1 (-0.1 to -2.0) μIU/mL, p=.0329); and changes in ISI were significantly higher after 3 min (2.4 (1.2 to 3.6), p=.0003) and 10 min (1.3 (0.3 to 2.4), p=.0143) but not 1 min (1.2 (0.0 to 2.5), p=.0587). Conclusion: Postprandial glucose and insulin were improved with as little as 1 minute, and insulin resistance improved with as little as 3 minutes, of SCD at a self-selected, comfortable pace, after consumption of a mixed meal in apparently healthy young adults. None. 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":"One minute of stair climbing and descending reduces postprandial insulin and glucose with three-minutes improving insulin resistance following a mixed meal in young adults: A Randomized Controlled Trial","authors":"Jeffrey R. Moore, Jochen Kressler","doi":"10.1152/physiol.2024.39.s1.999","DOIUrl":"https://doi.org/10.1152/physiol.2024.39.s1.999","url":null,"abstract":"Glycemic markers, including postprandial glucose, insulin, and insulin sensitivity, are strong predictors of morbidity and mortality in individuals with and without diabetes. Stair-climbing and -descending (SCD) at a comfortable pace for as little as 1 to 3 minutes after a sugary beverage (300 kilocalories; 100% carbohydrate) improves glucose and insulin, with insulin sensitivity improving with as little as 10 minutes. Objective: To determine if benefits to glucose, insulin, and insulin sensitivity are seen with SCD following consumption of a meal with mixed macronutrients. Hypothesis: SCD will improve to glucose, insulin, and insulin sensitivity in a dose response manner following a mixed meal. Methods: In a randomized, controlled, crossover trial, young adults (N=31) in apparent good health performed SCD for 0, 1, 3, and 10 minutes after a mixed meal (650 kilocalories; 53% carbohydrates, 33% fat, and 14% protein). Differences in glucose, insulin, and insulin sensitivity (ISI) from baseline to 30 minutes were analyzed using a mixed-effects ANOVA. Results: A significant fixed-effect was found for change in glucose [F(2.551,67.17)=4.724, p=.0071)], insulin [F(2.692,74.49)=11.28, p<.0001)], and ISI [F(2.127,56.00)=5.848, p=.0042)]. Compared to control, changes in glucose (mean (95%CI)) were significantly lower after 1 min (-14 (-7 to -21) mg/dL, p=.0006), 3 min (-18 (-9 to -28) mg/dL, p=.0007), and 10 min (-10.0 (-1 to -20) mg/dL, p=.0387); changes in insulin were significantly lower after 1 min (-1.8 (-0.8 to -2.8) μIU/mL, p=.0011), 3 min (-2.8 (-1.7 to -4.0) μIU/mL, p<.0001), and 10 min (-1.1 (-0.1 to -2.0) μIU/mL, p=.0329); and changes in ISI were significantly higher after 3 min (2.4 (1.2 to 3.6), p=.0003) and 10 min (1.3 (0.3 to 2.4), p=.0143) but not 1 min (1.2 (0.0 to 2.5), p=.0587). Conclusion: Postprandial glucose and insulin were improved with as little as 1 minute, and insulin resistance improved with as little as 3 minutes, of SCD at a self-selected, comfortable pace, after consumption of a mixed meal in apparently healthy young adults. None. 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":"141136262","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.s1.389
Sanna Darvish, Katelyn R. Ludwig, Akpevwe P Ikoba, Morgan Berryman-Maciel, Mckinley Coppock, K. Murray, Michel B Chonchol
BACKGROUND: Midlife and older (ML/O) adults with mild-to-moderate renal dysfunction (MRD) are at increased risk for cardiovascular disease (CVD). A key antecedent to CVD in ML/O adults with MRD is vascular endothelial dysfunction, mediated by declines in nitric oxide (NO) bioavailability due to excess reactive oxygen species (ROS)-related oxidative stress. We have shown that targeting the nitrate-nitrite-NO pathway with sodium nitrite in heathy ML/O adults improves endothelial function and changes the circulating milieu to lower endothelial cell (EC) ROS bioactivity. However, if nitrate-rich beetroot juice (N-BRJ) is effective for improving endothelial function in ML/O men and women with MRD is unknown. HYPOTHESES: We tested the hypotheses that chronic N-BRJ in ML/O men and women with MRD would: 1) improve endothelial function and 2) induce changes to the circulating milieu to increase EC NO production and lower EC ROS bioactivity. We also assessed possible sex differences in the effcacy of N-BRJ for improving endothelial function. METHODS: Twenty-six ML/O men and women with MRD (estimated glomerular filtration rate [eGFR; CKD-EPI]: 40-89 mL/min/1.73m2) underwent three months of supplementation with N-BRJ (70 mL with 6.45 mmol nitrate/day) (n=13, 7 women; age: 65±2 years; eGFR: 69.2±3.3 mL/min/1.73m2) or nitrate-depleted BRJ (placebo, PBO) (n=13, 7 women; age: 68±2 years; eGFR: 79.8±3.1 mL/min/1.73m2) in a randomized, placebo-controlled, parallel-group design clinical trial. Endothelial function was assessed by brachial artery flow-mediated dilation (FMDBA). Smooth muscle sensitivity to NO was assessed by brachial artery dilation to sublingual nitroglycerin. Human aortic ECs (HAECs) in culture were exposed to 10% subject serum (n=10[6-7 women]/group) collected before and after N-BRJ and PBO supplementation. Acetylcholine-stimulated NO production (DAR-4M-AM) and whole-cell ROS bioactivity (CellROX) were assessed in HAECs using immunofluorescence. Results: N-BRJ supplementation increased FMDBA by 28% (pre: 4.6±0.7%, post: 5.9±0.8%; p=0.03). FMDBA did not change with PBO (pre: 4.6±0.9%, post: 4.7±0.8%; p>0.05). Traditional CVD risk factors (i.e., blood pressure, cholesterol) and smooth muscle sensitivity to NO were unchanged in both groups (p>0.05). Preliminary assessments suggest greater improvements in endothelial function with N-BRJ in women (Δ=post-pre intervention; ΔFMDBA=1.6±0.4) compared to men (ΔFMDBA=0.9±1.0). Compared to pre-intervention, NO production was (trending) 7% higher (p=0.05) and ROS bioactivity was 25% lower (p=0.02) in HAECs exposed to serum collected post N-BRJ. Serum from PBO had no effects (p>0.05). CONCLUSION: N-BRJ supplementation in ML/O adults with MRD holds promise for improving endothelial function, in part by inducing changes to the circulating milieu that increase NO production and decrease oxidative stress in ECs. The effects on endothelial function may be greater in women compared to men. Targeting the nitrate-nitr
{"title":"Nitrate-rich beetroot juice supplementation in midlife and older adults with renal dysfunction increases vascular endothelial function and changes the circulating milieu to improve endothelial cell nitric oxide production and oxidative stress","authors":"Sanna Darvish, Katelyn R. Ludwig, Akpevwe P Ikoba, Morgan Berryman-Maciel, Mckinley Coppock, K. Murray, Michel B Chonchol","doi":"10.1152/physiol.2024.39.s1.389","DOIUrl":"https://doi.org/10.1152/physiol.2024.39.s1.389","url":null,"abstract":"BACKGROUND: Midlife and older (ML/O) adults with mild-to-moderate renal dysfunction (MRD) are at increased risk for cardiovascular disease (CVD). A key antecedent to CVD in ML/O adults with MRD is vascular endothelial dysfunction, mediated by declines in nitric oxide (NO) bioavailability due to excess reactive oxygen species (ROS)-related oxidative stress. We have shown that targeting the nitrate-nitrite-NO pathway with sodium nitrite in heathy ML/O adults improves endothelial function and changes the circulating milieu to lower endothelial cell (EC) ROS bioactivity. However, if nitrate-rich beetroot juice (N-BRJ) is effective for improving endothelial function in ML/O men and women with MRD is unknown. HYPOTHESES: We tested the hypotheses that chronic N-BRJ in ML/O men and women with MRD would: 1) improve endothelial function and 2) induce changes to the circulating milieu to increase EC NO production and lower EC ROS bioactivity. We also assessed possible sex differences in the effcacy of N-BRJ for improving endothelial function. METHODS: Twenty-six ML/O men and women with MRD (estimated glomerular filtration rate [eGFR; CKD-EPI]: 40-89 mL/min/1.73m2) underwent three months of supplementation with N-BRJ (70 mL with 6.45 mmol nitrate/day) (n=13, 7 women; age: 65±2 years; eGFR: 69.2±3.3 mL/min/1.73m2) or nitrate-depleted BRJ (placebo, PBO) (n=13, 7 women; age: 68±2 years; eGFR: 79.8±3.1 mL/min/1.73m2) in a randomized, placebo-controlled, parallel-group design clinical trial. Endothelial function was assessed by brachial artery flow-mediated dilation (FMDBA). Smooth muscle sensitivity to NO was assessed by brachial artery dilation to sublingual nitroglycerin. Human aortic ECs (HAECs) in culture were exposed to 10% subject serum (n=10[6-7 women]/group) collected before and after N-BRJ and PBO supplementation. Acetylcholine-stimulated NO production (DAR-4M-AM) and whole-cell ROS bioactivity (CellROX) were assessed in HAECs using immunofluorescence. Results: N-BRJ supplementation increased FMDBA by 28% (pre: 4.6±0.7%, post: 5.9±0.8%; p=0.03). FMDBA did not change with PBO (pre: 4.6±0.9%, post: 4.7±0.8%; p>0.05). Traditional CVD risk factors (i.e., blood pressure, cholesterol) and smooth muscle sensitivity to NO were unchanged in both groups (p>0.05). Preliminary assessments suggest greater improvements in endothelial function with N-BRJ in women (Δ=post-pre intervention; ΔFMDBA=1.6±0.4) compared to men (ΔFMDBA=0.9±1.0). Compared to pre-intervention, NO production was (trending) 7% higher (p=0.05) and ROS bioactivity was 25% lower (p=0.02) in HAECs exposed to serum collected post N-BRJ. Serum from PBO had no effects (p>0.05). CONCLUSION: N-BRJ supplementation in ML/O adults with MRD holds promise for improving endothelial function, in part by inducing changes to the circulating milieu that increase NO production and decrease oxidative stress in ECs. The effects on endothelial function may be greater in women compared to men. Targeting the nitrate-nitr","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":"141137092","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.s1.462
Bella Raphael, Carlos Matellan, Mario Manresa
BACKGROUND AND AIMS: A single layer of epithelial cells that are supported by resident mucosal fibroblasts, provides an intestinal barrier against pathogens. In Inflammatory Bowel Disease (IBD), this barrier is disrupted by mechanisms which are poorly understood. Intestinal fibroblasts produce WNT, BMP and Notch mediators that contribute to epithelial homeostasis and an impairment on these signals results in the loss of barrier integrity which has been observed in IBD. In fact, fibroblasts producing these signals may be lost during inflammation. Yet the mediators and mechanism that drive this loss of homeostatic stromal-derived signals are unknown. TWEAK is a member of the tumour necrosis factor superfamily (TNFSF) that was found to be upregulated in IBD biopsies and dysregulated tissue repair and promote chronic inflammation in in vivo murine models. However, whether TWEAK exerts its effects on fibroblasts and how these may contribute to barrier breakdown remains unknown. My central hypothesis is that TWEAK dysregulates the crosstalk between fibroblasts and epithelial cells in the intestinal tract by impairing a homeostatic signalling network. METHODS: To assess the effect of TWEAK on WNT signalling and wound healing in fibroblasts and epithelial cells, the expression of WNT ligands and receptors were assessed. Primary human colonic fibroblasts and human colonic epithelial cells were stimulated with TWEAK at various time points and analysed by qPCR, Western blot and Flow cytometry and scratch wound assay. RESULTS: Both Fibroblasts and epithelial cells displayed abundant Fn14 surface receptor, although epithelial cells at a level lower than that found on colonic fibroblasts. Transcriptional signatures at gene RSPO2 (0.5-fold ± decrease, *p<0.05, n=4), WNT5A (1 fold ± decrease, **p<0.01, n=4) and BMP6 (1 fold ± decrease, ***p<0.001, n=4) and protein level RSPO2 (50% ± decrease respectively, n=5) showed a TWEAK-mediated suppression after prolonged exposure (24-48h), but not in epithelial cells. Moreover, TWEAK delayed fibroblast healing capacity after 24h (50% ± decrease in wound closure, n=4) in a wound-scratch assay. CONCLUSION: TWEAK represses the expression of homeostatic factors in colonic fibroblasts but not on epithelial cells, suggesting this mechanism could be specific to the intestinal stroma. The effect that this impairment of WNT signals in stromal cells may have on their differentiation and communication with the epithelium will be subject for further study. UCD Ad Astra PhD Scholarship. 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":"Modulation of WNT signalling by inflammatory factor TWEAK, and its consequences on fibroblast-epithelial communication","authors":"Bella Raphael, Carlos Matellan, Mario Manresa","doi":"10.1152/physiol.2024.39.s1.462","DOIUrl":"https://doi.org/10.1152/physiol.2024.39.s1.462","url":null,"abstract":"BACKGROUND AND AIMS: A single layer of epithelial cells that are supported by resident mucosal fibroblasts, provides an intestinal barrier against pathogens. In Inflammatory Bowel Disease (IBD), this barrier is disrupted by mechanisms which are poorly understood. Intestinal fibroblasts produce WNT, BMP and Notch mediators that contribute to epithelial homeostasis and an impairment on these signals results in the loss of barrier integrity which has been observed in IBD. In fact, fibroblasts producing these signals may be lost during inflammation. Yet the mediators and mechanism that drive this loss of homeostatic stromal-derived signals are unknown. TWEAK is a member of the tumour necrosis factor superfamily (TNFSF) that was found to be upregulated in IBD biopsies and dysregulated tissue repair and promote chronic inflammation in in vivo murine models. However, whether TWEAK exerts its effects on fibroblasts and how these may contribute to barrier breakdown remains unknown. My central hypothesis is that TWEAK dysregulates the crosstalk between fibroblasts and epithelial cells in the intestinal tract by impairing a homeostatic signalling network. METHODS: To assess the effect of TWEAK on WNT signalling and wound healing in fibroblasts and epithelial cells, the expression of WNT ligands and receptors were assessed. Primary human colonic fibroblasts and human colonic epithelial cells were stimulated with TWEAK at various time points and analysed by qPCR, Western blot and Flow cytometry and scratch wound assay. RESULTS: Both Fibroblasts and epithelial cells displayed abundant Fn14 surface receptor, although epithelial cells at a level lower than that found on colonic fibroblasts. Transcriptional signatures at gene RSPO2 (0.5-fold ± decrease, *p<0.05, n=4), WNT5A (1 fold ± decrease, **p<0.01, n=4) and BMP6 (1 fold ± decrease, ***p<0.001, n=4) and protein level RSPO2 (50% ± decrease respectively, n=5) showed a TWEAK-mediated suppression after prolonged exposure (24-48h), but not in epithelial cells. Moreover, TWEAK delayed fibroblast healing capacity after 24h (50% ± decrease in wound closure, n=4) in a wound-scratch assay. CONCLUSION: TWEAK represses the expression of homeostatic factors in colonic fibroblasts but not on epithelial cells, suggesting this mechanism could be specific to the intestinal stroma. The effect that this impairment of WNT signals in stromal cells may have on their differentiation and communication with the epithelium will be subject for further study. UCD Ad Astra PhD Scholarship. 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":"141136882","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.s1.248
Jackson Klump, Julian Vallejo, Mark Gray, Mark Dallas, Mark Johnson, Michael J. Wacker
Mechanical loading of bone creates interstitial fluid flow and shear stress within the bone lacunocanalicular system, leading to alterations of bone size and mass. Bone plays an important role as an endocrine organ, releasing endocrine signaling molecules that impact systemic physiology. Further, the central and peripheral nervous systems regulate bone mass in response to strain through alterations in autonomic tone. This suggests the potential for interplay between bone and other organs via endocrine signaling and autonomic innervation. In this study, our group investigated this potential interplay by focusing on bone and heart. We hypothesized that mechanical bone loading of mice in vivo would result in altered cardiac function. To test this hypothesis, we performed acute in vivo mechanical loading on right leg tibias of anesthetized TOPGAL and CD-1 mice. Tibias underwent compressive cyclic loading (a sine wave) that modulates between -0.3N and -9.0N for 300 cycles at 2 Hz. Cardiac function was monitored with lead II electrocardiogram (ECG) data, heart rate (HR), and heart rate variability (HRV). Immediate, transient reduction in resting HR (0.93 ± 0.013 fold change from baseline, n=6-7, p<0.01 compared to control) was achieved during tibial loading in 6-month-old male and female mice, with concurrent increase in HRV (1.24 ± 0.11 fold change from baseline, n=6-7, p<0.01). Both HR and HRV returned to baseline levels upon completion of the loading process. ECG measurements, QRS and corrected QT (QTc), were not found to be altered (p>0.05) during loading and 30 minutes following loading. In further studies, 1N-2N did not produce a decrease in HR, while 3N (0.92 ± 0.077 fold change from baseline, n=12, p<0.05) and 9N (0.93 ± 0.061 fold change from baseline, n=13, p<0.05) decreased HR. There was decreased magnitude and responsiveness with aging to 11 months old at 3N and 9N (p>0.05), suggesting the response may weaken with age. The immediate, transient nature of the changes to resting HR and HRV suggest a neural mechanism for this response. To test this mechanism, we inhibited local neuronal afferent activity by injecting lidocaine (2.5mg/kg) near the tibia prior to loading. In doing so, the decrease in HR during loading was significantly diminished (vehicle 0.90 ± 0.060 vs. lidocaine 0.97 ± 0.042 fold change from baseline, n=7-8, p<0.05). To test the efferent arm of the response, mice were injected with the parasympathetic, muscarinic acetylcholine receptor antagonist atropine (2mg/kg), or the sympathetic, β1/β2 receptor antagonist propranolol (10mg/kg). Propranolol significantly inhibited the HR decrease during loading (vehicle 0.88 ± 0.095 vs. propranolol 0.98 ± 0.026 fold change from baseline, n=7-8, p<0.05), while atropine did not (n=8-11, p>0.05). These findings suggest that reductions in sympathetic tone on the heart during bone loading led to the decrease in HR. In conclusion, this study uncovered a reflexive neural connection between bone a
{"title":"Bone Mechanical Loading Reduces Heart Rate and Increases Heart Rate Variability via the Autonomic Nervous System in Anesthetized Mice","authors":"Jackson Klump, Julian Vallejo, Mark Gray, Mark Dallas, Mark Johnson, Michael J. Wacker","doi":"10.1152/physiol.2024.39.s1.248","DOIUrl":"https://doi.org/10.1152/physiol.2024.39.s1.248","url":null,"abstract":"Mechanical loading of bone creates interstitial fluid flow and shear stress within the bone lacunocanalicular system, leading to alterations of bone size and mass. Bone plays an important role as an endocrine organ, releasing endocrine signaling molecules that impact systemic physiology. Further, the central and peripheral nervous systems regulate bone mass in response to strain through alterations in autonomic tone. This suggests the potential for interplay between bone and other organs via endocrine signaling and autonomic innervation. In this study, our group investigated this potential interplay by focusing on bone and heart. We hypothesized that mechanical bone loading of mice in vivo would result in altered cardiac function. To test this hypothesis, we performed acute in vivo mechanical loading on right leg tibias of anesthetized TOPGAL and CD-1 mice. Tibias underwent compressive cyclic loading (a sine wave) that modulates between -0.3N and -9.0N for 300 cycles at 2 Hz. Cardiac function was monitored with lead II electrocardiogram (ECG) data, heart rate (HR), and heart rate variability (HRV). Immediate, transient reduction in resting HR (0.93 ± 0.013 fold change from baseline, n=6-7, p<0.01 compared to control) was achieved during tibial loading in 6-month-old male and female mice, with concurrent increase in HRV (1.24 ± 0.11 fold change from baseline, n=6-7, p<0.01). Both HR and HRV returned to baseline levels upon completion of the loading process. ECG measurements, QRS and corrected QT (QTc), were not found to be altered (p>0.05) during loading and 30 minutes following loading. In further studies, 1N-2N did not produce a decrease in HR, while 3N (0.92 ± 0.077 fold change from baseline, n=12, p<0.05) and 9N (0.93 ± 0.061 fold change from baseline, n=13, p<0.05) decreased HR. There was decreased magnitude and responsiveness with aging to 11 months old at 3N and 9N (p>0.05), suggesting the response may weaken with age. The immediate, transient nature of the changes to resting HR and HRV suggest a neural mechanism for this response. To test this mechanism, we inhibited local neuronal afferent activity by injecting lidocaine (2.5mg/kg) near the tibia prior to loading. In doing so, the decrease in HR during loading was significantly diminished (vehicle 0.90 ± 0.060 vs. lidocaine 0.97 ± 0.042 fold change from baseline, n=7-8, p<0.05). To test the efferent arm of the response, mice were injected with the parasympathetic, muscarinic acetylcholine receptor antagonist atropine (2mg/kg), or the sympathetic, β1/β2 receptor antagonist propranolol (10mg/kg). Propranolol significantly inhibited the HR decrease during loading (vehicle 0.88 ± 0.095 vs. propranolol 0.98 ± 0.026 fold change from baseline, n=7-8, p<0.05), while atropine did not (n=8-11, p>0.05). These findings suggest that reductions in sympathetic tone on the heart during bone loading led to the decrease in HR. In conclusion, this study uncovered a reflexive neural connection between bone a","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":"141137504","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.s1.1117
Francois Gould, Ireneusz D. Wojtas, Nicole Charles
Parkinson’s disease results in pathological swallowing, or dysphagia, in up to 90% of cases. Severity and extent of functional impairment of feeding is highly variable in this disease. Feeding is a multi step neuromuscular process of tightly coordinated orofacial behaviors -transport, food reduction, pharyngeal swallowing- involving multiple musculoskeletal systems — tongue, jaw muscles, hyolaryngeal muscles — innervated by multiple cranial and cervical spinal nerves. The type of food being ingested further affects this sequence. The pesticide rotenone, a type II mitochondrial inhibitor, has been epidemiologically linked to Parkinson’s disease. The goal of this project is to identify how parkinsonian neurodegeneration affects this sequence in an animal model. We hypothesize that not all elements of the sequence will be equally affected. Twelve young adult male Lewis rats received daily intraperitoneal injections of either 2.75 mg/kg of rotenone or vehicle control for 8 days. The rats were trained to eat breakfast cereal and drink water mixed with barium in front of a high speed (200 fps) videofluoroscope. From the high speed video recording duration of intraoral transport and chewing of solid food as well as lick duration for liquid drinking were measured for multiple swallows per individual on day 0 (before injection), day 1, day 4, and day 7. On day 8 animals were perfused and brains harvested, sliced, stained with immunofluorescent markers for striatal tyrosine hydroxylase to confirm effectiveness of the model. Mixed model ANOVA was used to test the hypothesis that duration of the phases varied over the course of treatment. Duration of intra oral transport changed in neither control nor rotenone treated animals (p=0.1136), but duration of chewing increased in rotenone treated rats only by day 4 (p<0.001). Duration of licks increased in liquid drinking rats from day 0. Different components of the oral feeding process vary in degree and timing of impairment in the rat rotenone model of Parkinson’s disease, with coordinated rhythmic tongue and jaw movements (licking and chewing) being most sensitive. The neurological basis for this differential sensitivity remains unclear. Internal Rowan funds to Dr. Gould supported this work. 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.
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Pub Date : 2024-05-01DOI: 10.1152/physiol.2024.39.s1.639
Hannah Costello, G. Crislip, K. Cheng, Annalisse R. Mckee, Victor M. Mendez, Lauren A. Douma, M. Gumz
BMAL1 is a core circadian clock protein that is important for circadian rhythms of physiological function, as well as maintaining physiological homeostasis, including aspects of kidney function. Global Bmal1 knockout (KO) male mice exhibit loss of diurnal rhythm of renal sodium (Na) excretion in response to a normal or high salt diet. However, renal Na excretion rhythm remained intact in kidney-specific Bmal1 KO male mice. The adrenal gland synthesizes hormones, such as aldosterone, which influence renal electrolyte handling. The role of adrenal BMAL1 in the regulation of renal function remains unknown. The study objective was to test the hypothesis that adrenal BMAL1 is required for normal rhythms of aldosterone and renal Na handling. Male and female adrenal-specific aldosterone synthase Cre positive (AS) Bmal1 KO and littermate Cre negative, floxed control mice ( n=5-9/genotype) were acclimated to metabolic cages for 3 days then samples were collected for three days with mice on a normal salt diet followed by 7 days on a low salt diet to challenge the mice to stimulate aldosterone production. Twelve-hour food intake was measured, and urine samples were collected to measure night/day patterns in renal Na balance. Urinary aldosterone excretion was measured by ELISA. Both day and night urinary aldosterone excretion were increased following a low salt diet in control and KO male mice (ANOVA main effect of diet, p<0.05). Male AS Bmal1 KO mice displayed a significant increase in day urinary aldosterone excretion following a normal and low salt diet (ANOVA main effect of genotype, p=0.0230), with a trend for an increase in night urinary aldosterone excretion ( p=0.0571). Interestingly, these genotype effects were not seen in female AS Bmal1 KO mice. Urinary aldosterone was increased following a low salt diet in female mice, but only during the nighttime in control and KO mice ( p=0.0205). Sex differences were also observed in renal Na balance, where Na balance was more positive during the day in male, but not female, AS Bmal1 KO vs. control mice (ANOVA main effect of genotype, p=0.0282). Together, these data suggest adrenal BMAL1 is required for normal rhythms of aldosterone and renal Na balance in a sex-dependent manner. Future work will investigate whether the changes in aldosterone contribute to changes in renal Na balance. This work was supported by the American Heart Association (Postdoctoral FellowshipP0240441 to H.C.; Established Investigator Award 19EIA34660135 to M.G), theRobert and Mary Cade Professorship in Physiology (to M.G.) and the NIH(F32DK121424 to G.R.C.). 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.
BMAL1是一种核心昼夜节律钟蛋白，对生理功能的昼夜节律以及维持生理平衡（包括肾功能的各个方面）非常重要。全球 Bmal1 基因敲除（KO）雄性小鼠在正常或高盐饮食条件下，肾脏钠（Na）排泄的昼夜节律消失。然而，肾脏特异性 Bmal1 KO 雄性小鼠的肾脏钠排泄节律保持不变。肾上腺合成的激素（如醛固酮）会影响肾电解质的处理。肾上腺 BMAL1 在肾功能调节中的作用尚不清楚。本研究的目的是验证肾上腺 BMAL1 是醛固酮和肾钠处理正常节律所必需的这一假设。将雄性和雌性肾上腺特异性醛固酮合成酶 Cre 阳性（AS）Bmal1 KO 小鼠和同窝 Cre 阴性、Floxed 对照小鼠（n=5-9/基因型）在代谢笼中驯化 3 天，然后在小鼠摄入正常盐饮食的 3 天内采集样本，随后摄入低盐饮食 7 天，以刺激小鼠产生醛固酮。对小鼠 12 小时的食物摄入量进行测量，并收集尿样以测量肾脏钠平衡的日夜模式。尿液中醛固酮的排泄量是通过酶联免疫吸附法测定的。对照组和 KO 雄性小鼠在低盐饮食后，昼夜尿醛固酮排泄量均增加（饮食的方差分析主效应，P<0.05）。雄性 AS Bmal1 KO 小鼠在正常和低盐饮食后，日尿醛固酮排泄量显著增加（方差分析基因型的主效应，p=0.0230），夜尿醛固酮排泄量也有增加趋势（p=0.0571）。有趣的是，这些基因型效应在雌性 AS Bmal1 KO 小鼠中未见。雌性小鼠在低盐饮食后尿醛固酮增加，但对照组和 KO 小鼠仅在夜间增加（p=0.0205）。在肾脏 Na 平衡方面也观察到了性别差异，雄性 AS Bmal1 KO 小鼠与对照组相比，在白天 Na 平衡更积极，而雌性则不然（基因型的方差分析主效应，p=0.0282）。总之，这些数据表明肾上腺 BMAL1 是醛固酮和肾钠平衡正常节律所必需的，且具有性别依赖性。未来的工作将研究醛固酮的变化是否会导致肾脏 Na 平衡的变化。这项工作得到了美国心脏协会（H.C.获博士后奖学金P0240441；M.G.获19EIA34660135设立的研究者奖）、罗伯特和玛丽-凯德生理学教授职位（M.G.）以及美国国立卫生研究院（G.R.C.获F32DK121424）的支持。这是在 2024 年美国生理学峰会上发表的摘要全文，只有 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。
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Pub Date : 2024-05-01DOI: 10.1152/physiol.2024.39.s1.1445
Donghee Kim, Carl White
Carotid body (CB) glomus cells sense changes in arterial O2 pressure (PO2) and pH, and adjust the secretory and carotid sinus nerve activity and ventilation to help maintain normal levels of blood PO2 and pH. Our recent studies showed that isolated CB cell clusters perfused with physiological buffer solution generate spontaneous Ca2+ oscillations at low frequency in normoxia. Mild and moderate levels of hypoxia (2-5%O2) and acidosis (pHo7.2-7.3) increased the frequency and amplitude of Ca2+ oscillations. Inhibitors of voltage-dependent Ca2+ channels and removal of external Ca2+ abolished Ca2+ oscillations, indicating that Ca2+ influx was critical for generating Ca2+ oscillations. To better understand the phenomenon of Ca2+oscillations in glomus cells, we examined the potential role of oscillations in cell membrane potential (Em) in CB cells in triggering Ca2+ influx and Ca2+ oscillations. Using the cell-attached patch configuration, we assessed cell Em by recording TASK single channels, because a linear relationship exists between TASK amplitude and cell Em. Recording of TASK in CB cells in normoxia showed that many CB cells exhibit oscillations in TASK amplitude, indicating the presence of spontaneous oscillations in cell Em. The oscillation frequency of cell Em was similar to that of Ca2+ oscillations. Oscillations in TASK single channel amplitude were blocked by nifedipine (Ca2+ channel antagonist), by removal of extracellular Ca2+, and by 2-APB (an inhibitor of ER Ca2+ channel and store-operated Ca2+ entry). Mild hypoxia increased the frequency of oscillations of TASK amplitude, indicating that mild hypoxia increased the frequency of cell Em oscillations. These findings suggest that cell Em oscillations (that open voltage-dependent Ca2+ channels and increase Ca2+ influx) are an integral component of the cellular signaling mechanism by which Ca2+ oscillations are produced in CB cells. This work was funded by National Institutes of Health (NIH) grants to D.K. (HL111497) and C.W. (HL142906), and an award from Rosalind Franklin University of Medicine and Science. 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.
颈动脉体（CB）神经胶质细胞能感知动脉血氧压力（PO2）和 pH 值的变化，并调节分泌神经和颈动脉窦神经的活动和通气，以帮助维持正常的血液 PO2 和 pH 值。我们最近的研究表明，用生理缓冲溶液灌注的离体 CB 细胞簇在常氧状态下会产生低频率的自发 Ca2+ 振荡。轻度和中度缺氧（2-5%O2）和酸中毒（pHo7.2-7.3）会增加 Ca2+ 振荡的频率和振幅。电压依赖性 Ca2+ 通道抑制剂和去除外部 Ca2+ 可消除 Ca2+ 振荡，这表明 Ca2+ 流入是产生 Ca2+ 振荡的关键。为了更好地理解胶团细胞中的 Ca2+ 振荡现象，我们研究了 CB 细胞中细胞膜电位（Em）的振荡在触发 Ca2+ 流入和 Ca2+ 振荡中的潜在作用。由于 TASK 振幅与细胞 Em 之间存在线性关系，因此我们使用细胞连接贴片配置，通过记录 TASK 单通道来评估细胞 Em。在常氧状态下记录 CB 细胞的 TASK 显示，许多 CB 细胞的 TASK 振幅呈现振荡，这表明细胞 Em 存在自发振荡。细胞Em的振荡频率与Ca2+振荡频率相似。硝苯地平（Ca2+通道拮抗剂）、去除细胞外Ca2+和2-APB（ER Ca2+通道和储存操作的Ca2+进入抑制剂）均可阻断TASK单通道振幅的振荡。轻度缺氧增加了TASK振幅的振荡频率，表明轻度缺氧增加了细胞Em振荡的频率。这些发现表明，细胞Em振荡（打开电压依赖性Ca2+通道并增加Ca2+流入）是CB细胞产生Ca2+振荡的细胞信号机制的一个组成部分。这项工作得到了美国国立卫生研究院（NIH）对 D.K. (HL111497) 和 C.W. (HL142906) 的资助，以及罗莎琳德-富兰克林医科大学（Rosalind Franklin University of Medicine and Science）的奖励。本文是在 2024 年美国生理学峰会上发表的摘要全文，只有 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。
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Pub Date : 2024-05-01DOI: 10.1152/physiol.2024.39.s1.1132
Yu Qin, Ben Zhao, Sarah Lovett, Cristina Besosa, J. Kennedy, Sara Burke, Andrew P. Maurer
A consistently observed characteristic of hippocampal place fields is the shifting of the field's center of mass and the subsequent development of asymmetry. This is evidenced by the expansion of the place field in an asymmetric manner over repeated traversals, wherein a rat's initial entry into the field prompts a low firing rate that substantially increases as it exits. Our study delves deeper into these spatiotemporal asymmetries of place field spiking, specifically examining their relationship with theta oscillations and disentangling the effects from environmental factors. Analysis of neuronal data from a T-maze alternation task revealed a distinct non-uniform firing pattern of place cells. This pattern was markedly skewed in relation to the phases of theta cycles, indicating a phase precession effect. We found that as the rat navigates through the place field, there is a systematic advancement of spike timing, with action potentials tending to cluster in the early phases of theta during the exit phase of the field. Such temporal coordination of spikes suggests that the timing of neural activity within theta cycles is as integral as spatial location, influencing the dynamics of place field expansion and potentially affecting the hippocampal local field potential. This discovery underscores the role of theta phase precession in spatial encoding, proposing a novel temporal component that could underpin the cognitive map within the hippocampus. R01 MH126236 R01 AG055544. 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.
海马位置场的一个持续观察到的特征是场的质心移动以及随后的不对称发展。这表现为位置场在反复穿越过程中以不对称的方式扩大，大鼠最初进入位置场时的点燃率较低，而当它离开时点燃率大幅上升。我们的研究深入探讨了位置场尖峰的这些时空不对称现象，特别是研究了它们与θ振荡的关系，并将其与环境因素的影响区分开来。通过分析T迷宫交替任务的神经元数据，发现了位置细胞明显的非均匀点燃模式。这种模式与θ周期的相位明显偏斜，表明存在相位前冲效应。我们发现，当大鼠穿过位置场时，尖峰时间会有系统性的提前，动作电位倾向于聚集在位置场出口阶段的θ早期阶段。尖峰的这种时间协调表明，θ周期内神经活动的时间与空间位置一样不可或缺，它影响着位置场的扩展动态，并可能影响海马局部场电位。这一发现强调了θ相位前冲在空间编码中的作用，提出了一种可能支撑海马认知图谱的新的时间成分。R01 MH126236 R01 AG055544。这是在 2024 年美国生理学峰会上发表的摘要全文，只有 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。
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Pub Date : 2024-05-01DOI: 10.1152/physiol.2024.39.s1.1717
Angela Galeos, Rodion Isakovich, Valerie C Cates, Anthony Marullo, Nicholas Strzalkowski, Trevor Day
Wearing medical barriers has recently expanded from healthcare to public settings, and could increase dead space and facilitate rebreathing of expired air resulting in heat accumulation, hypercapnia, and hypoxia, particularly during physical activity. We recently showed that participants wearing surgical masks (SM) and N95 respirators (N95) over 60-min during seated rest had mild and immediately reversible (a) increases face microclimate temperature, (b) increases in the pressure of end-tidal (PET)CO2, (c) decreases in PETO2, but (d) no differences in peripheral oxygen saturation (SpO2). Previous publications showed conflicting results of superimposed barrier wearing during physical activity, and there are limited studies that assessed face microclimate temperature and end-tidal gases, particularly comparing superimposed SM and N95. We hypothesized that participants wearing SM and N95 will experience mild face microclimate hyperthermia, hypoxia, and hypercapnia during 3mph treadmill walking. Participants (n=18; 8F) randomly wore (a) no barrier (NB), (b) SM or (c) N95 during a 10-min standing baseline, 20-min treadmill walking (3 mph), and a 10-min standing recovery. We continuously measured face microclimate temperature (thermistor), end tidal gases (PETCO2, PETO2; oro-nasal cannula), SpO2 (peripheral pulse oximeter). Average 20-min PETCO2 (higher; p<0.0001, P=0.0001) and PETO2 (lower; P=0.0003, P=0.0178) were significantly from baseline for both SM and N95, respectively. The delta between the 20-min average compared to the baseline data was not statistically significant for PETCO2 or PETO2 in all three conditions, except for ΔPETCO2 NB vs. N95 (higher; P=0.0344). Additionally, there was no difference in SpO2 across all barrier conditions during exercise. These mild physiological effects may account for qualitative reports of shortness of breath and increased perceived exertion while wearing barriers during physical activity. However, these effect-magnitudes are not physiologically-meaningful, and are immediately reversed upon cessation of exercise and/or barrier removal. NSERC. 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.
佩戴医疗屏障最近已从医疗机构扩展到公共场所，可能会增加死腔，促进呼出气体的再吸入，导致热量积聚、高碳酸血症和缺氧，尤其是在体育活动期间。我们最近的研究表明，在坐着休息时佩戴外科口罩（SM）和 N95 呼吸器（N95）超过 60 分钟的参与者会出现轻微且可立即逆转的以下情况：(a) 面部微气候温度升高；(b) 潮气末二氧化碳（PET）压力升高；(c) PETO2 降低；但 (d) 周围血氧饱和度（SpO2）无差异。以前的出版物显示，在体育活动中佩戴叠加屏障的结果相互矛盾，评估面部微气候温度和潮气末气体的研究有限，特别是比较叠加 SM 和 N95 的研究。我们假设，佩戴 SM 和 N95 的参与者在每小时 3 英里的跑步机行走过程中会出现轻微的面部微气候高热、缺氧和高碳酸血症。参与者（n=18；8F）在 10 分钟站立基线、20 分钟跑步机行走（3 英里/小时）和 10 分钟站立恢复期间随机佩戴（a）无屏障（NB）、（b）SM 或（c）N95。我们连续测量面部微气候温度（温度计）、潮气末（PETCO2、PETO2；口鼻插管）、SpO2（外周脉搏血氧计）。20 分钟平均 PETCO2（较高；P<0.0001，P=0.0001）和 PETO2（较低；P=0.0003，P=0.0178）分别与 SM 和 N95 的基线相比有显著差异。除 ΔPETCO2 NB 与 N95（较高；P=0.0344）外，在所有三种情况下，20 分钟平均值与基线数据相比，PETCO2 或 PETO2 的三角差均无统计学意义。此外，在运动过程中，所有屏障条件下的 SpO2 均无差异。这些轻微的生理影响可能是在体育活动中佩戴屏障时出现呼吸急促和体力消耗增加的定性报告的原因。不过，这些影响的程度在生理上没有意义，而且在停止运动和/或移除屏障后会立即逆转。国家科学研究中心。这是在 2024 年美国生理学峰会上发表的摘要全文，仅以 HTML 格式提供。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。
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Pub Date : 2024-05-01DOI: 10.1152/physiol.2024.39.s1.736
Tanvi Potluri, Tianming You, Ping Yin, Jonah Stulberg, Yang Dai, David Escobar, Hong Zhao
Background: Skeletal muscle fibrosis represents accumulation of extracellular matrix (ECM), often leading to muscle weakness and atrophy. Notably, lower abdominal muscle (LAM) fibrosis and atrophy cause inguinal herniation—a prevalent condition lacking pharmacological treatment. We developed a herniation mouse model, Aromhum, characterized by spontaneous scrotal hernias due to local estradiol (E2) production within LAM as well as hernia-associated fibroblasts (HAFs) that express platelet-derived growth factor alpha (PDGFRA) and estrogen receptor alpha (ESR1). Objectives & Hypothesis: Our objective was to investigate the mechanism of ESR1 signaling on LAM HAFs and subsequent development of hernias. Methods: We manipulated estrogen signaling in two ways: first, we generated fibroblast-specific estrogen receptor alpha knockout mice (fEsr1−/−-Aromhum) capable of local E2 production but incapable of signaling through ESR1 (n = 5-10 mice/group). Second, we blocked E2 signaling pharmacologically using the potent ESR1 antagonist fulvestrant (0.15mg/kg, 90 days, n=10-15 mice/group). We conducted in vitro experiments on primary LAM HAFs exposed to 10nM E2 ± 100nM Fulvestrant (24-48h). These cells underwent analysis via ESR1 ChIP, ATAC, and RNA-seq in 3 technical replicates (3-5 mice each). Additionally, to demonstrate clinical relevance, we probed human herniated LAM tissues from patients (n=25 samples, 21-76 years). Results: All Aromhum mice develop scrotal hernias by 6 weeks. However, fEsr1−/−-Aromhum mice did not develop hernias, while littermate controls exhibited hernias. Thus, HAF ESR1 depletion mitigated LAM fibrosis and atrophy. Similarly, administering fulvestrant prior to hernia onset prevented hernia development. Remarkably, fulvestrant treatment in mice that had developed large scrotal hernias (>200mm2) led to complete hernia regression with reversed muscle fibrosis and fiber atrophy (collagen levels comparable to wild-type mice). In vitro HAF culturing and subsequent multiomic analyses unveiled a core set of 58 genes directly influenced by E2/ESR1, including crucial ECM genes like fibulins ( Fbln5, Fbln7), metalloproteases ( Adamts3, Adamts6), and signaling molecules ( Ltbp1, Ncam1, Piezo2). Pathways such as TGFβ, WNT, and N-Glycan biosynthesis were significantly upregulated by E2. Human herniated LAM tissues exhibited substantial fibrosis, along with stromal HAF markers PDGFRA and ESR1. We also validated expression of the core E2-modulated genes in human LAM tissues ( NCAM1, LTBP1, ADAMTS6, PIEZO2). Collectively, these findings provide compelling evidence of ESR1 pathway activation and downstream gene involvement in both Aromhum scrotal hernias and human inguinal hernias. Conclusion: Our research underscores the central role of E2 in skeletal muscle fibrosis. Notably, we demonstrated that fibrosis can be entirely reversed by modulation of ESR1 signaling. Our study offers valuable insights into downstream genes and pathways that may serve as t
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