The mechanism of pulmonary venous remodeling (PVR) remains unclear. We tested the role of the calcium sensing receptor (CaSR) in PVR in pulmonary hypertension (PH).
Methods
PVR was investigated in two PH models, monocrotaline (MCT)-induced PH (MCT-PH) and hypoxia-induced PH (HPH). Human pulmonary venous smooth muscle cells (PVSMCs) were subjected to hypoxia. We examined whether CaSR is involved in the enhanced Ca2+ influx and proliferation in PVSMCs and whether CaSR mediates PVR.
Results
PVR presented in distal pulmonary veins (PV) in MCT-PH and HPH rats, accompanied by upregulated CaSR expression in PVSMCs from PH rats. Hypoxia promoted human PVSMCs proliferation with increased CaSR and HIF-1α expression in hypoxic cells. Extracellular Ca2+ restoration induced a huge increase in [Ca2+]i in MCT-PH PVSMCs and human hypoxic PVSMCs, which was significantly higher than that in normal cells. Both the basal [Ca2+]i and proliferate rate in MCT-PH PVSMCs and human hypoxic PVSMCs were higher than in normal PVSMCs. Spermine or R568 enhanced, whereas both NPS2143 or NPS2390 and siCaSR attenuated the extracellular Ca2+-induced [Ca2+]i increase in rat MCT-PH PVSMCs and human hypoxic PVSMCs and hypoxia-induced human PVSMCs proliferation. Blockade of CaSR with NPS2143 attenuated the increases in basal [Ca2+]i in PVSMCs, right ventricular systolic pressure, and Fulton index in PH rats and prevented PVR and PH development in rats injected with MCT or exposed to hypoxia.
Conclusions
Upregulated CaSR mediating excessive PVSMCs proliferation through enhanced CaSR function and increased intracellular Ca2+ signaling is an important pathogenic mechanism underlying the development of PVR in PH.
{"title":"Upregulated Calcium Sensing Receptor Mediates Pulmonary Venous Remodeling in Pulmonary Hypertension","authors":"Qiudi Mo, Xing Wen, Luyao Wang, Weitao Cao, Jieping Liang, Shaoxing Li, Zhenli Fu, Xiaohua Gao, Yan Xue, Hong Yuan, Zhenbo Xu, Wei Hong, Yumin Zhou, Gongyong Peng","doi":"10.1111/apha.70142","DOIUrl":"10.1111/apha.70142","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>The mechanism of pulmonary venous remodeling (PVR) remains unclear. We tested the role of the calcium sensing receptor (CaSR) in PVR in pulmonary hypertension (PH).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>PVR was investigated in two PH models, monocrotaline (MCT)-induced PH (MCT-PH) and hypoxia-induced PH (HPH). Human pulmonary venous smooth muscle cells (PVSMCs) were subjected to hypoxia. We examined whether CaSR is involved in the enhanced Ca<sup>2+</sup> influx and proliferation in PVSMCs and whether CaSR mediates PVR.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>PVR presented in distal pulmonary veins (PV) in MCT-PH and HPH rats, accompanied by upregulated CaSR expression in PVSMCs from PH rats. Hypoxia promoted human PVSMCs proliferation with increased CaSR and HIF-1α expression in hypoxic cells. Extracellular Ca<sup>2+</sup> restoration induced a huge increase in [Ca<sup>2+</sup>]<sub>i</sub> in MCT-PH PVSMCs and human hypoxic PVSMCs, which was significantly higher than that in normal cells. Both the basal [Ca<sup>2+</sup>]<sub>i</sub> and proliferate rate in MCT-PH PVSMCs and human hypoxic PVSMCs were higher than in normal PVSMCs. Spermine or R568 enhanced, whereas both NPS2143 or NPS2390 and siCaSR attenuated the extracellular Ca<sup>2+</sup>-induced [Ca<sup>2+</sup>]<sub>i</sub> increase in rat MCT-PH PVSMCs and human hypoxic PVSMCs and hypoxia-induced human PVSMCs proliferation. Blockade of CaSR with NPS2143 attenuated the increases in basal [Ca<sup>2+</sup>]<sub>i</sub> in PVSMCs, right ventricular systolic pressure, and Fulton index in PH rats and prevented PVR and PH development in rats injected with MCT or exposed to hypoxia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Upregulated CaSR mediating excessive PVSMCs proliferation through enhanced CaSR function and increased intracellular Ca<sup>2+</sup> signaling is an important pathogenic mechanism underlying the development of PVR in PH.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145740062","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}
Zhaobin Deng, Dongxu Zheng, Jinsook Son, Wen Du, Wendy M. McKimpson, Qingli Liu, Domenico Accili
Aim
Insulin resistance and pancreatic β-cell failure are key characteristics of type 2 diabetes (T2D). Impaired β-cell function is associated with loss of β-cell identity, resulting in β-cell dedifferentiation or trans-differentiation to other endocrine cells. We have shown that β-cell dedifferentiation can be reversed, restoring insulin secretion. The aim of this study was to investigate whether semaglutide or tirzepatide treatment can reverse early stages of β-cell dedifferentiation in db/db mice independent of their effect on body weight.
Methods
After 4 weeks of treatment, 12-week-old db/db mice were assessed by oral glucose tolerance test and immunofluorescence to evaluate glucose clearance capacity and effects on pancreatic β-cell. Body weight, fasting blood glucose, and plasma insulin levels were monitored weekly. Bulk RNA sequencing from islets was performed to identify potential targets.
Results
At the doses employed, tirzepatide stabilized, whereas semaglutide was unable to reverse the weight gain of db/db mice. After a 4-week course, both groups showed comparable glucose lowering and increased insulin levels. However, both treatments failed to reverse pancreatic β-cell dedifferentiation, as assessed by either the percentage of cells expressing the dedifferentiation marker ALDH1A3+ or FOXO1 translocation. Furthermore, the number of β-cells expressing low levels of PDX1 was higher in both treatment groups than in controls. Gene expression analyses showed a muted transcriptional response in overlapping patterns in islets treated with either compound but no obvious candidate target genes.
Conclusion
The findings highlight that the early glucose-lowering effects of semaglutide and tirzepatide in db/db mice occur independently of changes to β-cell identity.
{"title":"Effect of Weight-Neutral Treatment With Semaglutide or Tirzepatide on β-Cell Identity in db/db Mice","authors":"Zhaobin Deng, Dongxu Zheng, Jinsook Son, Wen Du, Wendy M. McKimpson, Qingli Liu, Domenico Accili","doi":"10.1111/apha.70141","DOIUrl":"10.1111/apha.70141","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Insulin resistance and pancreatic β-cell failure are key characteristics of type 2 diabetes (T2D). Impaired β-cell function is associated with loss of β-cell identity, resulting in β-cell dedifferentiation or trans-differentiation to other endocrine cells. We have shown that β-cell dedifferentiation can be reversed, restoring insulin secretion. The aim of this study was to investigate whether semaglutide or tirzepatide treatment can reverse early stages of β-cell dedifferentiation in <i>db/db</i> mice independent of their effect on body weight.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>After 4 weeks of treatment, 12-week-old <i>db/db</i> mice were assessed by oral glucose tolerance test and immunofluorescence to evaluate glucose clearance capacity and effects on pancreatic β-cell. Body weight, fasting blood glucose, and plasma insulin levels were monitored weekly. Bulk RNA sequencing from islets was performed to identify potential targets.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>At the doses employed, tirzepatide stabilized, whereas semaglutide was unable to reverse the weight gain of <i>db/db</i> mice. After a 4-week course, both groups showed comparable glucose lowering and increased insulin levels. However, both treatments failed to reverse pancreatic β-cell dedifferentiation, as assessed by either the percentage of cells expressing the dedifferentiation marker ALDH1A3<sup>+</sup> or FOXO1 translocation. Furthermore, the number of β-cells expressing low levels of PDX1 was higher in both treatment groups than in controls. Gene expression analyses showed a muted transcriptional response in overlapping patterns in islets treated with either compound but no obvious candidate target genes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The findings highlight that the early glucose-lowering effects of semaglutide and tirzepatide in <i>db/db</i> mice occur independently of changes to β-cell identity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145699527","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}
Martin Sládek, Vendula Lužná, Pavel Houdek, Alena Sumová
Aim
The circadian clock in the suprachiasmatic nuclei of the hypothalamus (SCN) is resistant to glucocorticoids (GC) in adults but responds to dexamethasone (DEX) during the fetal stage. Previously, this resistance of the adult SCN clock was attributed to a developmental loss of the glucocorticoid receptor (GR). The aim of our study was to re-examine the mechanism underlying SCN clock resistance.
Methods
We detected GR in the adult SCN at the mRNA level (Nr3c1) using RT-qPCR and at the protein level by immunohistochemistry, and examined the effects of DEX on the SCN clock of mPer2Luc mice ex vivo at embryonic day E17, postnatal days P1–2, P3, P5, P10, and adulthood.
Results
Surprisingly, we found that Nr3c1 expression gradually increases from the fetal stage to postnatal day (P)28. In the adult SCN, GR immunoreactivity is present in both neurons and glia. The effect of DEX on the SCN clock disappears shortly after birth. Although DEX does not entrain the adult SCN clock, it acutely increases the expression of Gilz and Sgk1, indicating that GRs in the adult SCN can activate downstream signaling pathways. Inhibition of glial metabolism by fluorocitrate had no effect on resistance to DEX, but treatment with tetrodotoxin sensitized the clock to DEX and induced phase shifts similar to those observed at the fetal stage.
Conclusion
These results indicate that the adult SCN possesses GRs capable of activating GC-signaling pathways, but the clock is resistant to GC in part due to coupling between individual cellular oscillators.
{"title":"Suprachiasmatic Nuclei Possess Glucocorticoid Receptors That Activate Downstream Signaling Pathways but Do Not Entrain Their Circadian Clock","authors":"Martin Sládek, Vendula Lužná, Pavel Houdek, Alena Sumová","doi":"10.1111/apha.70138","DOIUrl":"https://doi.org/10.1111/apha.70138","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>The circadian clock in the suprachiasmatic nuclei of the hypothalamus (SCN) is resistant to glucocorticoids (GC) in adults but responds to dexamethasone (DEX) during the fetal stage. Previously, this resistance of the adult SCN clock was attributed to a developmental loss of the glucocorticoid receptor (GR). The aim of our study was to re-examine the mechanism underlying SCN clock resistance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We detected GR in the adult SCN at the mRNA level (<i>Nr3c1</i>) using RT-qPCR and at the protein level by immunohistochemistry, and examined the effects of DEX on the SCN clock of <i>mPer2</i><sup><i>Luc</i></sup> mice ex vivo at embryonic day E17, postnatal days P1–2, P3, P5, P10, and adulthood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Surprisingly, we found that <i>Nr3c1</i> expression gradually increases from the fetal stage to postnatal day (P)28. In the adult SCN, GR immunoreactivity is present in both neurons and glia. The effect of DEX on the SCN clock disappears shortly after birth. Although DEX does not entrain the adult SCN clock, it acutely increases the expression of <i>Gilz</i> and <i>Sgk1</i>, indicating that GRs in the adult SCN can activate downstream signaling pathways. Inhibition of glial metabolism by fluorocitrate had no effect on resistance to DEX, but treatment with tetrodotoxin sensitized the clock to DEX and induced phase shifts similar to those observed at the fetal stage.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These results indicate that the adult SCN possesses GRs capable of activating GC-signaling pathways, but the clock is resistant to GC in part due to coupling between individual cellular oscillators.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70138","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145618913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Elissa Silva de Farias Mello, André Luiz Musmanno Branco Oliveira, Pedro Paulo da Silva Soares, Gabriel Dias Rodrigues
{"title":"Acute Normobaric Hypoxia Reveals Blunted Chemoreflex and Autonomic Dysfunction in Asymptomatic Post-COVID-19 Patients","authors":"Elissa Silva de Farias Mello, André Luiz Musmanno Branco Oliveira, Pedro Paulo da Silva Soares, Gabriel Dias Rodrigues","doi":"10.1111/apha.70136","DOIUrl":"10.1111/apha.70136","url":null,"abstract":"","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145595686","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}
<p>The recent study by Espejo and colleagues published in <i>Acta Physiologica</i> [<span>1</span>] caught my attention because it addresses a theme of particular interest to me, as well as a mechanism for which there is growing evidence: The differential expression and function of transporter molecules. In particular, this study focused on transporter molecules beyond the well-known ion channels and transporters responsible for the action potential and primary calcium handling [<span>2, 3</span>] in atrial and ventricular cardiomyocytes. On the one hand, this complicates the understanding of the functional role of these molecules (although it makes the life of a researcher more interesting). On the other hand, it opens up possibilities for more targeted interventions and therapeutic approaches.</p><p>The concept of differential expression and function of transporter molecules was previously addressed at the structural level [<span>4</span>] by the group that authored the study by Espejo and colleagues published in <i>Acta Physiologica</i> [<span>1</span>]. In this earlier study, the promoter activity of the electroneutral Na<sup>+</sup>, HCO<sub>3</sub><sup>−</sup> cotransporter NBCn1 (encoding gene Slc4a7) was observed in atrial, but not ventricular cardiomyocytes [<span>4</span>], and the differential expression of NBCn1 suggested a differential function of NBCn1 in atria and ventricles.</p><p>Notably, the authors remained curious about the functional consequences of the differential expression of NBCn1 in cardiomyocytes. Thus, when a specific tool for functionally exploring this question, namely an appropriate transgenic mouse, became available, Espejo and colleagues could address this issue [<span>1</span>]. The merit of their study lies in investigating the functional consequences of differential expression of NBCn1 with a clear and well-founded hypothesis at multiple levels: That NBCn1 influences structure, contractile function, and electrophysiological properties of the heart. The hypothesis was tested using a mouse model with global elimination of NBCn1. This model may have limitations, such as the possible development of compensatory mechanisms. However, for the present study, it was adequate as it simulates the effects of loss-of-function genetic variants or systemic therapeutic interventions.</p><p>What novel, additional insight was obtained by Espejo and colleagues in the <i>Acta Physiologica</i> publication [<span>1</span>] (see Figure 1)? It was shown that NBCn1 mRNA and protein expression are stronger in the atria compared to the ventricles. The knockdown of NBCn1 reduced acid transport function in the atria by more than 50%; alterations in net acid extrusion in the ventricles were not observed. These effects were accompanied by increased blood pressure and cardiac hypertrophy with slower ventricular relaxation, whilst detailed analysis of the ECG did not reveal alterations in electrophysiological properties. Further insight, howe
{"title":"Differential pH Regulation in Cardiomyocytes","authors":"Rudolf Schubert","doi":"10.1111/apha.70134","DOIUrl":"10.1111/apha.70134","url":null,"abstract":"<p>The recent study by Espejo and colleagues published in <i>Acta Physiologica</i> [<span>1</span>] caught my attention because it addresses a theme of particular interest to me, as well as a mechanism for which there is growing evidence: The differential expression and function of transporter molecules. In particular, this study focused on transporter molecules beyond the well-known ion channels and transporters responsible for the action potential and primary calcium handling [<span>2, 3</span>] in atrial and ventricular cardiomyocytes. On the one hand, this complicates the understanding of the functional role of these molecules (although it makes the life of a researcher more interesting). On the other hand, it opens up possibilities for more targeted interventions and therapeutic approaches.</p><p>The concept of differential expression and function of transporter molecules was previously addressed at the structural level [<span>4</span>] by the group that authored the study by Espejo and colleagues published in <i>Acta Physiologica</i> [<span>1</span>]. In this earlier study, the promoter activity of the electroneutral Na<sup>+</sup>, HCO<sub>3</sub><sup>−</sup> cotransporter NBCn1 (encoding gene Slc4a7) was observed in atrial, but not ventricular cardiomyocytes [<span>4</span>], and the differential expression of NBCn1 suggested a differential function of NBCn1 in atria and ventricles.</p><p>Notably, the authors remained curious about the functional consequences of the differential expression of NBCn1 in cardiomyocytes. Thus, when a specific tool for functionally exploring this question, namely an appropriate transgenic mouse, became available, Espejo and colleagues could address this issue [<span>1</span>]. The merit of their study lies in investigating the functional consequences of differential expression of NBCn1 with a clear and well-founded hypothesis at multiple levels: That NBCn1 influences structure, contractile function, and electrophysiological properties of the heart. The hypothesis was tested using a mouse model with global elimination of NBCn1. This model may have limitations, such as the possible development of compensatory mechanisms. However, for the present study, it was adequate as it simulates the effects of loss-of-function genetic variants or systemic therapeutic interventions.</p><p>What novel, additional insight was obtained by Espejo and colleagues in the <i>Acta Physiologica</i> publication [<span>1</span>] (see Figure 1)? It was shown that NBCn1 mRNA and protein expression are stronger in the atria compared to the ventricles. The knockdown of NBCn1 reduced acid transport function in the atria by more than 50%; alterations in net acid extrusion in the ventricles were not observed. These effects were accompanied by increased blood pressure and cardiac hypertrophy with slower ventricular relaxation, whilst detailed analysis of the ECG did not reveal alterations in electrophysiological properties. Further insight, howe","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70134","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145538146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Cerebrospinal fluid homeostasis typically refers to the dynamic equilibrium in the secretion, circulation, absorption, and physicochemical properties of cerebrospinal fluid (CSF). It is crucial for maintaining normal intracranial pressure, the stability of the intracranial internal environment, and normal cellular functions. In the November issue of <i>Acta Physiologica</i>, Henao et al. conducted further research on K<sup>+</sup> homeostasis in the CSF and published their findings in the article “Role of the choroid plexus Kir7.1 channel in the regulation of mouse cerebrospinal fluid K<sup>+</sup> concentration.” Using genome editing technology to establish models and observing the electrophysiological characteristics of mouse choroid plexus epithelial cells (CPE) and related K<sup>+</sup> transport pathways, they revealed a novel mechanism regulating K<sup>+</sup> concentration in the CSF and drew an important conclusion: Kir7.1 plays a critical role in the formation of the membrane potential in CPE and the regulation of [K<sup>+</sup>]<sub>CSF</sub> [<span>1</span>].</p><p>The choroid plexus, located in parts of the cerebral ventricles, is a key structure for CSF secretion. The apical and basolateral membranes of the CPE contain numerous ion transport pathways, including Na<sup>+</sup>-K<sup>+</sup>-ATPase, NKCC1, and Kir7.1 [<span>2</span>]. Kir (inward rectifying K<sup>+</sup> channels) are a class of K<sup>+</sup> channels with inward rectification properties. <i>Acta Physiologica</i> reported in 2017 on the important role of Kir4.1/Kir5.1 potassium channels in the renal distal tubules [<span>3</span>], suggesting that different Kir subtypes have distinct distributions and functions within the body. The gene name for Kir7.1 is KCNJ13. Unlike other “strong” rectifying channels, Kir7.1 exhibits weak inward rectification characteristics, very low single-channel conductance [<span>4</span>], and is highly sensitive to intra- and extracellular signals. NKCC1 stands for Na<sup>+</sup>-K<sup>+</sup>-2Cl<sup>−</sup> cotransporter 1. Its primary function is to mediate the coupled transport of Na<sup>+</sup>, K<sup>+</sup>, and CI<sup>−</sup> by utilizing the Na<sup>+</sup> and Cl<sup>−</sup> electrochemical gradients [<span>2</span>]. In summary, these three ion pathways interact and function cooperatively in K<sup>+</sup> transport.</p><p>Compared to the K<sup>+</sup> concentration in plasma (approximately 5.0 mmol/L), the K<sup>+</sup> level in the CSF is consistently maintained at a lower value of 2.5–3.0 mmol/L. Regarding this, MacAulay et al. conceptualized the “CPE-CSF K<sup>+</sup> cycle”, attributing the physiological recycling of K<sup>+</sup> in the CSF to the action of NKCC1 [<span>5</span>]. However, new research has found that Na<sup>+</sup>-K<sup>+</sup>-ATPase, NKCC1, and Kir7.1 are confirmed to co-localize and be highly expressed on the apical membrane of the CPE [<span>6</span>]. Specifically, Na<sup>+</sup>-K<sup>+</sup>-ATPase
{"title":"Physiology of K+ Homeostasis in Cerebrospinal Fluid: The Fine-Tuning Role of the Choroid Plexus Kir7.1 Channel","authors":"Peng Long, Gelei Xiao","doi":"10.1111/apha.70137","DOIUrl":"10.1111/apha.70137","url":null,"abstract":"<p>Cerebrospinal fluid homeostasis typically refers to the dynamic equilibrium in the secretion, circulation, absorption, and physicochemical properties of cerebrospinal fluid (CSF). It is crucial for maintaining normal intracranial pressure, the stability of the intracranial internal environment, and normal cellular functions. In the November issue of <i>Acta Physiologica</i>, Henao et al. conducted further research on K<sup>+</sup> homeostasis in the CSF and published their findings in the article “Role of the choroid plexus Kir7.1 channel in the regulation of mouse cerebrospinal fluid K<sup>+</sup> concentration.” Using genome editing technology to establish models and observing the electrophysiological characteristics of mouse choroid plexus epithelial cells (CPE) and related K<sup>+</sup> transport pathways, they revealed a novel mechanism regulating K<sup>+</sup> concentration in the CSF and drew an important conclusion: Kir7.1 plays a critical role in the formation of the membrane potential in CPE and the regulation of [K<sup>+</sup>]<sub>CSF</sub> [<span>1</span>].</p><p>The choroid plexus, located in parts of the cerebral ventricles, is a key structure for CSF secretion. The apical and basolateral membranes of the CPE contain numerous ion transport pathways, including Na<sup>+</sup>-K<sup>+</sup>-ATPase, NKCC1, and Kir7.1 [<span>2</span>]. Kir (inward rectifying K<sup>+</sup> channels) are a class of K<sup>+</sup> channels with inward rectification properties. <i>Acta Physiologica</i> reported in 2017 on the important role of Kir4.1/Kir5.1 potassium channels in the renal distal tubules [<span>3</span>], suggesting that different Kir subtypes have distinct distributions and functions within the body. The gene name for Kir7.1 is KCNJ13. Unlike other “strong” rectifying channels, Kir7.1 exhibits weak inward rectification characteristics, very low single-channel conductance [<span>4</span>], and is highly sensitive to intra- and extracellular signals. NKCC1 stands for Na<sup>+</sup>-K<sup>+</sup>-2Cl<sup>−</sup> cotransporter 1. Its primary function is to mediate the coupled transport of Na<sup>+</sup>, K<sup>+</sup>, and CI<sup>−</sup> by utilizing the Na<sup>+</sup> and Cl<sup>−</sup> electrochemical gradients [<span>2</span>]. In summary, these three ion pathways interact and function cooperatively in K<sup>+</sup> transport.</p><p>Compared to the K<sup>+</sup> concentration in plasma (approximately 5.0 mmol/L), the K<sup>+</sup> level in the CSF is consistently maintained at a lower value of 2.5–3.0 mmol/L. Regarding this, MacAulay et al. conceptualized the “CPE-CSF K<sup>+</sup> cycle”, attributing the physiological recycling of K<sup>+</sup> in the CSF to the action of NKCC1 [<span>5</span>]. However, new research has found that Na<sup>+</sup>-K<sup>+</sup>-ATPase, NKCC1, and Kir7.1 are confirmed to co-localize and be highly expressed on the apical membrane of the CPE [<span>6</span>]. Specifically, Na<sup>+</sup>-K<sup>+</sup>-ATPase ","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70137","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145538174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Binding the Problem: Galectin-3's Emerging Role in Advanced Glycation End Product Dynamics","authors":"Vera A. Kulow","doi":"10.1111/apha.70133","DOIUrl":"10.1111/apha.70133","url":null,"abstract":"","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145533939","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}
M. D. Lee, R. A. Clark, C. Buckley, X. Zhang, P. Uhlen, C. Wilson, J. G. McCarron
Aim
The endothelium regulates cardiovascular function by detecting and interpreting multiple extracellular signals from blood and surrounding tissues, even when these inputs are complex and conflicting. The major challenge faced by the endothelium is decoding this dynamic chemical environment to produce coordinated endothelial cellular responses. In addition to the problems of detection, extracellular signals must be processed correctly intracellularly to generate a functional outcome.
Methods
Ca2+ imaging, network analysis and spectral graph theory across ~1000 endothelial cells in intact arteries and veins.
Results
The venous endothelial cell population forms distinct, non-overlapping communities, each tuned to specific agonists. Within these communities, responsive cells act as bridges, linking members through the most direct communication route. Activation of one cell increases the likelihood of activation occurring in its neighbors, creating localized zones of high responsiveness. Only a small (5%) subset of cells responds to multiple activators. These multifunctional cells form unique connections that integrate and distribute signals between the agonist-specific sensing communities. We also show that different agonists elicit unique signaling patterns determined by the stimulus, not by intrinsic cellular properties. Finally, signal decoding strategies differ across vascular beds: venous endothelial cells rely on Ca2+ signal frequency, while arterial cells use signal amplitude.
Conclusion
The endothelium comprises functionally specialized populations. A small subset of pharmacologically distinct cells plays a key role in signal integration. These hubs are especially vulnerable to disconnection and dysfunction in disease, highlighting them as potential therapeutic targets. The findings presented reveal specialized encoding strategies that distinguish the arterio–venous axis.
{"title":"Endothelial Cell Organization Drives Distinct Agonist-Specific Ca2+ Dynamics in Arteries and Veins","authors":"M. D. Lee, R. A. Clark, C. Buckley, X. Zhang, P. Uhlen, C. Wilson, J. G. McCarron","doi":"10.1111/apha.70132","DOIUrl":"10.1111/apha.70132","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>The endothelium regulates cardiovascular function by detecting and interpreting multiple extracellular signals from blood and surrounding tissues, even when these inputs are complex and conflicting. The major challenge faced by the endothelium is decoding this dynamic chemical environment to produce coordinated endothelial cellular responses. In addition to the problems of detection, extracellular signals must be processed correctly intracellularly to generate a functional outcome.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Ca<sup>2+</sup> imaging, network analysis and spectral graph theory across ~1000 endothelial cells in intact arteries and veins.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The venous endothelial cell population forms distinct, non-overlapping communities, each tuned to specific agonists. Within these communities, responsive cells act as bridges, linking members through the most direct communication route. Activation of one cell increases the likelihood of activation occurring in its neighbors, creating localized zones of high responsiveness. Only a small (5%) subset of cells responds to multiple activators. These multifunctional cells form unique connections that integrate and distribute signals between the agonist-specific sensing communities. We also show that different agonists elicit unique signaling patterns determined by the stimulus, not by intrinsic cellular properties. Finally, signal decoding strategies differ across vascular beds: venous endothelial cells rely on Ca<sup>2+</sup> signal frequency, while arterial cells use signal amplitude.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The endothelium comprises functionally specialized populations. A small subset of pharmacologically distinct cells plays a key role in signal integration. These hubs are especially vulnerable to disconnection and dysfunction in disease, highlighting them as potential therapeutic targets. The findings presented reveal specialized encoding strategies that distinguish the arterio–venous axis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12621180/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145533910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Blood lactate concentration ([La−]), usually measured in mmol/L, is one of the most frequently measured parameters during clinical exercise tests as well as during performance assessments of athletes. Therefore, the purpose of this review is to examine the methodological and biological factors that influence [La−] in order to improve the accuracy and interpretation of its measurement during clinical, research, and athletic testing.
Methods
A narrative review of the scientific literature was conducted, focusing on studies addressing the biological as well as methodological variables that may affect the measurement of [La−].
Results
According to the lactate shuttle theory, blood [La−] depends on production, transport, and consumption. Both methodological and biological factors can substantially alter these processes and, subsequently, [La−], potentially leading to misinterpretation when comparing data across sessions or individuals.
Conclusion
Since lactate is commonly measured in research, medical, and training testing, it is important to understand these factors to avoid misinterpretation. The main recommendation is to control all these factors when measuring [La−] and to carry out the measurements under the same conditions when monitoring the evolution of a specific person or comparing different individuals.
{"title":"Factors Influencing Blood Lactate Concentration During Exercise: A Narrative Review With a Lactate Shuttle Perspective","authors":"José Antonio Benítez-Muñoz, Rocío Cupeiro","doi":"10.1111/apha.70131","DOIUrl":"10.1111/apha.70131","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Blood lactate concentration ([La<sup>−</sup>]), usually measured in mmol/L, is one of the most frequently measured parameters during clinical exercise tests as well as during performance assessments of athletes. Therefore, the purpose of this review is to examine the methodological and biological factors that influence [La<sup>−</sup>] in order to improve the accuracy and interpretation of its measurement during clinical, research, and athletic testing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A narrative review of the scientific literature was conducted, focusing on studies addressing the biological as well as methodological variables that may affect the measurement of [La<sup>−</sup>].</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>According to the lactate shuttle theory, blood [La<sup>−</sup>] depends on production, transport, and consumption. Both methodological and biological factors can substantially alter these processes and, subsequently, [La<sup>−</sup>], potentially leading to misinterpretation when comparing data across sessions or individuals.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Since lactate is commonly measured in research, medical, and training testing, it is important to understand these factors to avoid misinterpretation. The main recommendation is to control all these factors when measuring [La<sup>−</sup>] and to carry out the measurements under the same conditions when monitoring the evolution of a specific person or comparing different individuals.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12619971/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145533913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vincent Marcangeli, Laura Girard-Côté, Valeria Di Leo, Marie-Pier Roussel, Conor Lawless, Olivier Charest, Anteneh Argaw, Maude Dulac, Guy Hajj-Boutros, José A. Morais, Amy Vincent, Gilles Gouspillou, Jean-Philippe Leduc-Gaudet, Elise Duchesne
Background
Myotonic dystrophy type 1 (DM1) is caused by expanded CTG repeats in the DMPK gene, causing the accumulation of toxic RNA that sequesters RNA-binding proteins. Clinically, DM1 is characterized by progressive muscle weakness and atrophy, resulting in reduced physical capacity and quality of life. Recent evidence implicates mitochondrial dysfunction in DM1 pathophysiology. While aerobic exercise has been shown to improve skeletal muscle and mitochondrial health in individuals with DM1, the benefits of strength training remain unexplored.
Objectives
We investigated the effects of a 12-week strength training program on mitochondrial respiration, reactive oxygen species (ROS) production and muscle integrity in women with DM1.
Methods
Vastus lateralis muscle biopsies were collected pre- and post-training in participants with DM1 and once in unaffected/untrained individuals. Mitochondrial respiration and hydrogen peroxide emission (marker of ROS production) were assessed in permeabilized myofibers, while OXPHOS protein contents were quantified by immunoblotting and immunofluorescence. Markers of myofiber denervation (NCAM+) and integrity (centrally located myonuclei, damaged laminin, nuclear clumps) were assessed on histological sections.
Results
At baseline, DM1 participants exhibited lower mitochondrial respiration compared to unaffected individuals. Strength training significantly improved mitochondrial respiration and content in DM1 participants. At baseline, absolute ROS production was lower, while ROS production normalized to oxygen consumption (free radical leak) was higher, in DM1. Histological signs of denervation and altered muscle integrity were observed. Strength training partially normalized mitochondrial free radical leak and restored some markers of myofiber integrity.
Conclusion
Collectively, our results indicate that strength training enhances mitochondrial health and improves myofiber integrity in women with DM1.
{"title":"A 12-Week Strength Training Improves Mitochondrial Respiration, H2O2 Emission and Skeletal Muscle Integrity in Women With Myotonic Dystrophy Type 1","authors":"Vincent Marcangeli, Laura Girard-Côté, Valeria Di Leo, Marie-Pier Roussel, Conor Lawless, Olivier Charest, Anteneh Argaw, Maude Dulac, Guy Hajj-Boutros, José A. Morais, Amy Vincent, Gilles Gouspillou, Jean-Philippe Leduc-Gaudet, Elise Duchesne","doi":"10.1111/apha.70135","DOIUrl":"10.1111/apha.70135","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Myotonic dystrophy type 1 (DM1) is caused by expanded CTG repeats in the <i>DMPK</i> gene, causing the accumulation of toxic RNA that sequesters RNA-binding proteins. Clinically, DM1 is characterized by progressive muscle weakness and atrophy, resulting in reduced physical capacity and quality of life. Recent evidence implicates mitochondrial dysfunction in DM1 pathophysiology. While aerobic exercise has been shown to improve skeletal muscle and mitochondrial health in individuals with DM1, the benefits of strength training remain unexplored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>We investigated the effects of a 12-week strength training program on mitochondrial respiration, reactive oxygen species (ROS) production and muscle integrity in women with DM1.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Vastus lateralis muscle biopsies were collected pre- and post-training in participants with DM1 and once in unaffected/untrained individuals. Mitochondrial respiration and hydrogen peroxide emission (marker of ROS production) were assessed in permeabilized myofibers, while OXPHOS protein contents were quantified by immunoblotting and immunofluorescence. Markers of myofiber denervation (NCAM+) and integrity (centrally located myonuclei, damaged laminin, nuclear clumps) were assessed on histological sections.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>At baseline, DM1 participants exhibited lower mitochondrial respiration compared to unaffected individuals. Strength training significantly improved mitochondrial respiration and content in DM1 participants. At baseline, absolute ROS production was lower, while ROS production normalized to oxygen consumption (free radical leak) was higher, in DM1. Histological signs of denervation and altered muscle integrity were observed. Strength training partially normalized mitochondrial free radical leak and restored some markers of myofiber integrity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Collectively, our results indicate that strength training enhances mitochondrial health and improves myofiber integrity in women with DM1.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12619986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145533963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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