Acta Physiologica最新文献

{"title":"Pressure-Induced Changes in Intracellular pH Facilitate the Myogenic Response of Rat Small Tail Arteries","authors":"Ulrike Krien,&nbsp;Rudolf Schubert","doi":"10.1111/apha.70309","DOIUrl":"10.1111/apha.70309","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>The myogenic response contributes considerably to blood flow autoregulation. Intracellular pH (pH_i) has a substantial impact on small artery contractility. However, the role of putative pH_i changes during myogenic constriction is unknown. Therefore, the hypothesis was tested that changes in pH_i are associated with and contribute to the myogenic response in small arteries.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Rat small tail arteries were studied using isobaric myography and BCECF- as well as FURA-2-fluorimetry.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that in response to a pressure increase, pH_i decreased. It initially reached a peak and then recovered partly. The initial pH_i peak is augmented in bicarbonate-free solution, but was not affected by inhibitors of Na⁺/H⁺ exchange. The pH_i recovery was not altered in bicarbonate-free solution, but was reduced by inhibitors of Na⁺/H⁺ exchange. Proton fluxes were larger at 80 mmHg than at 10 mmHg. Bicarbonate-free solution had no effect on proton fluxes at either 80 mmHg or 10 mmHg. Inhibitors of Na⁺/H⁺ exchange reduced proton fluxes only at 80 mmHg. Pressure-induced changes in intracellular calcium were not affected by either bicarbonate-free solution or inhibitors of Na⁺/H⁺ exchange.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study showed that in rat small tail arteries a pressure increase is accompanied by a decrease in pH_i that appears to facilitate the myogenic response. The results of this study suggest that the pressure-induced immediate fall in pH_i is caused by a release of protons from the contractile machinery, and that the subsequent pH_i recovery is due to activation of Na⁺/H⁺ exchange.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 10","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70309","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148981614","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":"TGF-β1 Directly Sensitizes Capsaicin-Sensitive Lung Vagal Neurons to Promote Airway Hypersensitivity","authors":"Yueh-Yin Chen,&nbsp;Nai-Ju Chan,&nbsp;Chun-Chun Hsu","doi":"10.1111/apha.70311","DOIUrl":"10.1111/apha.70311","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Transforming growth factor-β1 (TGF-β1) is a pleiotropic cytokine implicated in the pathogenesis of inflammatory airway diseases such as asthma. Airway hypersensitivity (AHS), arising from sensitization of capsaicin-sensitive lung vagal (CSLV) afferents, is a hallmark of these airway diseases. Although the immunoregulatory roles of TGF-β1 in airway diseases are well documented, its effects on pulmonary sensory neurons remain unexplored. Since TGF-β1 sensitizes dorsal root ganglion neurons, a somatic counterpart of CSLV neurons, we investigated whether TGF-β1 could sensitize CSLV afferents, thereby promoting AHS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Male Brown-Norway rats were used to examine the effects of TGF-β1 on airway reflexes and the excitability of CSLV afferents in vivo using breathing pattern and single-fiber recordings, and its direct action on isolated CSLV neurons in vitro using Ca²⁺ imaging and immunofluorescence.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Intratracheal instillation of TGF-β1 enhanced the apneic responses and fiber activities of CSLV afferents elicited by capsaicin injections in vivo. The sensitizing effect emerged at 20 min and returned toward baseline by 90 min after TGF-β1 instillation. In isolated CSLV neurons, perfusion with TGF-β1 increased capsaicin- and ⍺,β-methylene ATP-evoked Ca²⁺ transients, indicating a direct sensitizing effect. Immunofluorescence demonstrated the expression of TGF-β receptors in these neurons. Pharmacological inhibition of TGF-β receptor I (TGF-βRI), Smad3, or transient receptor potential ankyrin 1 (TRPA1), scavenging of reactive oxygen species (ROS), and TRPA1-targeting small interfering RNA attenuated TGF-β1-induced enhancement of capsaicin-evoked responses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>TGF-β1 enhances CSLV-afferent excitability and directly sensitizes CSLV neurons, thereby promoting AHS. The cellular sensitizing effect involves TGF-βRI, Smad3, ROS, and TRPA1-associated mechanisms.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 10","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13573142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148962744","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":"A Migraine-Associated Na/K-ATPase Mutation Disrupts Hepatic Glucose Uptake and Peripheral Metabolism in Mice","authors":"Marco T. Pessoa,&nbsp;Vaibhav Sidarala,&nbsp;Sandrine V. Pierre","doi":"10.1111/apha.70312","DOIUrl":"10.1111/apha.70312","url":null,"abstract":"&lt;p&gt;Migraine, long regarded as a disorder of the nervous system, is increasingly recognized as a systemic disease [&lt;span&gt;1, 2&lt;/span&gt;]. The recent study of Staehr et al. in Acta Physiologica marks a significant advance in our understanding of migraine-associated genetic mutations and peripheral metabolic disturbances. In their article entitled &lt;i&gt;“Impaired hepatic glucose metabolism is associated with glucose intolerance in mice carrying α2 isoform Na,K-ATPase mutation&lt;/i&gt;” [&lt;span&gt;3&lt;/span&gt;], the authors describe the first comprehensive assessment of the metabolic phenotype of the familial hemiplegic migraine Type 2 (FHM2)-associated Na/K-ATPase mutant α2&lt;sup&gt;+/G301R&lt;/sup&gt; mouse, a model that mimics the human disease trait. The work reveals a significant alteration of peripheral metabolism with disrupted hepatic glucose handling.&lt;/p&gt;&lt;p&gt;The investigators used a comprehensive experimental approach to assess age-dependent changes of metabolic profile in α2&lt;sup&gt;+/G301R&lt;/sup&gt; mice of both sexes. By 8 months, male and female mutants showed significant glucose intolerance. This was not due to insulin resistance or altered insulin secretion, ruling out these common culprits in metabolic syndrome. Rather, PET-MRI scans revealed reduced glucose uptake in the liver, while glucose uptake in skeletal muscle and cardiac tissue remained unaffected. Mechanistically, high-resolution respirometry in isolated liver mitochondria revealed decreased respiratory control ratios for both complex I and complex I + II due to increased leak respiration in females, indicative of an overall reduction in coupling efficiency (ATP synthesis-coupled electron transport), leading to impaired ATP production in the liver (Figure 1). In contrast, the overall reduced oxygen consumption observed in male α2&lt;sup&gt;+/G301R&lt;/sup&gt; liver mitochondria was not accompanied by a detectable functional alteration of the electron transport chain complexes. A comprehensive proteomics analysis of the liver tissue suggested a link between mitochondrial dysfunction and the downregulation of key proteins of the electron transport chain complexes in mutant mouse livers, including NADH dehydrogenase and ATP synthase subunits. The authors propose that these changes in hepatic mitochondrial oxidative phosphorylation drive an energy deficit that impairs the ATP-demanding process of glycogenesis. Consistent with a link between hepatic mitochondrial dysfunction and altered glycogen synthesis, the liver protein content of glycogen synthase kinase-3α (GSK-3α), the serine/protein kinase GSK-3 paralog that inhibits glycogen synthesis through inhibitory phosphorylation of glycogen synthase (GS), was elevated in α2&lt;sup&gt;+/G301R&lt;/sup&gt; livers.&lt;/p&gt;&lt;p&gt;The sexually dimorphic hepatic phenotype of the α2&lt;sup&gt;+/G301R&lt;/sup&gt; mouse is notable in the context of the tissue-specific distribution of Na/K-ATPase α-isoforms, which is well documented in mammals [&lt;span&gt;4&lt;/span&gt;]. Unlike the ubiquitous Na/K-ATPase α1 isoform, Na/K-ATPase α2 e","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 10","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13573069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148962699","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":"Exercise and Autonomic Cardiovascular Function—Insights From Spinal Cord-Injured Humans: A Narrative Review","authors":"Rasmus Kopp Hansen,&nbsp;Ryan Godsk Larsen,&nbsp;Tom E. Nightingale,&nbsp;Daniel D. Hodgkiss,&nbsp;Niels H. Secher,&nbsp;Stefanos Volianitis","doi":"10.1111/apha.70306","DOIUrl":"10.1111/apha.70306","url":null,"abstract":"<p>The cardiovascular response to acute exercise is mediated by the autonomic nervous system (ANS) control mechanisms that modulate vascular resistance to support blood pressure and ensure adequate blood flow to active muscles. These autonomic neurocirculatory control mechanisms include a feedforward mechanism, known as central command, and three feedback mechanisms, namely, (1) the exercise pressor reflex, (2) the baroreflex, and (3) the arterial chemoreflex. The purpose of this narrative review is to present the alterations in autonomic cardiovascular function during dynamic exercise with insights from individuals living with spinal cord injury (SCI). To fully appreciate these alterations, we first provide a general overview of ANS control of cardiovascular responses to exercise in non-injured individuals with intact supraspinal control, followed by an overview of the acute cardiovascular response to exercise in individuals with SCI. We also review the impact of exercise interventions in individuals with SCI on autonomic cardiovascular control and cardiac and vascular adaptations.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 10","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70306","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148917602","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":"Impaired Hepatic Glucose Metabolism Is Associated With Glucose Intolerance in Mice Carrying α2 Isoform Na,K-ATPase Mutation","authors":"Christian Staehr,&nbsp;Tue Duy Nguyen,&nbsp;Tina Myhre Pedersen,&nbsp;Mikkel Vendelbo,&nbsp;Hans Christian Beck,&nbsp;Mads Kjolby,&nbsp;Rajkumar Rajanathan,&nbsp;Elena V. Bouzinova,&nbsp;Niels Jessen,&nbsp;Per Bendix Jeppesen,&nbsp;Alexander V. Chibalin,&nbsp;Vladimir V. Matchkov","doi":"10.1111/apha.70291","DOIUrl":"10.1111/apha.70291","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>The Na,K-ATPase is important for energy demanding cellular processes, including essential components of substrate metabolism and metabolic flexibility. Mice heterozygous for the hemiplegic migraine-related mutation, G301R, of the Na,K-ATPase α₂ isoform (α₂^+/G301R) demonstrated altered metabolism in the heart. We hypothesized that mitochondrial dysfunction in α₂^+/G301R mice is associated with abnormal systemic glucose metabolism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>3- and 8-month-old α₂^+/G301R and wild type (WT) mice of both sexes were metabolically phenotyped. Glucose uptake in peripheral tissues was assessed by [¹⁸F]-2-fluoro-2-deoxyglucose (FDG) MRI. Mitochondrial function in liver was assessed with high-resolution respirometry. Protein expression was assessed by proteomics and Western blot. Glycated hemoglobin (HbA1c) was measured with immunoassay.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The 3-month-old α₂^+/G301R mice had normal responses to glucose tolerance test, but males showed a reduced insulin response. The 8-month-old α₂^+/G301R mice exhibited glucose intolerance associated with impaired glucose uptake in the liver while unaltered in skeletal muscle associated with unchanged GLUT-4 and insulin receptor levels. Insulin secretion and insulin sensitivity were similar between 8-month-old genotypes. In the liver, 8-month-old α₂^+/G301R mice of both sexes showed reduced expression of the α₂ Na,K-ATPase and several key mitochondrial proteins from the electron transport chain. Accordingly, mitochondrial oxygen consumption was reduced in 8-month-old α₂^+/G301R males, and 8-month-old α₂^+/G301R females showed a complex I-mediated dysfunction in the liver mitochondria.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Migraine-associated mutation of the Na,K-ATPase α₂ isoform was associated with impaired mitochondrial respiratory capacity in the liver. Hence, α₂^+/G301R mice exhibited reduced capacity of ATP-demanding metabolic pathways in the liver resulting in age-dependent impaired glucose homeostasis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 10","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70291","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148917613","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":"Aerobic Exercise Ameliorates Renal Injury in High-Fat Diet-Fed Mice: A Novel Effect Mediated by the Drp1-mtROS Pathway","authors":"Huiqian Ren,&nbsp;Haofeng Sun,&nbsp;Zheying Ma,&nbsp;Qi Wang,&nbsp;Huiduo Yang,&nbsp;Xiaoqin Zhao,&nbsp;Yuxiang Liu,&nbsp;Shou Pan,&nbsp;Zujie Xu","doi":"10.1111/apha.70310","DOIUrl":"10.1111/apha.70310","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Aberrant activation of dynamin-related protein 1 (Drp1) promotes excessive mitochondrial reactive oxygen species (mtROS) production; however, whether the Drp1-mtROS pathway mediates the renoprotective effects of aerobic exercise remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>High-fat diet (HFD)-fed mice were subjected to aerobic exercise or were intraperitoneally injected with the Drp1 inhibitor Mdivi-1 for 8 weeks. Fat mass, serum biochemical parameters, renal histopathology, mtROS production, oxidative stress-related markers, mitochondrial ultrastructure, mitochondrial membrane potential, ATP content, and protein expression were assessed. In parallel, Drp1 was knocked down in palmitic acid (PA)-treated HK-2 cells to further evaluate the role of the Drp1-mtROS pathway in lipid overload-induced renal tubular cell injury.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Aerobic exercise reduced body weight and fat mass, improved circulating lipid profiles, and decreased serum creatinine and blood urea nitrogen levels in HFD-fed mice. Exercise also alleviated renal tubular injury, mesangial expansion, interstitial fibrosis, podocyte foot process effacement, and renal lipid accumulation. Mechanistically, aerobic exercise suppressed Drp1 phosphorylation at Ser616, reduced renal mtROS production and oxidative stress, improved mitochondrial morphology, restored mitochondrial membrane potential and ATP production, and modulated the expression of lipid-metabolism-related proteins. Pharmacological inhibition of Drp1 with Mdivi-1 largely reproduced the metabolic, mitochondrial, and renoprotective effects of aerobic exercise. Furthermore, Drp1 knockdown attenuated PA-induced mtROS accumulation, oxidative stress, mitochondrial dysfunction, and lipid deposition in HK-2 cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Aerobic exercise exerts a protective effect on the kidneys of HFD-fed mice, at least in part, by inhibiting the Drp1-mtROS pathway. This provides insights into the benefits of aerobic exercise in obesity-related nephropathy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 10","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148899769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Acidic Tubulointerstitial Microenvironment Delays Cell-Cycle Progression in Proximal Tubule Cells and Fibroblasts and Synergizes With Lactate to Drive Phenotypic Alterations","authors":"Marie-Christin Schulz,&nbsp;Virginie Dubourg,&nbsp;Lea Schaude,&nbsp;Natalie Schröder,&nbsp;Eva Janßen,&nbsp;Isabelle Görlich,&nbsp;Stefanie Ruhs,&nbsp;Michael Kopf,&nbsp;Michael Gekle","doi":"10.1111/apha.70302","DOIUrl":"10.1111/apha.70302","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Chronic kidney disease (CKD) is characterized by progressive tubulointerstitial inflammation and fibrosis, particularly affecting the proximal tubule. Both proximal tubular epithelial cells and interstitial fibroblasts contribute to CKD progression through cell-cycle arrest and phenotypic transitions. The aim of the present study was to address whether lactic acidosis contributes to these processes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Human proximal tubular cells (HK-2 cells) and fibroblasts (CCDSk cells) were exposed to lactic acid, hydrochloric acid, or sodium lactate. Transcriptomic changes were assessed by RNA sequencing followed by GO term enrichment as well as canonical pathway and upstream-regulator analyses. Predicted effects on the cell cycle were validated experimentally using BrdU incorporation and digital microscopy-based cell-cycle analysis. Protein expression of IL-6, c-FOS, phospho-JAK1 and JAK2, STAT3, SRF, and p38 was assessed by Western blot.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Transcriptomic analysis revealed synergistic effects of lactate and acidification on gene expression, which were associated with cell type-specific phenotypic changes. Biological assays confirmed these predictions: HK-2 cells underwent a sustained G1 arrest with reduced DNA synthesis, while CCDSk cells displayed only a transient arrest resolving after 48 h. Predictions further indicated that lactic acidosis amplifies these effects, driving fibrotic reprogramming in HK-2 cells and promoting a phenotypic switch of CCDSk cells toward an inflammatory state.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings suggest that extracellular lactic acidosis primes tubular cells for fibrotic remodeling and CCDSk cells for inflammatory activation, and may therefore represent an initiating microenvironmental trigger for maladaptive changes in CKD progression.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 10","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13548072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148899736","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":"ATP Release and Purinergic Signaling Potentiate β-Adrenergic Effects on Brown Adipocytes","authors":"Marco Tozzi,&nbsp;Emilie B. Berggreen,&nbsp;Rui Zhang,&nbsp;Anders Gudiksen,&nbsp;Wei Li,&nbsp;Mathias B. Matz,&nbsp;Henriette Pilegaard,&nbsp;Jacob B. Hansen,&nbsp;Ivana Novak","doi":"10.1111/apha.70307","DOIUrl":"10.1111/apha.70307","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Brown adipose tissue (BAT) specializes in energy consumption and thermogenesis in response to cold stress. Brown adipocytes (BA) express purinergic receptors, yet little is known about the source of extracellular ATP and the role of purinergic signaling, and the potential interaction with β-adrenergic signaling. We aimed at elucidating whether: BA could release extracellular ATP; ATP/purinergic signaling impacts β-adrenergic responses; and the expression of purinergic receptors in BAT of mice and cultured BA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Real-time ATP release was monitored in a mature BA cell model exposed to adrenergic agonists, insulin, glucose, and pharmacological inhibitors. Cellular assays included oxygen consumption, glycolysis, and lipolysis assays, and Ca²⁺ imaging. The protein level of ATP-release protein, pannexin-1, was determined. RNA-sequencing was performed on mouse BAT and cultured BA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We show that β-adrenergic stimulation of BA causes ATP release through pannexin-1 in a cAMP-protein kinase A-dependent manner. ATP release is increased with glucose but decreased with insulin, the latter due to phosphodiesterase 3 activation. β-Adrenergic stimulation increases oxygen consumption, glycolysis, and lipolysis, while apyrase and pannexin-1 inhibitors decrease these effects. Both extracellular ATP and β-adrenergic stimulation induce Ca²⁺ signals, albeit with different kinetics. BAT from mice exposed to cold and BA treated with norepinephrine show regulation of several purinergic receptors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The present study demonstrates that ATP is released from BA via pannexin-1 channels in response to β-adrenergic stimulation, that extracellular ATP, acting through P2 receptor signaling, potentiates β-adrenergic effects on BA function, and that expression of several purinergic receptors changes in response to β-adrenergic stimulation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 10","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13548067/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148899722","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":"Conference Details","authors":"","doi":"10.1111/apha.70297","DOIUrl":"https://doi.org/10.1111/apha.70297","url":null,"abstract":"","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 S737","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Binding of Fibroblast Growth Factor 23 (FGF23) to FGF Receptor-αKlotho Complex Increases Sinoatrial Electrical Activity","authors":"Giorgia Bertoli,&nbsp;Patrizia Benzoni,&nbsp;Serena Canzolino,&nbsp;David Molla,&nbsp;Raffaella Milanesi,&nbsp;Chiara Piantoni,&nbsp;Makoto Kuro-o,&nbsp;Carmen Delgado,&nbsp;Gema Ruiz-Hurtado,&nbsp;Mirko Baruscotti,&nbsp;Annalisa Bucchi","doi":"10.1111/apha.70293","DOIUrl":"10.1111/apha.70293","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>This study aims to investigate whether the Fibroblast Growth Factor 23 (FGF23) modulates the electrical activity of sinoatrial (SAN) cells. The canonical function of FGF23 is to regulate body phosphorus and calcium homeostasis by activating the FGF1 receptors (FGFR1)/α-Klotho complex in the kidney and parathyroid glands. High levels of FGF23 can induce cardiac arrhythmias by affecting cardiomyocyte's function in an α-Klotho independent manner. Although SAN cells are not traditionally considered targets of FGF23, the presence of α-Klotho in pacemaker and not in ventricular cells has raised this possibility.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The effect of FGF23 was evaluated by patch-clamp experiments on mouse SAN and on human-induced pluripotent stem cells-derived pacemaker-like cardiomyocytes (hiPSC-derived pCMs).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our data reveal that mouse SAN cells express both membrane α-Klotho and FGF23 receptors (FGFR) and that 48 h tissue incubation with FGF23 (10 ng/mL) increases the spontaneous action potential (AP) frequency of these cells through an increase in the funny <i>I</i>_f current. Patch-clamp experiments carried out using the pan-FGFR inhibitor, PD173074, and SAN cells isolated from α-Klotho hypomorphic mice suggested that FGF23 effects are mediated by the activation of the FGFR-α-Klotho complex. FGFRs expression data and FGF23-induced electrical modification were further confirmed in hiPSC-derived pCMs. Indeed, 48 h incubation of these cells with FGF23 increases both the AP frequency, in a dose-dependent manner, and the <i>I</i>_f current.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study represents the first evidence that FGF23 directly regulates the SAN electrical activity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 10","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13531400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148862631","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}