Acta Physiologica最新文献

{"title":"Hypoxia and ischemic stroke modify cerebrovascular tone by upregulating endothelial BK(Ca) channels—Lessons from rat, pig, mouse, and human","authors":"Christian Staehr,&nbsp;Victoria Hinkley,&nbsp;Vladimir V. Matchkov,&nbsp;Rajkumar Rajanathan,&nbsp;Line Mathilde B. Hansen,&nbsp;Yvonne Eiby,&nbsp;Nathan Luque,&nbsp;Ian Wright,&nbsp;Stella T. Bjorkman,&nbsp;Stephanie M. Miller,&nbsp;Rohan S. Grimley,&nbsp;Andrew Dettrick,&nbsp;Kirat Chand,&nbsp;Hong L. Nguyen,&nbsp;Nicole M. Jones,&nbsp;Tim V. Murphy,&nbsp;Shaun L. Sandow","doi":"10.1111/apha.70030","DOIUrl":"10.1111/apha.70030","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>In animal models and human cerebral arteries, the changes in endothelial cell (EC)-large conductance calcium-activated potassium channel (BK_Ca) distribution, expression, and function were determined in hypoxia and ischemic stroke. The hypothesis that hypoxia and ischemic stroke induce EC-BK_Ca in cerebral arteries was examined.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Immunohistochemistry analyzed BK_Ca expression in EC and smooth muscle (SM) of the middle-cerebral artery (MCA) from rat, piglet, and mouse, and pial arteriole of human. Pressure myography with pharmacological intervention characterized EC-BK_Ca and TRPV4 function in rat MCA. Electron microscopy determined caveolae density and vessel properties in rat and mouse MCA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In rat, pig, and human cerebral vessels, EC-BK_Ca was absent in normoxia; present after <i>chronic</i> (rat) and <i>acute</i> hypoxia (pig), post-ischemic stroke in human vessels, and after endothelin-1-induced stroke in rats. Mouse MCA EC-BK_Ca expression increased after <i>acute</i> hypoxia. In rat MCA post-hypoxia and stroke, EC and SMC caveolae density increased, with reduced medial thickness, and unchanged diameter. Caveolae and BK_Ca did not colocalize. In rat MCA, iberiotoxin (IbTx) potentiated pressure-induced tone in hypoxia/stroke, but not in normoxia. In normoxia, overall MCA tone was unaffected by endothelial removal, but was increased in hypoxia/stroke, where there was no additive effect of endothelial removal and IbTx on tone. Functional TRPV4 was expressed in EC of rat MCA post-stroke.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In post-hypoxia/stroke, but not in normoxia, EC-BK_Ca contribute to the regulation of MCA tone. Identifying unique up- and downstream signaling mechanisms associated with EC-BK_Ca is a potential therapeutic target to control blood flow post-hypoxia/stroke.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11926774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672973","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":"Les lésions anciennes: Evolution conserves noradrenergic regulation of astroglial homeostatic support","authors":"Alexei Verkhratsky","doi":"10.1111/apha.70032","DOIUrl":"https://doi.org/10.1111/apha.70032","url":null,"abstract":"&lt;p&gt;It is a truth universally acknowledged that every neurone needs an astrocyte to survive and operate. Supportive, homeostatic, and protective neuroglial cells emerged early in evolution together with the centralised nervous system (although some collateral cells of non-neural origin aiding neurones and axons probably existed in even earlier diffuse nervous system of Cnidarians and Ctenophoa). In the February issue of&lt;i&gt;Acta Physiologica&lt;/i&gt;, a team of researchers led by Nina Vardjan and Robert Zorec&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; reveals ancient evolutionary roots of noradrenergic signalling and describes the association with astrocytes, astrocytic Ca&lt;sup&gt;2+&lt;/sup&gt; signalling, and astrocyte physiology.&lt;/p&gt;&lt;p&gt;The very first glial cells were parts of sensory organs, known as sensillas, in invertebrates; incidentally, glial-neuronal sensory organs are common in all species (for example, the organ of Corti, taste buds and olfactory epithelium have ~50% of sustenacular glial cells, which are indispensable for proper sensory function&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt;). The rise of neuroglia reflects the main evolutionary principle of division of functions: neurones are so specialised for the generation of action potentials and synaptic transmission that they cannot sustain the major homeostatic and defensive tasks that define the optimal performance and survival of the nervous tissue. These tasks are fulfilled by neuroglia.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Astroglial cells, which include many types of parenchymal and radial astrocytes, ependymoglia, and astrocyte-like stem cells, are major homeostatic cells in the central nervous system (CNS) that control and execute various functions at all levels of biological organisation, ranging from molecules to organs. In particular, astrocytes control ion homeostasis of the interstitium (also known as ionostasis) and are the main elements of production, clearance, and catabolism of major neurotransmitters and neuromodulators including L-glutamate, GABA, adenosine, catecholamines, and D-serine.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Astrocytes are electrically non-excitable cells, which employ intercellular ion and second messenger signalling as the substrate of excitability.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Astrocytic ionic signalling is mediated by Ca&lt;sup&gt;2+&lt;/sup&gt;, Na&lt;sup&gt;+&lt;/sup&gt;, and Cl&lt;sup&gt;−&lt;/sup&gt; &lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt;; the main second messengers are inositol-1,4,5-trisphosphate (InsP&lt;sub&gt;3&lt;/sub&gt;, linked to Ca&lt;sup&gt;2+&lt;/sup&gt; signalling) and cyclic AMP (cAMP) regulating multiple intracellular enzymatic cascades.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Coordination of ionic and second messenger excitability is critical for astrocytic function in many physiological and pathophysiological contexts.&lt;/p&gt;&lt;p&gt;Noradrenergic innervation of the CNS is mainly associated with the locus coeruleus, the brain stem nucleus containing (in humans) ~20 000–50 000 noradrenergic neurones full of neuromelanin that gives them a dark blue appearance. The locus coeruleus was discovere","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70032","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633032","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":"Cold-induced fibrosis and metabolic remodeling in the turtle (Trachemys scripta) ventricle","authors":"Adam N. Keen,&nbsp;James C. McConnell,&nbsp;John J. Mackrill,&nbsp;John Marrin,&nbsp;Alex J. Holsgrove,&nbsp;Janna Crossley,&nbsp;Alex Henderson,&nbsp;Gina L. J. Galli,&nbsp;Dane A. Crossley II,&nbsp;Michael J. Sherratt,&nbsp;Peter Gardner,&nbsp;Holly A. Shiels","doi":"10.1111/apha.70026","DOIUrl":"https://doi.org/10.1111/apha.70026","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Cardiac fibrosis contributes to systolic and diastolic dysfunction and can disrupt electrical pathways in the heart. There are currently no therapies that prevent or reverse fibrosis in human cardiac disease. However, animals like freshwater turtles undergo seasonal remodeling of their hearts, demonstrating the plasticity of fibrotic remodeling. In <i>Trachemys scripta</i>, cold temperature affects cardiac load, suppresses metabolism, and triggers a cardiac remodeling response that includes fibrosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We investigated this remodeling using Fourier transform infrared (FTIR) imaging spectroscopy, together with functional assessment of muscle stiffness, and molecular, histological, and enzymatic analyses in control (25°C) <i>T. scripta</i> and after 8 weeks of cold (5°C) acclimation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>FTIR revealed an increase in absorption bands characteristic of protein, glycogen, and collagen following cold acclimation, with a corresponding decrease in bands characteristic of lipids and phosphates. Histology confirmed these responses. Functionally, micromechanical stiffness of the ventricle increased following cold exposure assessed via atomic force microscopy (AFM) and was associated with decreased activity of regulatory matrix metalloproteinases (MMPs) and increased expression of MMP inhibitors (TMPs) which regulate collagen deposition.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>By defining the structural and metabolic underpinnings of the cold-induced remodeling response in the turtle heart, we show commonalities between metabolic and fibrotic triggers of pathological remodeling in human cardiac disease. We propose the turtle ventricle as a novel model for studying the mechanisms underlying fibrotic and metabolic cardiac remodeling.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70026","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622666","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":"Editorial related to the special issue: “Extrarenal functions of the renin-angiotensin-system”","authors":"Rhian M. Touyz,&nbsp;U. Muscha Steckelings","doi":"10.1111/apha.70027","DOIUrl":"https://doi.org/10.1111/apha.70027","url":null,"abstract":"&lt;p&gt;A recent collection of five review articles published in this journal highlights some state-of-the-art research that has been presented at the Gordon Research Conference on Angiotensin in February 2024. These articles feature a broad spectrum of research areas related to the renin-angiotensin-aldosterone system (RAAS), authored by experts in the field.&lt;/p&gt;&lt;p&gt;Two articles of this collection focus on novel approaches for the understanding of angiotensin receptor signaling.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; Gironacci and Bruna-Haupt elucidate how RAAS receptor dimerization with other RAAS- or non-RAAS receptors alters receptor affinity, trafficking, signaling, and biological function.&lt;span&gt;&lt;sup&gt;1, 3&lt;/sup&gt;&lt;/span&gt; For example, cross-inhibition is a dimer-specific phenomenon leading to antagonism of one receptor in a dimer by an antagonist specific for the other receptor in the dimer. New drug candidates are in development that target receptor dimers instead of single receptors, making use of dimer-specific crosstalk between receptors. However, the authors also point out that receptor dimerization and its functional consequences are understudied, which means that many drug actions caused by receptor dimerization (e.g. AT&lt;sub&gt;1&lt;/sub&gt;-receptor antagonism by beta&lt;sub&gt;2&lt;/sub&gt;-adrenergic receptor antagonists&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;) are underestimated and their potential clinical consequences unknown and not taken into therapeutic consideration.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Verano-Braga, Steckelings, and co-authors highlight new approaches to study angiotensin receptor signaling through quantitative phosphoproteomics, i.e. the monitoring of all protein phospho- and dephosphorylation events in a cell, as a hypothesis-generating method for identifying so-far unknown angiotensin receptor signaling mechanisms.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; The article reviews the literature on phosphoproteomics addressing biased signaling, beta-arrestin-dependent AT&lt;sub&gt;1&lt;/sub&gt;-receptor (AT&lt;sub&gt;1&lt;/sub&gt;R) signaling, or signaling of receptors of the protective arm of the RAAS, namely AT&lt;sub&gt;2&lt;/sub&gt;-receptor (AT&lt;sub&gt;2&lt;/sub&gt;R), receptor Mas, and Mas-related G-protein coupled receptor D (MrGD). While all angiotensin receptors are categorized as being G-protein coupled receptors (GPCRs), receptors of the protective arm of the RAAS usually do not induce “classical” GPCR-mediated signaling cascades but rather unconventional, and in large part unknown, pathways, which makes a non-targeted methodology for their identification a useful approach. Extrarenal effects of the protective arm of the RAAS identified by phosphoproteomics include anti-senescence effects (e.g. inhibition of mTOR signaling), effects on histone acetylation with impact on cell cycle control and tumor-suppressor (p53) actions, or effects on glucose homeostasis.&lt;span&gt;&lt;sup&gt;5-8&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The article highlights future applications of this technology, such as the exploration of cell-specific angiotensin receptor signalin","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622529","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":"Introducing a special issue: Acid–base regulation and sensing in health and disease","authors":"Stine Falsig Pedersen,&nbsp;Ebbe Boedtkjer","doi":"10.1111/apha.70021","DOIUrl":"https://doi.org/10.1111/apha.70021","url":null,"abstract":"<p>Cell metabolism continuously generates acid, primarily in the form of H⁺ from fermentation and CO₂ from oxidative phosphorylation. However, the normal physiological functions at all levels of biological organization depend on pH being regulated within narrow ranges. The homeostatic regulation of acid–base status is therefore fundamentally important in virtually all aspects of physiology. At the cellular and organellar level, ion transport proteins import and export acids and bases across membranes, and passive H⁺-buffering systems limit changes in pH upon acid–base challenges and facilitate H⁺ movement to and from sites of production and transport. Signaling events—initiated, for example, by H⁺-sensing G-protein coupled receptors, ion channels, and transmembrane or soluble HCO₃⁻-sensing proteins<span>¹</span>—control the expression and activity of the pH regulatory systems and produce functional adaptations in response to acid–base disturbances. In vertebrates, acid extruded from cells enters the vasculature and moves via the blood to the lungs and kidneys where it is finally eliminated.</p><p>Given the pivotal physiological importance of acid–base regulation and its disturbances, it is not surprising that key studies on this topic have been published in <i>Acta Physiologica</i>. Over 120 years ago in 1904, when <i>Acta Physiologica</i> was the Skandinavisches Archiv Für Physiologie, August Krogh published pioneering organism-level experiments on cutaneous respiration, that is, the elimination of CO₂ across the frog skin.<span>²</span> Already then, studies of the physiological relevance of pH spanned from organism to molecule, as the same year, Christian Bohr, with Hasselbalch and Krogh, revealed how variation in CO₂ levels (with associated changes in pH) alter O₂ binding to hemoglobin.<span>³</span> This essential observation, widely known as the Bohr effect, was the first demonstration that CO₂/H⁺ binding can alter protein function in a physiologically relevant manner. Since then, the concept of protonation as a posttranslational modification has been studied in great molecular detail. Important examples<span>⁴</span> now illustrate how pH regulates the function of proteins with protonatable amino acid residues, from enzymes to ion channels to cell adhesion proteins. Thus, we now appreciate a complex landscape of pH sensitivity that extends far beyond the <i>bona fide</i> H⁺ sensing receptors.</p><p>More recent work highlights the essential roles that disturbances in acid–base regulation and sensing play in several pathophysiological conditions. This includes solid tumors characterized by extracellular accumulation of acidic metabolic waste products that have been shown to favor cancer progression and limit anti-cancer immunity.<span>¹</span> The","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70021","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622526","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":"Slow rather than fast calcium events encode physiological inputs and propagate within islets: Lessons from ultrafast imaging on acute pancreatic tissue slices","authors":"Matthieu Raoux,&nbsp;Dorian Chapeau,&nbsp;Jochen Lang","doi":"10.1111/apha.70028","DOIUrl":"https://doi.org/10.1111/apha.70028","url":null,"abstract":"&lt;p&gt;Pancreatic islets are micro-organs, mainly composed of insulin-secreting β cells, which play a central role in nutrient homeostasis and diabetes. They can be viewed as “mini-brains” of glucose homeostasis, as they present networks of excitable cells that express numerous neural proteins&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; and integrate nutritional, hormonal, and neuronal inputs in real time to continuously provide the amount of insulin required to cover physiological needs. In type 2 diabetes, which accounts for 90% of diabetes cases, both individual and collective β cell activities are impaired. Consequently, many groups have attempted to explore the single-cell and multicellular behavior of β cells for years using either intracellular electrophysiology, which offers high-temporal resolution but is invasive and limited to one cell, or optical methods, mainly Ca&lt;sup&gt;2+&lt;/sup&gt; imaging, which provides excellent spatial resolution but very limited temporal resolution, with a typical sampling rate of 0.5–2 Hz. This temporal resolution allows the detection of only slow Ca&lt;sup&gt;2+&lt;/sup&gt; events, namely Ca&lt;sup&gt;2+&lt;/sup&gt; bursts, and prevents the detection of fast Ca&lt;sup&gt;2+&lt;/sup&gt; events, namely Ca&lt;sup&gt;2+&lt;/sup&gt; spikes, although Ca&lt;sup&gt;2+&lt;/sup&gt; spikes represent the trigger for insulin granule exocytosis. In this issue of &lt;i&gt;Acta Physiologica&lt;/i&gt;, Dolenšek et al. present high-temporal-resolution optical measurements (40–178 Hz) of selected islet areas using line scan confocal imaging on acute pancreas slices (i.e. in their native environment) in response to physiological levels of glucose and acetylcholine (Figure 1).&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Their detailed characterization of both Ca&lt;sup&gt;2+&lt;/sup&gt; bursts and spikes at individual and collective levels offers new insights into the respective roles of these signals in islets, their encoding of glucose levels and cholinergic inputs, and their propagation within the micro-organ, and finally opens new perspectives for understanding islet “mini-brain” networks deregulation in diabetes.&lt;/p&gt;&lt;p&gt;The classical approach to measure spikes with sufficient temporal resolution in islets has so far been the perforated patch-clamp.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; However, this complex and invasive technique allows measurements at the single-cell level rather than the multicellular level and only for a few minutes, whereas islets are stimulated for 2–3h during digestion. Very few ultrafast Ca&lt;sup&gt;2+&lt;/sup&gt; measurements on isolated β cells&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; or whole islets&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; had been performed prior to this study, but they were limited in time and did not include spike analysis. Dolenšek et al. show now the correspondence between electrical and Ca&lt;sup&gt;2+&lt;/sup&gt; events,&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; consequently, their work paves the way for multicellular optical approaches as an alternative to patch-clamp for laboratories lacking the necessary equipment or expertise.&lt;/p&gt;&lt;p&gt;Their work provides new insights into islet biology ","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622295","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":"Early signs of neuron autonomous and non-autonomous hyperexcitability in locus coeruleus noradrenergic neurons of a mouse model of tauopathy and Alzheimer's disease","authors":"Zhong-Min Wang,&nbsp;Valentina Grinevich,&nbsp;William R. Meeker,&nbsp;Jie Zhang,&nbsp;María Laura Messi,&nbsp;Evgeny Budygin,&nbsp;Osvaldo Delbono","doi":"10.1111/apha.70022","DOIUrl":"https://doi.org/10.1111/apha.70022","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>The locus coeruleus (LC) is one of the earliest brain regions affected by phosphorylated tau (p-tau) in Alzheimer's disease (AD). Using the P301S mouse model, we investigated the temporal progression of tau pathology and its functional consequences.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Immunohistochemistry was used to assess p-tau deposition in LC noradrenergic neurons at 2–3 and 5–6 months. Electrophysiological recordings evaluated neuronal hyperexcitability, measuring membrane potential, rheobase, and spontaneous action potential (AP) frequency in P301S and wild-type (WT) mice. Fast-scan cyclic voltammetry (FSCV) was used to measure norepinephrine (NE) release. GABA(A) receptor subunit expression was analyzed via immunoblotting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>P-tau was detected in LC neurons as early as 2–3 months, with a rostral-to-caudal gradient, and by 5–6 months, nearly all LC neurons exhibited p-tau immunoreactivity. P301S neurons showed hyperexcitability, characterized by depolarized membrane potentials, a more negative rheobase, and increased spontaneous AP frequency. Synaptic blockade elicited a reduced increase in AP frequency, suggesting diminished inhibitory tone. GABA(A) α2 subunit expression significantly declined with age in P301S mice, whereas α3 remained unchanged. FSCV showed significantly elevated NE release in P301S mice at 3 and 6 months compared to WT.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The findings highlight early LC dysfunction in tauopathies, characterized by increased excitability, reduced inhibitory tone, and exaggerated NE release. This hyperactivity may contribute to excitotoxicity and downstream dysfunction in LC-regulated brain regions. Targeting LC hyperactivity and restoring inhibitory signaling could be promising therapeutic strategies for mitigating AD progression.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622528","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 isolated, perfused working heart preparation of the mouse—Advantages and pitfalls","authors":"Diana S. Usai,&nbsp;Ellen Aasum,&nbsp;Morten B. Thomsen","doi":"10.1111/apha.70023","DOIUrl":"https://doi.org/10.1111/apha.70023","url":null,"abstract":"<p>Isolated, perfused hearts are viable for hours outside the body, and important research findings have been made using mouse hearts ex vivo. In the Langendorff perfusion mode, the coronary tree is perfused via retrograde flow of a perfusate down the ascending aorta. Although the Langendorff setup is generally simpler and quicker to establish, the working heart mode allows the heart to function in a more physiologically relevant manner, where the perfusate is directed into the left ventricle via the left atrium. The contracting, fluid-filled ventricle will eject the perfusate into the aorta in a more physiologically relevant manner, lifting the physiological relevance of the contractile and energetic data. The workload on the heart (preload, afterload and heart rate) can be precisely adjusted in the working, isolated heart, and the ventricular performance, for example, end-diastolic and end-systolic pressures, stroke volume, cardiac output, and oxygen consumption can be determined. Moreover, using pressure-volume catheters, ventricular performance can be assessed in great detail. With the present review, we highlight the benefits and drawbacks of the technique and indicate where particular attention must be put when building the working heart setup, designing experiments, executing the studies, and analyzing the obtained data.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70023","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602727","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":"Fam163a knockdown and mitochondrial stress in the arcuate nucleus of hypothalamus reduce AgRP neuron activity and differentially regulate mitochondrial dynamics in mice","authors":"Cihan Suleyman Erdogan,&nbsp;Yavuz Yavuz,&nbsp;Huseyin Bugra Ozgun,&nbsp;Volkan Adem Bilgin,&nbsp;Sami Agus,&nbsp;Ugur Faruk Kalkan,&nbsp;Bayram Yilmaz","doi":"10.1111/apha.70020","DOIUrl":"https://doi.org/10.1111/apha.70020","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Mitochondria play key roles in neuronal activity, particularly in modulating agouti-related protein (AgRP) and proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC), which regulates food intake. FAM163A, a newly identified protein, is suggested to be part of the mitochondrial proteome, though its functions remain largely unknown. This study aimed to investigate the effects of <i>Fam163a</i> knockdown and mitochondrial dysfunction on food intake, AgRP neuron activity, and mitochondrial function in the hypothalamus.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Male C57BL/6 and AgRP-Cre mice received intracranial injections of either <i>Fam163a</i> shRNA, rotenone, or appropriate controls. Behavioral assessments included food intake, locomotor activity, and anxiety-like behaviors. qRT-PCR was used to quantify the expression of the genes related to food intake, mitochondrial biogenesis, dynamics, and oxidative stress. Blood glucose, serum insulin, and leptin levels were measured. Electrophysiological patch-clamp recordings were used to assess the AgRP neuronal activity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p><i>Fam163a</i> knockdown in the ARC increased the cumulative food intake in short term (first 7 days) without altering the 25-day food intake and significantly increased the <i>Pomc</i> mRNA expression. <i>Fam163a</i> silencing significantly reduced leptin levels. Both <i>Fam163a</i> knockdown and rotenone significantly reduced the firing frequency of AgRP neurons. Neither <i>Fam163a</i> silencing nor rotenone altered locomotor or anxiety-like behaviors. <i>Fam163a</i> knockdown and rotenone differentially altered the expression of mitochondrial biogenesis-, mitophagy-, fusion-, and oxidative stress-related genes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Hypothalamic FAM163A may play a role in modulating AgRP neuronal activity through regulating mitochondrial biogenesis, dynamics, and redox state. These findings provide insights into the role of FAM163A and mitochondrial stress in the central regulation of metabolism.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70020","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595466","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":"Heat treatment activates futile calcium cycling in brown adipose tissue to modulate energy metabolism and alters gut microbiota in C57BL/6 mice","authors":"Rong Fan,&nbsp;Galaxie Story,&nbsp;Judy Kim,&nbsp;Zhuoheng Li,&nbsp;Sean T. Bannon,&nbsp;Hyunji Cho,&nbsp;Ravi Ranjan,&nbsp;Young-Cheul Kim,&nbsp;Gwenael Layec,&nbsp;Soonkyu Chung","doi":"10.1111/apha.70025","DOIUrl":"https://doi.org/10.1111/apha.70025","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Aging decreases the metabolic rate and increases the risk of metabolic diseases, highlighting the need for alternative strategies to improve metabolic health. Heat treatment (HT) has shown various metabolic benefits, but its ability to counteract aging-associated metabolic slowdown remains unclear. This study aimed to investigate the impact of whole-body HT on energy metabolism, explore the potential mechanism involving the heat sensor TRPV1, and examine the modulation of gut microbiota.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Ten-month-old female C57BL/6 mice on a high-fat (HF) diet (45% calories from fat) were exposed to daily HT in a 40–41°C heat chamber for 30 min, 5 days a week for 6 weeks. Metabolic changes, including core body temperature and lipid metabolism transcription in adipose tissue and liver, were assessed. Human brown adipocytes were used to confirm metabolic effects in vitro.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>HT significantly reduced serum lactate dehydrogenase levels, indicating mitigation of tissue damage. HT attenuated weight gain, improved insulin sensitivity, and increased beta-oxidation in the liver and brown fat. In thermogenic adipose tissue, HT enhanced TRPV1 and Ca²⁺/ATPase pump expression, suggesting ATP-dependent calcium cycling, which was confirmed in human brown adipocytes. Interestingly, HT also reduced the firmicutes/bacteroides ratio and altered gut microbiota, suppressing HF diet-enriched microbial genera such as <i>Tuzzerella</i>, <i>Defluviitaleaceae_UCG-011</i>, <i>Alistipes</i>, and <i>Enterorhabdus</i>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>HT attenuates aging- and diet-associated metabolic slowdown by increasing futile calcium cycling, enhancing energy expenditure, and altering gut microbiota in middle-aged female C57BL/6 mice. HT may offer a promising strategy to improve metabolic health, especially in aging populations.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595465","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}