Acta Physiologica最新文献

{"title":"RyR1 Calcium Leak and Mitochondrial Ca2+ Homeostasis in Skeletal Muscle","authors":"Nicolas Place","doi":"10.1111/apha.70272","DOIUrl":"10.1111/apha.70272","url":null,"abstract":"<p>Ca<sup>2+</sup> signaling is central to skeletal muscle function. During excitation-contraction coupling, depolarization of the transverse tubular system is transmitted to type 1 ryanodine receptors (RyR1) in the sarcoplasmic reticulum (SR) membrane, triggering Ca<sup>2+</sup> release and allowing force production through Ca<sup>2+</sup> binding to troponin C. Under resting conditions, RyR1 channels remain tightly controlled, notably through their association with FK506-binding protein 12 (FKBP12), which helps stabilize the channel in a closed state and limits Ca<sup>2+</sup> leak into the cytosol.</p><p>This tight regulation is essential for normal function. Yet, under pathological conditions, post-translational modifications of RyR1, including oxidation and nitrosylation, may destabilize the channel, promote dissociation of FKBP12, and increase SR Ca<sup>2+</sup> leak. Such abnormal RyR1 leak has been implicated in skeletal muscle dysfunction in several chronic conditions, including cancer-associated muscle weakness [<span>1</span>] and muscular dystrophy [<span>2</span>]. In dystrophic muscle in particular, previous work has shown that RyR1 destabilization contributes to impaired muscle performance, while pharmacological stabilization of the channel can improve contractile function and exercise capacity [<span>2</span>].</p><p>In this context, the study by Gaglianone et al. [<span>3</span>] provides an important step forward. Using mechanically skinned fibers from extensor digitorum longus muscles of mdx mice, the authors assessed RyR1-dependent Ca<sup>2+</sup> leak with an elegant and technically demanding approach based on rhod-5N trapped within sealed transverse tubules. Consistent with earlier observations [<span>4</span>], they confirmed that RyR1 Ca<sup>2+</sup> leak is increased in dystrophic muscle. However, the real strength of their study lies in going beyond leak quantification alone. By using this preparation to assess Ca<sup>2+</sup> distribution across intracellular compartments [<span>5</span>], the authors show that increased RyR1 leak in mdx fibers is associated with reduced SR Ca<sup>2+</sup> content, elevated cytosolic Ca<sup>2+</sup> levels, and ~4-fold increase in mitochondrial Ca<sup>2+</sup> content.</p><p>This compartmental view is particularly valuable because it highlights that RyR1 leak is not merely a defect at the level of the SR channel, but rather a perturbation of intracellular Ca<sup>2+</sup> homeostasis as a whole. In skeletal muscle, Ca<sup>2+</sup> redistribution across SR, cytosolic, and mitochondrial pools is likely to have broad functional consequences, affecting not only force production but also energy metabolism, redox balance, and long-term muscle remodeling.</p><p>This broader perspective is important because enhanced mitochondrial Ca<sup>2+</sup> uptake is not necessarily detrimental per se. Indeed, transient increases in mitochondrial Ca<sup>2+</sup> may support oxidative metabolism and adaptive","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 8","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70272","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148373953","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":"Chemogenetic Stimulation of the Dorsal Motor Nucleus of the Vagus Mitigates Autonomic Dysfunction and Memory Decline in Rat Model of Alzheimer-Like Disease.","authors":"Beatriz Pacheco Sousa, Karoline Martins Dos Santos, Vagner Roberto Antunes","doi":"10.1111/apha.70261","DOIUrl":"10.1111/apha.70261","url":null,"abstract":"<p><strong>Aim: </strong>To test the hypothesis that Alzheimer-like metabolic neurodegeneration rat model leads to an autonomic dysfunction, memory impairment, and hippocampal amyloid pathology and that long-term chemogenetic stimulation of the dorsal motor nucleus of the vagus reverses these alterations.</p><p><strong>Methods: </strong>Male and female transgenic Long Evans rats received intracerebroventricular streptozotocin to induce sporadic Alzheimer-like pathology. Cardiovascular parameters and sympathetic and parasympathetic tone were evaluated in conscious animals. Episodic-like memory was assessed using the novel object recognition test. Hippocampal amyloid density was quantified by immunofluorescence. In male rats, cholinergic neurons of the dorsal motor nucleus of the vagus were selectively activated for 15 days using a chemogenetic approach, and autonomic, cognitive, and neuropathological outcomes were reassessed.</p><p><strong>Results: </strong>In male rats, the intracerebroventricular streptozotocin induced a significant increase in cardiac sympathetic tone, reduced object discrimination index performance, and increased hippocampal amyloid density compared with vehicle-treated controls, without altering mean arterial pressure or heart rate. Female rats showed no significant autonomic, memory, or hippocampal alterations at the same time point. Long-term chemogenetic stimulation of cholinergic neurons in the dorsal motor nucleus of the vagus in male rats reduced sympathetic tone to control levels, improved recognition memory, and attenuated hippocampal amyloid density compared with the non-stimulated control group.</p><p><strong>Conclusion: </strong>These findings demonstrate a link between autonomic imbalance, memory dysfunction, and hippocampal amyloid pathology, and selective stimulation of the dorsal motor nucleus of the vagus restores autonomic balance and improves episodic-like memory and neuropathological outcomes, identifying this brainstem nucleus as a physiologically relevant therapeutic target in Alzheimer-related neuropathology.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 7","pages":"e70261"},"PeriodicalIF":5.7,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148012738","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":"Functional Differences in Electrolyte Transport Between the Mouse Proximal and Distal Trachea","authors":"Tábata Apablaza,&nbsp;Sandra Villanueva,&nbsp;Araceli Olave-Ruiz,&nbsp;Anita Guequen,&nbsp;Marcelo A. Catalán,&nbsp;Carlos A. Flores","doi":"10.1111/apha.70270","DOIUrl":"https://doi.org/10.1111/apha.70270","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>The mammalian tracheal epithelium is composed of different cell types distributed along the proximal-distal axis. Nevertheless, variations in expression and function of ion channels and transporters participating in fluid absorption and secretion have never been studied separately in proximal and distal mouse trachea. This work aims to characterize basal and stimulated absorption and secretion of fluid obtained from proximal and distal trachea from the same animal.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Ussing chamber was performed using a custom-made tissue slider allowing small tracheal sections mounting, where response to agonists and blockers was recorded. The role of NKCC1 co-transporter was studied using the <i>Slc12a2</i>^−/− mouse. A genetically tomato-induced mouse model was used to assess co-expression of NKCC1 and ASCL3 by immunofluorescence. Animals were instilled with interleukins (ILs) to determine changes in absorption, secretion, and mucus properties.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Proximal trachea didn't participate in sodium absorption but exhibited higher cAMP- and succinate-induced anion secretion than the distal section. NBCe1-dependent bicarbonate and TMEM16A-driven chloride secretion were significantly higher in distal trachea. NKCC1+ cells were found in the submucosal glands (SMGs) and abundant patches of NKCC1+ cells in the distal region. Isolated NKCC1+ cells co-expressing ASCL3 were also detected. ILs treatment changed the electrophysiological properties of the distal trachea exclusively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our experiments determined that the mouse trachea organizes its functions differentially in proximal and distal regions, based on the functional distribution of channels, transporters, and receptors. While the distal trachea changed its responses to agonists inducing anion secretion, the proximal trachea was unperturbed by ILs addition.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 8","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148322484","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":"Of Mice and Men: Toward Mouse-Specific Diastolic Echocardiography","authors":"Markus B. Harbo,&nbsp;Emil Espe","doi":"10.1111/apha.70269","DOIUrl":"10.1111/apha.70269","url":null,"abstract":"&lt;p&gt;The Scottish poet Robert Burns wrote in 1785 that the best laid plans of mice and men often go awry. The observation carries relevance for preclinical cardiac research, where parameters borrowed from clinical echocardiography continue to govern how diastolic function is assessed in the mouse. In this issue of &lt;i&gt;Acta Physiologica&lt;/i&gt;, Marterstock and colleagues address technical and physiological challenges in the assessment of diastolic function in mice, advancing the case for mouse-specific diastolic indices [&lt;span&gt;1&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Mouse models remain indispensable for studying disease mechanisms and developing targeted therapies [&lt;span&gt;2&lt;/span&gt;]. Yet preclinical models struggle to fully recapitulate the clinical phenotype of heart failure with preserved ejection fraction (HFpEF), and the tools used to measure diastolic dysfunction in mice are largely inherited from human echocardiography [&lt;span&gt;3&lt;/span&gt;]. Closing these gaps matters. On the first point, HFpEF accounts for approximately half of all heart failure cases and places a substantial and growing burden on healthcare systems worldwide, demanding deeper mechanistic insight [&lt;span&gt;4&lt;/span&gt;]. On the second point, clinical diastolic assessment relies on transmitral inflow velocities (E and A waves), tissue velocities (e' and a'), and derived ratios such as E/A and E/e' [&lt;span&gt;5&lt;/span&gt;]. Applying these parameters to the mouse is complicated by considerable physiological differences between species [&lt;span&gt;6&lt;/span&gt;]. The murine heart beats at 400 to 700 bpm, leaving tens of milliseconds for diastole, whereas diastole in the human heart can span nearly a second. Clinical algorithms derived from the human heart were never designed for this murine timescale (Figure 1).&lt;/p&gt;&lt;p&gt;Schnelle et al. [&lt;span&gt;7&lt;/span&gt;] have previously evaluated diastolic indices across multiple mouse models of heart disease and proposed a mouse-specific framework built on left atrial area, reverse longitudinal strain rate, and isovolumetric relaxation time (IVRT). The protocol has gained traction, though one practical aspect has remained: While left atrial area and longitudinal strain rate can be derived from a standard parasternal long-axis (PLAX) B-mode cine loop, IVRT has typically required pulsed-wave Doppler acquisition in the apical four-chamber view, which can be technically demanding.&lt;/p&gt;&lt;p&gt;Marterstock et al. propose a solution, demonstrating that a standard B-mode cine loop already contains the information needed to derive mitral inflow timing, without a dedicated Doppler recording. Their Non-A4C-view-dependent Echocardiographic Measurement (NAEM) approach uses speckle-tracking analysis of standard parasternal long-axis B-mode cine loops to determine IVRT by identifying characteristic slope changes in the volume curve that occur between aortic valve closure and mitral valve opening. This yielded IVRT values in close agreement with the Doppler reference (&lt;i&gt;r&lt;/i&gt;&lt;sup&gt;2&lt;/sup&gt; = 0.93, bias −1.4 ms), with inter-observ","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 7","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70269","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148306251","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":"Myosin Post-Translational Modifications Associated With Critical Illness Myopathy","authors":"Fernando Ribeiro,&nbsp;Bruno Di Geronimo,&nbsp;Nicola Cacciani,&nbsp;Anna Widgren,&nbsp;Yvette Hedström,&nbsp;Anselmo S. Moriscot,&nbsp;Peter M. Kasson,&nbsp;Shina C. L. Kamerlin,&nbsp;Jonas Bergquist,&nbsp;Lars Larsson","doi":"10.1111/apha.70240","DOIUrl":"10.1111/apha.70240","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Critical illness myopathy is a common and devastating consequence of critical care, causing dramatic loss of muscle mass and function in intensive care unit patients. Functional deficits often exceed the loss in muscle mass and myosin content. However, the mechanisms underlying the loss of force and emergence of myosin-expressing non-force-generating fibers remain elusive.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Myosin dysfunction was investigated in six intensive care unit patients exposed to a 12-day mechanical ventilation and immobilization period using mass spectrometry-based proteomics and molecular dynamics simulations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Previous single muscle fiber analyses revealed decreased fiber size and specific force from the 1st to the 12th days in all patients. A subset of myosin-expressing fibers exhibiting a complete loss of contractile function was identified in three of the patients despite similar atrophy levels (~30%, <i>p</i> &lt; 0.05) after 12 days. All fibers had decreased specific force after 12 days of mechanical ventilation, but 9% to 21% of the fibers were non-force generating. The decline in specific force was linked to 27 post-translational myosin modifications, including oxidation, ubiquitination, acetylation, and methylation. Molecular dynamics simulations indicated oxidation-induced rigidity of the myosin head, predicted to compromise the flexibility of the actin-binding and converter domains. Non-force-generating fibers exhibited a unique proteomic signature predicted to enhance myosin motor domain exposure and rigidity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In addition to muscle wasting and myosin loss, abnormal myosin post-translational modifications contribute to muscle weakness in ICU patients with CIM, including the development of muscle fibers incapable of generating contractile force.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 7","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70240","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148275254","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":"Phenylalanine Versus Tyrosine (Pos. 367/332 in MCT1/MCT4) in the Substrate Binding Site Defines Affinity and Preferred Directionality of Human Monocarboxylate Transporters 1–4","authors":"Maike Menzel,&nbsp;Ioana-Daniela Dumitru,&nbsp;Josh Peters,&nbsp;Jan-Bernd Hövener,&nbsp;Andrey N. Pravdivtsev,&nbsp;Ana-Nicoleta Bondar,&nbsp;Eric Beitz","doi":"10.1111/apha.70267","DOIUrl":"10.1111/apha.70267","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Human monocarboxylate transporters 1–4, MCT, are key for the lactate/H⁺ exchange between glycolytic and oxidative cancer cells, white and red muscle fibers, or in the astrocyte-neuron shuttle. The common MCT transport mechanism involves three conserved residues, that is, a substrate-attracting Lys and a conformation-locking Asp/Arg salt bridge (positions 38 and 309/313 in MCT1). Yet, it remained unclear which sites define isoform-specific substrate affinity and preferred transport directionality.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here, we analyzed structural differences in the binding sites of MCT1–4 and determined their impact on the biophysical transport properties and inhibitor binding using radiolabeled transport assays in yeast.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found differences in amino acid positions with sidechain hydroxyl groups. While the higher affinity MCT1 and MCT2 carry Phe/Ser-OH (pos. 367/371 in MCT1), the lower affinity MCT3 and MCT4 have Tyr-OH/Gly. Mutation of Phe/Ser-OH in MCT1 to Tyr-OH/Gly markedly decreased the affinity for lactate and pyruvate, while it did not change the affinity for propionate. The maximal transport velocity increased with decreasing affinity, and the preferred transport directionality shifted toward export. Likewise, replacing Met151 by Ala shifted transport bias possibly by eliminating conformation-stabilizing sulfur-aromatic interactions. Moreover, these mutations lowered the activity of the clinical candidate MCT1 inhibitor AZD3965 by three orders of magnitude providing insight into the molecular drug binding mode and explaining the strong preference for MCT1 over MCT4.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Together, subtle changes in the arrangement of sidechains in the MCT binding site determine basic monocarboxylate/H⁺ transport properties that impact lactate-related physiology, namely cellular metabolism, reprogramming, and signaling.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 7","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70267","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148248227","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":"Aberrant Potassium Handling by Astrocytes and Epileptic Seizures: A Synthetic Update","authors":"Jan Albrecht,&nbsp;Stanisław J. Czuczwar,&nbsp;Władysław Lasoń,&nbsp;Alexei Verkhratsky,&nbsp;Magdalena Zielińska","doi":"10.1111/apha.70263","DOIUrl":"10.1111/apha.70263","url":null,"abstract":"<div>\u0000 \u0000 <p>Excessive extracellular accumulation of K⁺ plays a key role in the induction and propagation of seizures associated with temporal lobe epilepsy (TLE), and astrocytes are largely responsible for K⁺ clearance from the extracellular space. Here, we review the TLE-related changes in the content and/or activity of proteins contributing to K⁺ transport across the astrocytic cell membranes. Seizures, whether genetic or acquired, are linked with decreased expression and/or mislocalization of the two key astroglia-specific drivers of K⁺ uptake: the inward rectifying potassium channel K_ir4.1 and its spatial and functional partner, the water channel aquaporin 4 (AQP4). Among neural cells of the CNS, the high K⁺-responsive α2 isoform of Na⁺/K⁺-ATPase is specific for astrocytes and is substantially inactivated in the brains of TLE patients and experimental animals, albeit not always in epilepsies with a genetic background. The above data consistently support the involvement of malfunctional astrocytic K⁺ transport as a factor facilitating seizures. By contrast, complex and variable, region-dependent dynamics of the two-pore domain potassium channels (K2P; TWIK, TASK, and TREK) were observed in astrocytes in the hippocampus, rendering their contribution to seizures difficult to interpret. Anti-seizure medication targeting metabolic processes not directly related to astrocytic K⁺ transport often reversed the unfavorably changed status of the astrocytic mediators of K⁺ buffering.</p>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 7","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148209343","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":"Thermoneutrality Reveals True Cardiac Adaptations to Exercise, Disease, and Aging in Male Mice","authors":"Zhijian Rao,&nbsp;Xue Geng,&nbsp;Peng Huang,&nbsp;Qiangman Wei,&nbsp;Shijie Liu,&nbsp;Xiaokan Zhuang,&nbsp;Chaoyi Qu,&nbsp;Jiexiu Zhao","doi":"10.1111/apha.70266","DOIUrl":"10.1111/apha.70266","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Standard laboratory housing (21°C) imposes chronic cold stress on mice, yet its fundamental impact on cardiac plasticity remains poorly defined. We systematically interrogated how environmental temperature dictates cardiac responses to endurance exercise, doxorubicin (DOX)-induced cardiotoxicity, and aging.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Male mice were housed at standard room temperature (RT) or thermoneutrality (30°C, TN) and subjected to exercise, detraining, DOX treatment, or natural aging. Cardiac remodeling was evaluated by integrating physiological phenotyping (echocardiography, body composition) with comprehensive transcriptomic and proteomic profiling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Housing temperature fundamentally alters cardiac molecular baselines and adaptive trajectories. Exercise at TN elicited a coordinated, extracellular matrix (ECM)-focused transcriptional program, improving contractile function without inducing overt hypertrophy. Conversely, RT triggered a broad, uncoordinated stress response. Notably, while RT permitted classic regression of exercise-induced hypertrophy, detraining at TN revealed a unique cardiac structural economy, where cardiac mass significantly dropped below sedentary controls while maintaining enhanced functional efficiency. In pathological models, RT-induced compensatory survival pathways masked the true structural severity of DOX cardiotoxicity and paradoxically buffered against fibrosis. Furthermore, RT exacerbated cardiac aging phenotypes, inducing widespread fibrosis and upregulating senescence markers and specific microRNAs that remained quiescent under TN.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Environmental temperature profoundly reshapes cardiac adaptive plasticity. The chronic thermal stress of standard housing distorts intrinsic molecular signaling, highlighting thermoneutrality as a crucial baseline for revealing true physiological adaptations and ensuring the translational validity of cardiovascular models.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 7","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148209419","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":"A New Aspect of Fentanyl-Induced Respiratory Depression","authors":"Astrid G. Stucke,&nbsp;Gary C. Mouradian","doi":"10.1111/apha.70265","DOIUrl":"10.1111/apha.70265","url":null,"abstract":"&lt;p&gt;For many years, respiratory rate depression was considered the main mechanism through which opioids caused respiratory depression and death, and the competitive antagonist naloxone was promoted as the treatment of choice. The shift in illicit substance use toward the highly potent, synthetic opioid fentanyl increased the interest of researchers and clinicians in the opioid effect on airway patency and compliance. In this issue, Parks et al. describe the effect of fentanyl on lower airway compliance, a pathophysiologic mechanisms that had not been well described previously [&lt;span&gt;1&lt;/span&gt;]. The authors used an in vivo, ventilated mouse model and measured lower airway compliance with pressure-volume loops during a 70-min ventilation period. Intraperitoneal (IP) fentanyl caused an increase in lower airway resistance, which could not be reversed with IP naloxone, but which was attenuated by IP administration of the bronchodilators salbutamol, a beta-2-adrenergic agonist (Figure 1, insert), or atropine, an acetylcholine-receptor antagonist. A limitation to the animal model is that airway resistance increases somewhat even in the control group, i.e., through ventilation alone. However, the insert in Figure 1 shows that while IP salbutamol also attenuated the increase in airway resistance from ventilation alone (pink vs. blue line), the attenuation was greater after fentanyl (green vs. brown line), i.e., there was an additional attenuation of the fentanyl effect. The increase in airway resistance in the control group could be partially prevented with positive end-expiratory pressure ventilation, suggesting a degree of ventilator-associated lung injury, which could limit the extrapolation of the results to humans with healthy lungs. On the other hand, individuals with substance use disorder frequently have underlying lung pathology due to smoking or chronic micro-aspiration, and the negative effect of fentanyl on lower airway compliance may be greater in this population.&lt;/p&gt;&lt;p&gt;A recent study delineated the circuit for allergen-induced airway hyperreactivity [&lt;span&gt;9&lt;/span&gt;]: mast cell activation of Trpv1+ vagal fibers in the lungs activated Dbh + neurons in the nucleus of the solitary tract (NTS). Dbh + neurons activated cholinergic neurons in the nucleus ambiguus, and the vagal efferents resulted in activation of muscarinic receptors on airway smooth muscle cells and thus bronchoconstriction. Ablation of the cholinergic nucleus ambiguus neurons was sufficient to abolish airway hyperreactivity from allergens [&lt;span&gt;9&lt;/span&gt;]. While there is little mast cell degranulation with fentanyl compared to other opioids, it was shown that intravenous fentanyl caused laryngeal closure, pharyngeal constriction, and chest wall rigidity through stimulation of afferent vagal C-fibers [&lt;span&gt;6&lt;/span&gt;]. These fibers are mostly Trpv1+ [&lt;span&gt;10&lt;/span&gt;], suggesting that fentanyl-induced bronchoconstriction results from the same reflex arc as allergen-induced bronchospas","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 7","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70265","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148203319","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":"Clustering Properties of Neuronal Ryanodine Receptor 2 and Remodeling in the APP/PS1 Mouse Model of Alzheimer's Disease","authors":"Michelle L. Munro,&nbsp;Ruben Vergara Silva,&nbsp;Shane M. Ohline,&nbsp;Ei Phyo Khaing,&nbsp;Joan A. Chan,&nbsp;Mohamed F. Ibrahim,&nbsp;Tausi F. Tausi,&nbsp;Wickliffe C. Abraham,&nbsp;Peter P. Jones","doi":"10.1111/apha.70264","DOIUrl":"https://doi.org/10.1111/apha.70264","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>The ryanodine receptor (RyR2) is an intracellular Ca²⁺ release channel which mediates numerous cellular functions across different tissues. Dysregulation of RyR2 channel activity leads to pathological Ca²⁺ release, which often underlies disrupted cellular signaling in disease states. In the heart, RyR2 channels forms discrete clusters and calcium release units (CRUs) which control channel activity. These structures demonstrate nanoscale remodeling in disease states associated with pathological Ca²⁺ release activity in the heart. Hence, these nanoscale structures are critical in regulating Ca²⁺ release in health and disease. RyR2 is also expressed in brain; however, whether analogous clusters and CRUs form in neurons remains unexplored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using super-resolution imaging, we assessed RyR2 organization in CA1 pyramidal neurons of wild-type mice. Furthermore, we used the APP/PS1 mouse model of Alzheimer's disease (AD) to assess whether there is nanoscale remodeling of RyR2 in a setting associated with pathological Ca²⁺ release in neurons.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Here, we provide the first identification and detailed characterization of RyR2 clusters in central nervous system neurons, which are comparable to those reported in the heart. Moreover, we observed a decrease in RyR2 cluster size and reduced CRU organization in AD mice at an age associated with high plaque burden and cognitive deficits. This remodeling is analogous to that reported in pathological states in the heart.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Together, these findings implicate the nanoscale remodeling of RyR2 clusters and CRUs as a novel mechanism underlying Ca²⁺ channel dysregulation and neuronal dysfunction in AD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 7","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70264","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148174171","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}