Acta Physiologica最新文献

{"title":"A Structural Context for the Mechanisms of Uncoupling Protein 1 in Brown Fat Thermogenesis","authors":"Riccardo Cavalieri,&nbsp;Margeoux A. S. Dela Rosa,&nbsp;Camila A. Cotrim,&nbsp;Danielle Copeman,&nbsp;Mehmethan Aris,&nbsp;Callum Eke,&nbsp;Hannah Staggs-Sandy,&nbsp;Paul G. Crichton","doi":"10.1111/apha.70246","DOIUrl":"10.1111/apha.70246","url":null,"abstract":"<p>Uncoupling Protein 1 (UCP1) is a defining feature of brown fat and facilitates the specialized ability of the tissue to generate heat in the process of non-shivering thermogenesis. The protein is activated by fatty acids, which overcome its inhibition by purine nucleotides, to catalyze proton leak across the mitochondrial inner membrane, uncoupling nutrient oxidation from ATP production to release energy as heat. Thermogenesis through this process contributes to thermoregulation in many mammals and can promote nutrient turnover in humans to support metabolic health. UCP1 is a member of the mitochondrial carrier family of solute exchangers. For many years, its underlying mechanisms of activity and regulation have remained unclear. However, recent cryo-EM structures of UCP1 have clarified details on nucleotide inhibition and, with advances in our understanding of the mitochondrial carrier transport mechanism, provided important molecular constraints to rationalize how the protein may operate. Here, we review the molecular nature of UCP1, re-evaluating past structure–function relations in this structural context. Key carrier features and putative novel bonding that likely support state changes in the protein and proton leak activity are highlighted, as well as new hypotheses to explain subtleties in purine nucleotide binding discrimination.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13173328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147924946","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148078159","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":"Ryanodine Receptor Ca2+ Leak-Induced Redistribution of Ca2+ in Dystrophic mdx Mouse Muscle","authors":"Rhayanna B. Gaglianone,&nbsp;Cedric R. Lamboley,&nbsp;Taylor Dick,&nbsp;Aldo Meizoso-Huesca,&nbsp;Daniel P. Singh,&nbsp;Bradley S. Launikonis","doi":"10.1111/apha.70251","DOIUrl":"10.1111/apha.70251","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>The dystrophic mdx mouse is a widely used model of Duchenne muscular dystrophy. Altered Ca²⁺ handling is a key feature, including increased Ca²⁺ leak through the ryanodine receptor (RyR1's), the primary Ca²⁺ release channel in skeletal muscle. Such leak has important downstream consequences for intracellular Ca²⁺ homeostasis. Here, we quantified basal compartmentalized Ca²⁺ levels in mdx muscle compared with wild-type (WT).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Single extensor digitorum longus muscle fibers from WT and mdx mice were mechanically skinned. Transverse tubule Ca²⁺ dynamics were assessed using confocal microscopy with fluorescent Ca²⁺ indicators during caffeine-induced RyR1-mediated Ca²⁺ release. Sarcoplasmic reticulum (SR) and mitochondrial Ca²⁺ contents were quantified using established depletion protocols combined with force measurements.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Consistent with previous reports, mdx fibers exhibited increased RyR1 Ca²⁺ leak. Absolute quantification revealed a reduction in SR Ca²⁺ content accompanied by a ~4-fold increase in mitochondrial Ca²⁺ content. These shifts indicate a redistribution of intracellular Ca²⁺, triggered by the RyR1 Ca²⁺ leak to lower SR Ca²⁺ content and increase the Ca²⁺ permeability of the t-system membrane, leading to an elevation in cytoplasmic and mitochondrial Ca²⁺ levels in mdx muscle.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Redistribution of Ca²⁺ is a regulated process, proportional to RyR1 Ca²⁺ leak. In mdx muscle fibers, there is reduced SR and elevated mitochondrial and cytoplasmic Ca²⁺ compared to WT fibers. These alterations contribute to the dystrophic muscle pathology, likely through promotion of oxidative stress through increased reactive oxygen species production.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13176391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147939500","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":"Ca2+-Activated Cl− Channels: Do Bestrophins and TMEM16A Interact?","authors":"Christian Aalkjær,&nbsp;Vibeke Secher Dam,&nbsp;Holger Nilsson,&nbsp;Donna B. Boedtkjer,&nbsp;Vladimir Matchkov","doi":"10.1111/apha.70232","DOIUrl":"10.1111/apha.70232","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Ca²⁺-activated Cl– conductances are present in many cell types and are important for regulating membrane potential as well as other cellular functions. TMEM16A is widely accepted as the principal molecular basis for Ca²⁺-activated Cl– conductances, but also members of the bestrophin family may be important for some Ca²⁺-activated Cl– conductances.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this review, we discuss the possibility that members of the two families, bestrophins and TMEM16A, may interact.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In the cardiovascular system, the evidence is strongest. Here (1) TMEM16A and bestrophin-3 are closely located in the membrane, (2) TMEM16A may regulate the expression of bestrophin-3, and (3) a cGMP dependent Ca²⁺-activated Cl– conductance is dependent on both TMEM16A and bestrophin-3. Outside the cardiovascular system, both TMEM16A and bestrophins are implicated in the regulation of cellular Ca²⁺ independently of membrane potential, and both proteins are importantly associated with inflammation and pain transmission. However, it seems that little testing of a direct interaction of TMEM16A and bestrophins has been published.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We conclude that there is evidence for direct interaction between TMEM16A and bestrophins in the cardiovascular system, and it will be important to determine whether similar interactions extend to other tissues.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13168367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147924876","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148074582","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148073598","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":"Inhibiting Purinergic Receptor (P2X7R) Alleviates Depression- and Anxiety-Like Behaviors in Obese Rats With Immune Challenge","authors":"Titikorn Chunchai,&nbsp;Hiranya Pintana,&nbsp;Patcharapong Pantiya,&nbsp;Chanon Kunasol,&nbsp;Chanisa Thonusin,&nbsp;Nipon Chattipakorn,&nbsp;Siriporn C. Chattipakorn","doi":"10.1111/apha.70241","DOIUrl":"10.1111/apha.70241","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Chronic high-fat diet (HFD) consumption combined with lipopolysaccharide (LPS) challenge promotes microglial hyperactivation, brain inflammation, reduced neurogenesis, and depression-like behavior. LPS also increases adenosine triphosphate (ATP) release from immune and dying cells, activating microglia through the purinergic P2X7R receptor. However, the effects of P2X7 inhibitor on microglial hyperactivation, brain inflammation, neurogenesis, and depression-like behavior in obese models challenged with LPS remain unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Sixty-four male Wistar rats were fed either normal diet or HFD for 12 weeks and subsequently received an intraperitoneal (IP) injection of normal saline or LPS (500 μg/kg). LPS-treated rats were then given saline, minocycline (45 mg/kg, twice, IP), or the P2X7R inhibitor JNJ-55308942 (30 mg/kg, single dose, orally). Depression- and anxiety-like behaviors were assessed 24 h later.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>LPS alone induced pronounced peripheral and brain inflammation, elevated circulating LPS, microglial hyperactivation, increased ATP/P2X7-mediated neuroinflammation, excessive C1q-mediated synaptic pruning, and mood-related behavioral deficits. Chronic HFD additionally induced metabolic disturbances, oxidative stress, blood–brain barrier disruption, and reduced neurogenesis. Combined HFD and LPS exposures further amplified brain pathologies and the severity of mood-related deficits. P2X7R inhibitor effectively reduced oxidative stress, suppressed ATP/P2X7-mediated neuroinflammation, limited aberrant synaptic pruning, restored neurogenesis, and improved behaviors. Minocycline improved behavioral outcomes primarily by reducing endotoxemia and inflammation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The comparable neuroprotection produced by JNJ-55308942 and minocycline suggests that ATP/P2X7-mediated neuroinflammation plays a major role in regulating brain pathologies in HFD-fed rats, followed by LPS challenge. These findings suggest P2X7 signaling as a promising therapeutic target for depression and inflammation-associated neuropsychiatric disorders.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147865884","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148073597","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 E3 Ubiquitin Ligase RNF123 Mediates Pathological Cardiac Hypertrophy by Ubiquitinating PRDX1 and Upregulating Oxidative Stress in Cardiomyocytes","authors":"Qinyan Wang,&nbsp;Xiaochen Guo,&nbsp;Jiachen Xu,&nbsp;Jinfu Qian,&nbsp;Tianxiang Yu,&nbsp;Qingsong Zheng,&nbsp;Mengyang Wang,&nbsp;Wu Luo,&nbsp;Guang Liang","doi":"10.1111/apha.70244","DOIUrl":"10.1111/apha.70244","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Pathological cardiac hypertrophy is a key risk factor for heart failure (HF). Illustrating the pathogenesis of cardiac hypertrophy may contribute to the treatment of HF. Studies have emphasized that protein ubiquitination is a critical event in HF. In this study, we investigated the role of an E3 ubiquitin ligase, RNF123, in HF induced by angiotensin II (Ang II) infusion and transverse aortic constriction (TAC) surgery.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Heart failure was induced by Ang II infusion or TAC surgery in wild-type and RNF123 knockout mice. Liquid chromatography–tandem mass spectrometry (LC–MS/MS) analysis combined with co-immunoprecipitation (Co-IP) was used to identify PRDX1 as an interacting protein of RNF123.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The expression of RNF123 was significantly increased in cardiomyocytes of mice subjected to Ang II infusion or TAC surgery. RNF123 deficiency mitigated cardiac hypertrophy and dysfunction induced by Ang II infusion or TAC operation in mice. In vitro, RNF123 knockdown attenuated Ang II-induced hypertrophy, whereas RNF123 overexpression exacerbated the pathological alterations in neonatal rat ventricular myocytes (NRVMs). Mechanistically, LC–MS/MS and Co-IP assays revealed that RNF123 directly bound to the N-terminal domain of PRDX1 and added a K48-linked ubiquitin chain at the K7 site of PRDX1, subsequently facilitating PRDX1's proteasomal degradation. RNF123-mediated degradation of PRDX1 increased the ROS level in cardiomyocytes, driving the pathogenesis of myocardial hypertrophy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings identified that cardiomyocyte RNF123 mediates pathological cardiac hypertrophy via ubiquitinating PRDX1 and highlighted that targeting RNF123 may represent a promising therapeutic strategy for HF.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147865930","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":"Female Age and Prior Pregnancies Are Associated With Increased Propensity for Sodium Retention in Rats","authors":"Lene N. Nejsum","doi":"10.1111/apha.70237","DOIUrl":"10.1111/apha.70237","url":null,"abstract":"&lt;p&gt;Rodent models are indispensable when investigating renal handling of water and electrolytes in both health and disease. Most experiments induce disease states on healthy young animals, but these do not necessarily recapitulate renal function following aging or prior female reproduction. Thus, the physiological interpretation and translational potential may be partially limited. In a recent publication in Acta Physiologica entitled “Age-related Adaptations in Renal Tubular Function in Female Rats” [&lt;span&gt;1&lt;/span&gt;], Edwards and colleagues take an important leap forward by investigating the impact of age and past pregnancies on renal function by systematically comparing 12-month-old female breeder rats (corresponding to mid-life with reproductive history) to 4.5-month-old adolescent virgin females. Interestingly, in the 12-month-old breeder rats, the authors observed a tendency to higher glomerular filtration rate (GFR) of ~25% (&lt;i&gt;p&lt;/i&gt; = 0.10), similar urinary excretion of Na&lt;sup&gt;+&lt;/sup&gt; and K&lt;sup&gt;+&lt;/sup&gt; and an increased response to the diuretic hydrochlorothiazide (HCTZ). The response to a K&lt;sup&gt;+&lt;/sup&gt; rich meal was unchanged. Of note, overall aquaporin-2 (AQP2) abundance in the collecting duct principal cells was unaltered, but AQP2 phosphorylation on serine 256 (pS256-AQP2) was increased by ~50% which may indicate increased collecting duct water permeability (Figure 1).&lt;/p&gt;&lt;p&gt;In the kidneys, GFR largely determines the downstream need for tubular reabsorption of sodium and water. Renal sodium handling is mediated by different Na&lt;sup&gt;+&lt;/sup&gt; transporters, with most of the sodium handling occurring in the proximal tubule and thick ascending limb of Henle, with subsequent reabsorption in the distal tubule and fine-tuning in the collecting duct [&lt;span&gt;2&lt;/span&gt;]. Water reabsorption is mediated via aquaporins, with constitutive water reabsorption in the proximal tubule and subsequent hormone-regulated fine-tuning in the collecting duct [&lt;span&gt;3, 4&lt;/span&gt;]. Adaptive changes in renal expression and/or localization of several of these Na&lt;sup&gt;+&lt;/sup&gt; transporters and aquaporins are hormonally mediated in relation to changes in GFR as well as altered sodium and water intake.&lt;/p&gt;&lt;p&gt;Edwards and colleagues [&lt;span&gt;1&lt;/span&gt;] show that GFR was not significantly different between 4.5-month adolescent virgin female rats and 12-month mid-life female breeder rats where a tendency to higher GFR was observed. A systematic review by Guppy and colleagues from 2024 [&lt;span&gt;5&lt;/span&gt;] found an annual decline rate of GFR in human adults without hypertension of −0.37 to −1.07 mL/min/1.73 m&lt;sup&gt;2&lt;/sup&gt;/year. Similarly, age-related decline in GFR in male rats was reported by Reckelhoff and colleagues in 1992 comparing old male rats aged 20–22 months vs. adolescent male rats aged 4–5 months (0.67 ± 0.05 mL/min/g KW vs. 1.00 ± 0.08 mL/min/g KW, &lt;i&gt;p&lt;/i&gt; &lt; 0.02) when adjusted for kidney weight [&lt;span&gt;6&lt;/span&gt;]. Thus, the study by Edwards and colleagues [&lt;span&gt;1&lt;/span&gt;] ind","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70237","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147830832","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}