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Mitochondrial Dysfunction and Defects in Mitochondrial Adaptation to Exercise Training in the Muscle of Patients With COPD: Disease Versus Disuse 慢性阻塞性肺病患者肌肉运动训练线粒体功能障碍和线粒体适应缺陷:疾病与废用
IF 5.6 2区 医学
Acta Physiologica Pub Date : 2025-07-10 DOI: 10.1111/apha.70079
Aldjia Abdellaoui, Farés Gouzi, Cécile Notarnicola, Annick Bourret, Amandine Suc, Dalila Laoudj-Chenivesse, Nelly Héraud, Jacques Mercier, Christian Préfaut, Maurice Hayot, Pascal Pomiès
{"title":"Mitochondrial Dysfunction and Defects in Mitochondrial Adaptation to Exercise Training in the Muscle of Patients With COPD: Disease Versus Disuse","authors":"Aldjia Abdellaoui,&nbsp;Farés Gouzi,&nbsp;Cécile Notarnicola,&nbsp;Annick Bourret,&nbsp;Amandine Suc,&nbsp;Dalila Laoudj-Chenivesse,&nbsp;Nelly Héraud,&nbsp;Jacques Mercier,&nbsp;Christian Préfaut,&nbsp;Maurice Hayot,&nbsp;Pascal Pomiès","doi":"10.1111/apha.70079","DOIUrl":"https://doi.org/10.1111/apha.70079","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Chronic obstructive pulmonary disease (COPD) is frequently associated with skeletal muscle dysfunction, having a considerable impact on exercise tolerance and patient prognosis. Mitochondria play a role in skeletal muscle weakness and exercise intolerance in COPD, but the majority of studies on mitochondrial function are biased by the fact that physical activity is greater in healthy subjects than in patients. Furthermore, exercise training (ET) has been proposed as a therapeutic strategy to prevent skeletal muscle dysfunction in COPD, but very few results are available on mitochondrial adaptation in response to ET.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Skeletal muscle mitochondrial function and the potential efficacy of ET on this function were compared between 12 patients with COPD and 21 healthy subjects with similar low levels of physical activity. Various markers of mitochondrial respiration, oxidative stress, biogenesis, and dynamics were assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Lower oxidative phosphorylation (OxPhos; <i>p</i> &lt; 0.001) and increased nonphosphorylating respiration (<i>p</i> = 0.025) and mitochondrial oxidative damage (lipid peroxidation (<i>p</i> = 0.014) and protein carbonylation (<i>p</i> = 0.020)) were observed in patients. While ET increased OxPhos efficiency (<i>p</i> = 0.011) and reduced nonphosphorylating respiration (<i>p</i> &lt; 0.001) and lipid peroxidation (<i>p</i> &lt; 0.001) in patients' muscle mitochondria, it fails to improve maximal respiration (<i>p</i> = 0.835) and expression of the antioxidant enzyme MnSOD (<i>p</i> = 0.606), mitochondrial transcription factor TFAM (<i>p</i> = 0.246), and mitochondrial complexes I, III, and IV (<i>p</i> = 0.816, <i>p</i> = 0.664, <i>p</i> = 0.888, respectively) as observed in healthy subjects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The mitochondrial dysfunction and the defects in mitochondrial adaptation to ET that we observe in the muscle of patients with COPD are intrinsic to the disease and do not arise from muscle disuse.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70079","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144589761","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}
引用次数: 0
Loss of Na+,HCO3−-Cotransporter NBCn1 Inhibits Net Acid Extrusion in the Atria and Causes Hypertension-Associated Cardiac Hypertrophy Na+,HCO3−-共转运体NBCn1的缺失抑制心房净酸挤压并导致高血压相关性心脏肥厚
IF 5.6 2区 医学
Acta Physiologica Pub Date : 2025-07-09 DOI: 10.1111/apha.70078
María S. Espejo, Alejandro Orlowski, Trine M. Sørensen, Vladimir V. Matchkov, Ernesto A. Aiello, Ebbe Boedtkjer
{"title":"Loss of Na+,HCO3−-Cotransporter NBCn1 Inhibits Net Acid Extrusion in the Atria and Causes Hypertension-Associated Cardiac Hypertrophy","authors":"María S. Espejo,&nbsp;Alejandro Orlowski,&nbsp;Trine M. Sørensen,&nbsp;Vladimir V. Matchkov,&nbsp;Ernesto A. Aiello,&nbsp;Ebbe Boedtkjer","doi":"10.1111/apha.70078","DOIUrl":"https://doi.org/10.1111/apha.70078","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Metabolic disturbances challenge pH homeostasis in cardiomyocytes. The electroneutral Na<sup>+</sup>,HCO<sub>3</sub><sup>−</sup>-cotransporter NBCn1/Slc4a7 mediates net acid extrusion, and genetic variation in <i>SLC4A7</i> contributes to human hypertension and cardiovascular risk. Nonetheless, the cardiac consequences of disrupted NBCn1 expression and function remain unclear. Here, we test the hypothesis that NBCn1, either directly or indirectly, influences cardiac structure, contractile function, and electrophysiological properties.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Based on mice with global loss of NBCn1, we measure intracellular pH in atria and ventricles of the heart (fluorescence microscopy), membrane potential responses (patch clamping), electro- and echocardiographic variables, blood pressure (telemetry), and cardiac dimensions (in vivo and postmortem analyses).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We find that protein and mRNA expression of NBCn1 are more prominent in atrial than in ventricular cardiomyocytes. Disruption of NBCn1 expression lowers Na<sup>+</sup>,HCO<sub>3</sub><sup>−</sup>-cotransport activity more than 50% in atria without significantly influencing net acid extrusion activity of ventricular cardiomyocytes. Loss of NBCn1 is associated with hypertension (blood pressure increased by ~15 mmHg), cardiac hypertrophy (heart/body weight increased by ~10%), and prolonged ventricular isovolumic relaxation time (increased by ~25%). NBCn1 knockout does not affect cardiomyocyte size, collagen content in the heart wall, overall cardiac contractile function, electrophysiological properties of ventricular cardiomyocytes, or the electrocardiogram.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>NBCn1 is a main mechanism of Na<sup>+</sup>,HCO<sub>3</sub><sup>−</sup>-cotransport in atrial tissue and contributes substantially to net acid extrusion during intracellular acidification. NBCn1 does not play any major direct role in ventricular cardiomyocytes of unchallenged mice, but global knockout of NBCn1 increases systemic blood pressure and results in the development of cardiac hypertrophy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70078","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582211","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}
引用次数: 0
Hypotaurine Reduces Glucose-Mediated Vascular Calcification 次牛磺酸减少葡萄糖介导的血管钙化
IF 5.6 2区 医学
Acta Physiologica Pub Date : 2025-07-07 DOI: 10.1111/apha.70075
Marina A. Heuschkel, Armand Jaminon, Steffen Gräber, Anna Artati, Jerzy Adamski, Joachim Jankowski, Leon Schurgers, Nikolaus Marx, Willi Jahnen-Dechent, Claudia Goettsch
{"title":"Hypotaurine Reduces Glucose-Mediated Vascular Calcification","authors":"Marina A. Heuschkel,&nbsp;Armand Jaminon,&nbsp;Steffen Gräber,&nbsp;Anna Artati,&nbsp;Jerzy Adamski,&nbsp;Joachim Jankowski,&nbsp;Leon Schurgers,&nbsp;Nikolaus Marx,&nbsp;Willi Jahnen-Dechent,&nbsp;Claudia Goettsch","doi":"10.1111/apha.70075","DOIUrl":"https://doi.org/10.1111/apha.70075","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Vascular calcification (VC), a characteristic feature of peripheral artery disease in patients with diabetes and chronic kidney disease, has been associated with poor prognosis. We hypothesize that hyperglycemia drives VC through alterations in metabolomic and transcriptomic profiles.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Human coronary artery smooth muscle cells (SMCs) were cultured with 0, 5.5, and 25 mM glucose under calcifying conditions. Untargeted metabolomic and transcriptomic analyses were performed at different time points. Mitochondrial respiration was examined using Seahorse analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Glucose-treated SMCs promoted extracellular matrix (ECM) calcification in a concentration- and time-dependent manner. The absence of glucose entirely abolished SMC calcification but reduced SMC proliferation in control and calcifying conditions compared to 25 mM glucose. Multi-omics data integration revealed key players from the hypotaurine/taurine metabolic pathway as the center hub of the reconstructed network. Glucose promoted the hypotaurine secretion, while its intracellular abundance was not altered. Blocking hypotaurine production by propargylglycine increased ECM calcification, while hypotaurine treatment prevented it. Furthermore, omics data suggest energy remodeling in calcifying SMCs under hyperglycemia. Calcifying SMCs exhibited decreased oxygen consumption that was partially restored by hypotaurine. Validation of our in vitro models using the murine warfarin model demonstrated reduced hypotaurine/taurine transporter (TAUT) expression in SMCs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our multi-omics analysis revealed a role of the hypotaurine/taurine metabolic pathway in glucose-induced SMC calcification. Moreover, our data suggest a glucose-dependent energy remodeling in calcifying SMCs and that increasing glucose concentrations fuel ECM calcification. Our work highlights potential novel therapeutic targets that warrant further investigation in hyperglycemia-dependent in vitro SMC calcification.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70075","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144573927","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}
引用次数: 0
Lipocalin-2 Restores Soluble Guanylyl Cyclase-Dependent Dilation of the Afferent Arteriole After Renal Transplantation or Ex Vivo Hypoxia/Reoxygenation in Mice 脂钙素-2恢复小鼠肾移植或体外缺氧/再氧化后传入小动脉的可溶性关酰环化酶依赖性扩张
IF 5.6 2区 医学
Acta Physiologica Pub Date : 2025-07-04 DOI: 10.1111/apha.70077
Liang Zhao, Minze Xu, Anna Maria Pfefferkorn, Cem Erdogan, Hubert Schwelberger, Pinchao Wang, Pratik Hemant Khedkar, Marc Eigen, Falk-Bach Lichtenberger, Rusan Catar, En Yin Lai, Felix Aigner, Pontus B. Persson, Igor Maximilian Sauer, Andreas Patzak, Muhammad Imtiaz Ashraf
{"title":"Lipocalin-2 Restores Soluble Guanylyl Cyclase-Dependent Dilation of the Afferent Arteriole After Renal Transplantation or Ex Vivo Hypoxia/Reoxygenation in Mice","authors":"Liang Zhao,&nbsp;Minze Xu,&nbsp;Anna Maria Pfefferkorn,&nbsp;Cem Erdogan,&nbsp;Hubert Schwelberger,&nbsp;Pinchao Wang,&nbsp;Pratik Hemant Khedkar,&nbsp;Marc Eigen,&nbsp;Falk-Bach Lichtenberger,&nbsp;Rusan Catar,&nbsp;En Yin Lai,&nbsp;Felix Aigner,&nbsp;Pontus B. Persson,&nbsp;Igor Maximilian Sauer,&nbsp;Andreas Patzak,&nbsp;Muhammad Imtiaz Ashraf","doi":"10.1111/apha.70077","DOIUrl":"https://doi.org/10.1111/apha.70077","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Dilatory microvascular function is impaired in ischemia/reperfusion injury in the kidney. Nitric oxide independent activators of soluble guanylyl cyclase (sGC) provide renal protection by dilating microvessels and preserving perfusion, but their efficacy declines after severe hypoxia. This study explores whether lipocalin-2 (Lcn2), a key iron-transporting protein, can restore the sGC-mediated dilation in mouse afferent arterioles (AAs) after hypoxia/reoxygenation (<i>H</i>/<i>R</i>) and kidney transplantation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Dilation of isolated, angiotensin II (Ang II) pre-constricted, AAs was induced by application of sGC activator cinaciguat after pre-constriction with Ang II following <i>H</i>/<i>R</i> (<i>H</i>: 30 min, <i>R</i>: 10 min ± holo-rLcn2, apo-rLcn2, deferoxamine) and syngeneic kidney transplantation (cold ischemia: 30 min or 5.5 h, reperfusion: 20 h ± holo-rLcn2) in C57BL/6 mice. To corroborate the dilatory function at the organ level, vascular relaxation was assessed using an isolated mouse kidney perfusion system.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Dilation of AAs was impaired following <i>H</i>/<i>R</i>. Pretreatment with holo-rLcn2 (iron-bound) preserved dilation, whereas apo-rLcn2 (iron-free) had no effect. The reversal of holo-rLcn2's effect by deferoxamine confirmed the role of iron. AAs from kidney transplants showed reduced dilation compared to sham-operated controls, with greater impairment following prolonged ischemia. Treatment with holo-rLcn2 significantly improved dilatory function after extended cold ischemia (5.5 h), restoring it to levels seen with shorter ischemia (30 min). Ex vivo perfusion of the isolated mouse kidney with holo-rLcn2 enhanced cinaciguat-induced vascular relaxation, confirming its beneficial effect at the organ level.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study identifies a novel role for holo-rLcn2 in preserving renal vascular function post-<i>H</i>/<i>R</i> and kidney transplantation, apparently by upholding iron levels in vascular cells.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70077","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551124","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}
引用次数: 0
Reversal of Diabesity Through Modulating Sympathetic Inputs to Adipose Tissue Following Carotid Body Resection 颈动脉体切除后通过调节交感神经输入脂肪组织逆转糖尿病
IF 5.6 2区 医学
Acta Physiologica Pub Date : 2025-06-24 DOI: 10.1111/apha.70074
Bernardete F. Melo, Joana F. Sacramento, Julien Lavergne, Fátima O. Martins, Daniela Rosendo-Silva, Clara Panzolini, Cláudia S. Prego, Aidan Falvey, Elena Olea, Paulo Matafome, Asuncion Rocher, Jesus Prieto-Lloret, Miguel C. Correia, Phillipe Blancou, Silvia V. Conde
{"title":"Reversal of Diabesity Through Modulating Sympathetic Inputs to Adipose Tissue Following Carotid Body Resection","authors":"Bernardete F. Melo,&nbsp;Joana F. Sacramento,&nbsp;Julien Lavergne,&nbsp;Fátima O. Martins,&nbsp;Daniela Rosendo-Silva,&nbsp;Clara Panzolini,&nbsp;Cláudia S. Prego,&nbsp;Aidan Falvey,&nbsp;Elena Olea,&nbsp;Paulo Matafome,&nbsp;Asuncion Rocher,&nbsp;Jesus Prieto-Lloret,&nbsp;Miguel C. Correia,&nbsp;Phillipe Blancou,&nbsp;Silvia V. Conde","doi":"10.1111/apha.70074","DOIUrl":"https://doi.org/10.1111/apha.70074","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>The development of innovative strategies to treat diabesity and its comorbidities is of major societal importance. The carotid bodies (CB), classically defined as O<sub>2</sub> sensors, are also metabolic sensors whose dysfunction contributes to the genesis and progression of metabolic disturbances. Here, we tested the hypothesis that the CBs are key players in the neural hypothalamic-sympathetic circuit controlling glucose and energy homeostasis. Moreover, we investigated if abolishment of CB activity has an anti-diabesity effect in Wistar rats and C75BL/6J mice, associated with increased visceral white and brown adipose tissue (AT) metabolism and the restoration of sympathetic activity within these tissues.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We demonstrate that resection of the carotid sinus nerve, the CB-sensitive nerve, promotes weight loss and restores metabolic function in obese rats and mice by enhancing tyrosine hydroxylase expression at the paraventricular nucleus of the hypothalamus and its efferent sympathetic neurons to the AT. Moreover, we found that CSN resection increases sympathetic integration and catecholaminergic action in the AT in a manner that restores or even increases AT metabolism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We provide groundbreaking and innovative data showing a new circuit involving the CB-hypothalamus-sympathetic efferents and the AT in controlling glucose and energy homeostasis and so a novel pathway for managing diabesity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 7","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70074","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144367602","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}
引用次数: 0
Effects of Dietary BCAAs Intake on the Blood Pressure in Dahl Salt-Sensitive Rats 膳食中摄入支链氨基酸对达尔盐敏感大鼠血压的影响
IF 5.6 2区 医学
Acta Physiologica Pub Date : 2025-06-23 DOI: 10.1111/apha.70070
Meng Chen, Li Zeng, Xiangbo Chen, Lan Chen, Di Gao, Zhe Yang, Zhongmin Tian
{"title":"Effects of Dietary BCAAs Intake on the Blood Pressure in Dahl Salt-Sensitive Rats","authors":"Meng Chen,&nbsp;Li Zeng,&nbsp;Xiangbo Chen,&nbsp;Lan Chen,&nbsp;Di Gao,&nbsp;Zhe Yang,&nbsp;Zhongmin Tian","doi":"10.1111/apha.70070","DOIUrl":"https://doi.org/10.1111/apha.70070","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Circulating branched-chain amino acids (BCAAs) have been widely found to be associated with the risk of hypertension, but mechanisms remain unclear. In this study, we hypothesized that BCAAs could alleviate the development of salt-induced hypertension in Dahl salt-sensitive (SS) rats. The objective was to explore whether long-term high-salt diets (a major dietary risk for high blood pressure) alter BCAAs levels in SS rats and how dietary BCAAs influence salt-induced hypertension.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>SS rats received an 11-week dietary intervention to investigate the effects of dietary BCAAs on SS hypertension. Metabolic changes were studied using GC–MS and LC–MS/MS, as well as selected enzyme activity measurements. Western blotting was used to measure the protein levels of p-BCKDHA/BCKDHA and AQP. HUVECs and HK-2 cells were treated with 2 mM BCAAs for 24 h before measuring metabolites and enzyme activities.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>An 11-week high-salt diet increased blood pressure in SS rats, which was accompanied by reduced circulating BCAAs levels. Dietary BCAAs attenuated salt-induced hypertension, restored circulating BCAAs levels, and enhanced BCAAs metabolic activity. It also decreased aquaporin-1 (AQP1) levels in the renal cortex, promoting water and sodium excretion and improving renal function in SS rats. Additionally, metabolomic analysis demonstrated that dietary BCAAs enhanced arginine-NO metabolism in the kidneys and thoracic aorta of SS rats, promoting NOS-mediated NO synthesis and improving vasodilation. The promotion of NO synthesis by BCAAs was confirmed at the cellular level.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Long-term BCAAs intake promoted water and sodium excretion, enhanced NO synthesis in kidneys and thoracic aortas, and lowered blood pressure in SS rats on a high-salt diet, suggesting BCAAs may improve SS hypertension rather than exacerbate it.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 7","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339559","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}
引用次数: 0
Cardiolipin Remodeling in Cardiovascular Diseases: Implication for Mitochondrial Dysfunction 心血管疾病中的心磷脂重塑:对线粒体功能障碍的影响
IF 5.6 2区 医学
Acta Physiologica Pub Date : 2025-06-18 DOI: 10.1111/apha.70073
Huijie Zhang, Fengzhi Yu, Zhenjun Tian, Dandan Jia
{"title":"Cardiolipin Remodeling in Cardiovascular Diseases: Implication for Mitochondrial Dysfunction","authors":"Huijie Zhang,&nbsp;Fengzhi Yu,&nbsp;Zhenjun Tian,&nbsp;Dandan Jia","doi":"10.1111/apha.70073","DOIUrl":"https://doi.org/10.1111/apha.70073","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Mitochondrial dysfunction is pivotal in both the development and progression of cardiovascular diseases (CVDs), though its exact mechanisms remain unclear. Cardiolipin (CL), a key mitochondrial phospholipid, is involved in various mitochondrial functions, including dynamics, membrane integrity, oxidative phosphorylation, mitochondrial DNA maintenance, and mitophagy. Due to enzyme limitations in the CL biosynthesis pathway, premature CL undergoes remodeling to acquire the proper acyl content for its function. Disruption in CL composition leads to mitochondrial dysfunction, contributing significantly to CVDs. The purpose of this review is to explore the role of CL remodeling in the mechanism of mitochondrial dysfunction that occurs in CVDs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This review examines CL’s critical role in mitochondrial function, the consequences of CL deficiencies in CVDs, and the impact of mutations or deficiencies in CL remodeling enzymes-tafazzin (TAZ), Acyl-CoA:lysocardiolipin acyltransferase-1 (ALCAT1), and Monolysocardiolipin acyltransferase (MLCLAT1)-on CL homeostasis, mitochondrial function, and CVDs pathogenesis. Emerging CL-targeted therapies are also reviewed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Proper CL function is crucial for mitochondrial health and cardioprotection. Pathological CL remodeling due to mutations or deficiencies in TAZ, ALCAT1, or MLCLAT1, drives mitochondrial dysfunction and accelerates CVDs progression. Based on these insights, current CL-based therapeutic strategies are also summarized, including precision medicine/gene therapy, targeted pharmacotherapy, and dietary interventions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Targeting CL may represent a promising clinical therapeutic strategy for CVDs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 7","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144308706","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}
引用次数: 0
Fatty Acid Taste Quality Information via GPR40 and CD36 in the Posterior Tongue of Mice 小鼠后舌GPR40和CD36对脂肪酸味觉质量信息的影响
IF 5.6 2区 医学
Acta Physiologica Pub Date : 2025-06-13 DOI: 10.1111/apha.70071
Yumiko Nagai, Kenichi Tokita, Keiko Yasumatsu
{"title":"Fatty Acid Taste Quality Information via GPR40 and CD36 in the Posterior Tongue of Mice","authors":"Yumiko Nagai,&nbsp;Kenichi Tokita,&nbsp;Keiko Yasumatsu","doi":"10.1111/apha.70071","DOIUrl":"https://doi.org/10.1111/apha.70071","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Taste cells expressing GPR120 and connected chorda tympani nerve (CT) fibers are necessary for obtaining specific information on long-chain fatty acids (FA) in mice. However, the functions of GPR40, GPR120, and CD36 in the posterior part of the tongue remain unclear. Therefore, the present study has examined the neuron types coding for FA information in the glossopharyngeal (GL) nerve and their functions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed single-fiber recordings in the GL nerve from GPR120-knockout (KO) and wild-type (WT) mice and behavioral preference tests based on five-minute intake using WT mice after the CT (and greater petrosal) nerves were sectioned bilaterally.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Single fibers were classified into FA-(F), S-, M-, electrolyte-(E), Q-type, and N-best groups, based on their maximal responses to oleic acid (OA), sucrose, monopotassium glutamate, HCl, quinine hydrochloride, and NaCl. Among the GL fibers, 3.8% of GPR120-KO and 11.8% of WT mice were F-type. Furthermore, 81.8% or more of the S- and M-type fibers showed responses to FAs in both mouse genotypes. Residual responses to FAs were substantially suppressed by GPR40 and CD36 antagonists in GPR120-KO mice. Preference scores for OA decreased significantly with the addition of CD36 or GPR40 antagonists. Additionally, the preference scores for monopotassium glutamate and sucrose decreased when the mice were conditioned to avoid OA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These results suggest that GPR120 contributes only to the existence of F-type fibers and that CD36 and GPR40 mediate the palatable umami or sweet taste of FAs via the activation of S- and M-type fibers in the GL nerve.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 7","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144273245","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}
引用次数: 0
Molecular Dynamics Simulations of a Putative Novel Mechanism for UCP1-Assisted FA Anion Transport ucp1辅助FA阴离子运输新机制的分子动力学模拟
IF 5.6 2区 医学
Acta Physiologica Pub Date : 2025-06-11 DOI: 10.1111/apha.70068
Sanja Vojvodić, Giorgia Roticiani, Mario Vazdar, Elena E. Pohl
{"title":"Molecular Dynamics Simulations of a Putative Novel Mechanism for UCP1-Assisted FA Anion Transport","authors":"Sanja Vojvodić,&nbsp;Giorgia Roticiani,&nbsp;Mario Vazdar,&nbsp;Elena E. Pohl","doi":"10.1111/apha.70068","DOIUrl":"https://doi.org/10.1111/apha.70068","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Mitochondrial energy can be stored as ATP or released as heat by uncoupling protein 1 (UCP1) during non-shivering thermogenesis in brown adipose tissue. UCP1, located in the inner mitochondrial membrane, reduces the proton gradient in the presence of long-chain fatty acids (FA). FA act as weak, protein-independent uncouplers, with the transport of the FA anion across the membrane being the rate-limiting step. According to the fatty acid cycling hypothesis, UCP1 catalyzes this step through an as-yet-undefined mechanism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used computational and experimental techniques, including all-atom molecular dynamics (MD) simulations, membrane conductance measurements, and site-directed mutagenesis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified two novel pathways for fatty acid anion translocation (sliding) at the UCP1 protein–lipid interface, ending at key arginine residues R84 and R183 in a nucleotide-binding region. This region forms a stable complex with fatty acid anion, which is crucial for anion transport. Mutations of these two arginines reduced membrane conductance, consistent with the MD simulation prediction that the arachidonic acid anion slides between helices H2–H3 and H4–H5, terminating at R84 and R183. Protonation of the arachidonic acid anion predicts its release from the protein–lipid interface, allowing it to move to either cytosolic or matrix leaflets of the membrane.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We provide a novel, detailed mechanism by which UCP1 facilitates fatty acid anion transport, as part of the fatty acid cycling process originally proposed by Skulachev. The residues involved in this transport are conserved in other SLC25 proteins, suggesting the mechanism may extend beyond UCP1 to other members of the superfamily.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 7","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70068","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256036","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}
引用次数: 0
Aquaporin-4-Mediated Water Permeability Rescues Aquaporin-3 Deficiency Caused Nephrogenic Diabetes Insipidus 水通道蛋白-4介导的水渗透性修复水通道蛋白-3缺乏引起的肾源性尿崩症
IF 5.6 2区 医学
Acta Physiologica Pub Date : 2025-06-11 DOI: 10.1111/apha.70072
Yi Ying, Zhiwei Qiu, Jihan Liu, Yazhu Quan, Yongpan An, Feng Lu, Keying Wang, Min Li, Hong Zhou, Baoxue Yang
{"title":"Aquaporin-4-Mediated Water Permeability Rescues Aquaporin-3 Deficiency Caused Nephrogenic Diabetes Insipidus","authors":"Yi Ying,&nbsp;Zhiwei Qiu,&nbsp;Jihan Liu,&nbsp;Yazhu Quan,&nbsp;Yongpan An,&nbsp;Feng Lu,&nbsp;Keying Wang,&nbsp;Min Li,&nbsp;Hong Zhou,&nbsp;Baoxue Yang","doi":"10.1111/apha.70072","DOIUrl":"https://doi.org/10.1111/apha.70072","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>The aim of this study was to determine whether water or solute transport plays a critical role in AQP3-mediated urine concentrating ability, using AQP3 knockout (AQP3-KO) mice and a novel mouse model in which the AQP3 gene coding region is replaced with AQP4 cDNA (AQP4-KI).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>AQP3-KO and AQP4-KI mice were characterized using Western blot and immunofluorescence to confirm the absence of AQP3 and the in situ replacement of AQP4. Urinary output, osmolality and urea concentration were measured in mouse models under various conditions, including water deprivation, acute urea loading and high protein intake.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>AQP3-KO mice exhibited a significantly increased daily urine output (6 times that in wild-type mice) and reduced urinary osmolality (&lt; 1000 mOsm/kg), with a marked inability to concentrate urea and osmolality in response to water deprivation, urea loading or high protein intake. In contrast, AQP4-KI mice showed restoration of urine output, urinary osmolality and urea concentration, approaching wild-type levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In situ replacement of AQP3 with AQP4 restores AQP3-mediated water permeability in the renal collecting duct, rescuing the nephrogenic diabetes insipidus (NDI) phenotype in AQP3-deficient mice. This study provides evidence that AQP3-mediated water permeability plays a crucial role in the renal urine concentrating mechanism.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 7","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256035","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}
引用次数: 0
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