Acta Physiologica最新文献_第7页

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 Q1 PHYSIOLOGY

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

Aim

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.

Methods

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.

Results

Lower oxidative phosphorylation (OxPhos; p < 0.001) and increased nonphosphorylating respiration (p = 0.025) and mitochondrial oxidative damage (lipid peroxidation (p = 0.014) and protein carbonylation (p = 0.020)) were observed in patients. While ET increased OxPhos efficiency (p = 0.011) and reduced nonphosphorylating respiration (p < 0.001) and lipid peroxidation (p < 0.001) in patients' muscle mitochondria, it fails to improve maximal respiration (p = 0.835) and expression of the antioxidant enzyme MnSOD (p = 0.606), mitochondrial transcription factor TFAM (p = 0.246), and mitochondrial complexes I, III, and IV (p = 0.816, p = 0.664, p = 0.888, respectively) as observed in healthy subjects.

Conclusion

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.

目的慢性阻塞性肺疾病（COPD）常与骨骼肌功能障碍相关，对运动耐量和患者预后有相当大的影响。线粒体在COPD骨骼肌无力和运动不耐受中发挥作用，但大多数关于线粒体功能的研究都存在偏见，因为健康受试者的身体活动比患者更多。此外，运动训练（ET）已被提出作为预防COPD骨骼肌功能障碍的治疗策略。方法比较了12例COPD患者和21例具有相似低体力活动水平的健康受试者的骨骼肌线粒体功能和ET对该功能的潜在疗效。评估了线粒体呼吸、氧化应激、生物发生和动力学的各种标志物。结果氧化磷酸化(OxPhos；P < 0.001)，非磷酸化呼吸（P = 0.025）和线粒体氧化损伤（脂质过氧化（P = 0.014）和蛋白质羰基化（P = 0.020））增加。ET提高了患者肌肉线粒体的OxPhos效率（p = 0.011），降低了非磷酸化呼吸（p < 0.001）和脂质过氧化（p < 0.001），但未能改善最大呼吸（p = 0.835）和抗氧化酶MnSOD （p = 0.606）、线粒体转录因子TFAM （p = 0.246）以及线粒体复合物I、III、IV的表达（p = 0.816、p = 0.664、p = 0.888）。在健康受试者中观察到。结论慢性阻塞性肺病患者肌肉中线粒体功能障碍和线粒体对ET的适应缺陷是慢性阻塞性肺病固有的，而不是由肌肉废用引起的。

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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 Q1 PHYSIOLOGY

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

Aim

Metabolic disturbances challenge pH homeostasis in cardiomyocytes. The electroneutral Na⁺,HCO₃⁻-cotransporter NBCn1/Slc4a7 mediates net acid extrusion, and genetic variation in SLC4A7 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.

Methods

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).

Results

We find that protein and mRNA expression of NBCn1 are more prominent in atrial than in ventricular cardiomyocytes. Disruption of NBCn1 expression lowers Na⁺,HCO₃⁻-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.

Conclusion

NBCn1 is a main mechanism of Na⁺,HCO₃⁻-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.

目的代谢紊乱挑战心肌细胞pH稳态。电中性Na+，HCO3−-共转运体NBCn1/Slc4a7介导净酸挤压，Slc4a7的遗传变异与人类高血压和心血管风险有关。然而，NBCn1表达和功能紊乱对心脏的影响尚不清楚。在这里，我们验证了NBCn1直接或间接影响心脏结构、收缩功能和电生理特性的假设。方法：基于NBCn1整体缺失的小鼠，我们测量了心房和心室的细胞内pH值（荧光显微镜），膜电位反应（贴片夹紧），电和超声心动图变量，血压（遥测）和心脏尺寸（体内和死后分析）。结果NBCn1蛋白和mRNA在心房心肌细胞中的表达比在心室心肌细胞中的表达更为显著。NBCn1表达的中断使心房内Na+、HCO3−-共转运活性降低50%以上，但未显著影响心室心肌细胞的净酸挤压活性。NBCn1的缺失与高血压（血压升高~ 15mmhg）、心脏肥厚（心/体重增加~10%）和心室等容松弛时间延长（增加~25%）有关。NBCn1基因敲除不影响心肌细胞大小、心壁胶原含量、心脏整体收缩功能、心室心肌细胞电生理特性或心电图。结论NBCn1是心房组织Na+、HCO3−-共转运的主要机制，在细胞内酸化过程中对净酸挤压有重要作用。NBCn1在未攻毒小鼠的心室心肌细胞中没有任何主要的直接作用，但NBCn1的整体敲除会增加全身血压并导致心脏肥厚的发生。

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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 Q1 PHYSIOLOGY

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

Aim

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.

Methods

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.

Results

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.

Conclusions

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.

目的血管钙化（VC）是糖尿病和慢性肾脏疾病患者外周动脉疾病的特征性表现，与不良预后相关。我们假设高血糖通过代谢组学和转录组学谱的改变来驱动VC。方法用0、5.5、25 mM葡萄糖培养人冠状动脉平滑肌细胞。在不同时间点进行非靶向代谢组学和转录组学分析。采用海马分析法检测线粒体呼吸作用。结果葡萄糖处理的SMCs促进细胞外基质（ECM）钙化呈浓度依赖性和时间依赖性。与25 mM葡萄糖相比，葡萄糖的缺失完全消除了SMC钙化，但在对照和钙化条件下减少了SMC的增殖。多组学数据整合揭示了次牛磺酸/牛磺酸代谢途径的关键参与者是重建网络的中心枢纽。葡萄糖促进了低牛磺酸的分泌，但其在细胞内的丰度没有改变。丙基甘氨酸阻断次牛磺酸的产生增加了ECM钙化，而次牛磺酸治疗可以防止它。此外，组学数据表明，高血糖状态下钙化的SMCs存在能量重构。钙化的SMCs表现出氧气消耗减少，低牛磺酸部分恢复了这一现象。使用小鼠华法林模型验证我们的体外模型表明，SMCs中的次牛磺酸/牛磺酸转运蛋白（TAUT）表达降低。我们的多组学分析揭示了次牛磺酸/牛磺酸代谢途径在葡萄糖诱导的SMC钙化中的作用。此外，我们的数据表明，在钙化的SMCs中存在葡萄糖依赖的能量重塑，葡萄糖浓度的增加会促进ECM钙化。我们的工作强调了潜在的新的治疗靶点，值得进一步研究高血糖依赖性体外SMC钙化。

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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 Q1 PHYSIOLOGY

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

Aim

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 (H/R) and kidney transplantation.

Methods

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 H/R (H: 30 min, R: 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.

Results

Dilation of AAs was impaired following H/R. 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.

Conclusion

This study identifies a novel role for holo-rLcn2 in preserving renal vascular function post-H/R and kidney transplantation, apparently by upholding iron levels in vascular cells.

目的观察肾缺血再灌注损伤对微血管扩张功能的影响。可溶性关酰环化酶（sGC）的一氧化氮独立激活剂通过扩张微血管和保持灌注来保护肾脏，但在严重缺氧后其效果下降。本研究探讨了低氧/再氧（H/R）和肾移植后小鼠传入小动脉（AAs） sgc介导的扩张是否能恢复其关键的铁转运蛋白lipocalin-2 （Lcn2）。方法C57BL/6小鼠在H/R （H: 30 min, R: 10 min±holo-rLcn2, apo-rLcn2，去铁胺）和同系肾移植（冷缺血：30 min或5.5 H，再灌注：20 H±holo-rLcn2）后，用angii预缩后的sGC激活剂诱导离体血管紧张素II （Ang II）扩张。为了证实器官水平上的舒张功能，我们使用离体小鼠肾灌注系统来评估血管舒张。结果H/R后AAs的扩张功能受损。holo-rLcn2（铁结合）预处理保留了扩张，而apo-rLcn2（无铁）预处理没有影响。去铁胺逆转了holo-rLcn2的作用，证实了铁的作用。与假手术对照组相比，肾移植的AAs显示出扩张减少，在长时间缺血后损伤更大。用holo-rLcn2治疗可显著改善长时间冷缺血（5.5 h）后的舒张功能，使其恢复到短时间缺血（30 min）时的水平。用holo-rLcn2体外灌注离体小鼠肾脏，增强了辛西瓜诱导的血管松弛，证实了其在器官水平上的有益作用。结论本研究发现了holo-rLcn2在h /R和肾移植后维持肾血管功能中的新作用，显然是通过维持血管细胞中的铁水平。

{"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, 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","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 Q1 PHYSIOLOGY

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

Background and Aims

The development of innovative strategies to treat diabesity and its comorbidities is of major societal importance. The carotid bodies (CB), classically defined as O₂ 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.

Results

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.

Conclusion

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.

背景与目的发展治疗糖尿病及其合并症的创新策略具有重要的社会意义。颈动脉小体（CB）通常被定义为O2传感器，也是代谢传感器，其功能障碍有助于代谢紊乱的发生和发展。在这里，我们验证了CBs在控制葡萄糖和能量稳态的神经下丘脑-交感神经回路中起关键作用的假设。此外，我们还研究了消除CB活性是否对Wistar大鼠和C75BL/6J小鼠具有抗糖尿病作用，是否与内脏白色和棕色脂肪组织（AT）代谢增加以及这些组织内交感神经活动的恢复有关。结果表明，切除颈动脉窦神经，即cb敏感神经，通过增强下丘脑室旁核及其对at的输出交感神经元的酪氨酸羟化酶表达，促进肥胖大鼠和小鼠的体重减轻和代谢功能恢复。此外，我们发现CSN切除增加交感神经整合和AT中的儿茶酚胺能作用，从而恢复甚至增加AT代谢。结论我们提供了突破性的创新数据，揭示了一个涉及cbb -下丘脑-交感神经输出和AT的新回路控制葡萄糖和能量稳态，从而为糖尿病的治疗提供了新的途径。

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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 Q1 PHYSIOLOGY

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

Aim

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.

Methods

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.

Results

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.

Conclusions

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.

目的循环支链氨基酸（BCAAs）已被广泛发现与高血压风险相关，但其机制尚不清楚。在本研究中，我们假设支链氨基酸可以缓解Dahl盐敏感（SS）大鼠盐致高血压的发展。目的是探讨长期高盐饮食（高血压的主要饮食风险）是否会改变SS大鼠的支链氨基酸水平，以及膳食支链氨基酸如何影响盐诱导的高血压。方法对SS大鼠进行为期11周的饮食干预，观察BCAAs对SS高血压的影响。通过GC-MS和LC-MS /MS以及选定的酶活性测量来研究代谢变化。Western blotting检测p-BCKDHA/BCKDHA及AQP蛋白水平。用2 mM BCAAs处理HUVECs和HK-2细胞24 h，测定代谢产物和酶活性。结果11周的高盐饮食使SS大鼠血压升高，并伴有循环BCAAs水平降低。膳食BCAAs可减轻盐性高血压，恢复循环BCAAs水平，并增强BCAAs代谢活性。降低肾皮质水通道蛋白-1 （AQP1）水平，促进水钠排泄，改善SS大鼠肾功能。此外，代谢组学分析表明，膳食BCAAs可增强SS大鼠肾脏和胸主动脉的精氨酸-NO代谢，促进nos介导的NO合成，改善血管舒张。在细胞水平上证实了BCAAs对NO合成的促进作用。结论长期摄入BCAAs可促进高盐饮食SS大鼠的水钠排泄，增强肾脏和胸主动脉NO合成，降低血压，提示BCAAs可改善而非加重SS高血压。

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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 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2025-06-18 DOI: 10.1111/apha.70073

Huijie Zhang, Fengzhi Yu, Zhenjun Tian, Dandan Jia

Aim

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.

Methods

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.

Results

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.

Conclusion

Targeting CL may represent a promising clinical therapeutic strategy for CVDs.

目的线粒体功能障碍在心血管疾病（cvd）的发生和发展中起着关键作用，但其确切机制尚不清楚。心磷脂（Cardiolipin， CL）是一种关键的线粒体磷脂，参与线粒体的各种功能，包括动力学、膜完整性、氧化磷酸化、线粒体DNA维持和线粒体自噬。由于CL生物合成途径中的酶限制，过早的CL经历重塑以获得适当的酰基含量以发挥其功能。CL组成的破坏导致线粒体功能障碍，显著促进心血管疾病。这篇综述的目的是探讨线粒体功能障碍发生在心血管疾病的机制中CL重塑的作用。方法本文综述了CL在线粒体功能中的关键作用，cvd中CL缺乏的后果，以及CL重塑酶——他法津（TAZ）、酰基辅酶a：溶心磷脂酰基转移酶1 （ALCAT1）和单聚心磷脂酰基转移酶（MLCLAT1）的突变或缺乏对CL稳态、线粒体功能和cvd发病机制的影响。新兴的cl靶向治疗也进行了回顾。结果适当的CL功能对线粒体健康和心脏保护至关重要。由于TAZ、ALCAT1或MLCLAT1的突变或缺陷导致的病理性CL重塑驱动线粒体功能障碍并加速cvd的进展。基于这些见解，总结了目前基于cl的治疗策略，包括精准医学/基因治疗、靶向药物治疗和饮食干预。结论靶向CL可能是一种很有前途的cvd临床治疗策略。

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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 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2025-06-13 DOI: 10.1111/apha.70071

Yumiko Nagai, Kenichi Tokita, Keiko Yasumatsu

Aim

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.

Methods

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.

Results

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.

Conclusion

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.

目的表达GPR120的味觉细胞及其连接的鼓室索神经（CT）纤维是获取小鼠长链脂肪酸（FA）特异性信息的必要条件。然而，GPR40、GPR120和CD36在舌后部的功能尚不清楚。因此，本研究对舌咽神经编码FA信息的神经元类型及其功能进行了研究。方法对gpr120敲除（KO）小鼠和野生型（WT）小鼠的GL神经进行单纤维记录，并在双侧CT（和岩大神经）切除后，对WT小鼠进行基于5分钟摄食的行为偏好测试。结果根据纤维对油酸（OA）、蔗糖、谷氨酸二钾、盐酸、盐酸奎宁和NaCl的最大反应，将纤维分为FA-(F)、S-、M-、电解质-(E)、q -和N-best组。在GL纤维中，3.8%的GPR120-KO和11.8%的WT小鼠为f型。此外，81.8%或更多的S型和m型纤维在两种小鼠基因型中都对FAs有反应。GPR120-KO小鼠对FAs的残留应答被GPR40和CD36拮抗剂显著抑制。随着CD36或GPR40拮抗剂的加入，OA的偏好评分显著降低。此外，当小鼠习惯于避免OA时，对谷氨酸单钾和蔗糖的偏好得分降低。结论GPR120仅参与f型纤维的存在，而CD36和GPR40通过激活GL神经S型和m型纤维介导FAs的美味或甜味。

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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 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2025-06-11 DOI: 10.1111/apha.70068

Sanja Vojvodić, Giorgia Roticiani, Mario Vazdar, Elena E. Pohl

Background

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.

Methods

We used computational and experimental techniques, including all-atom molecular dynamics (MD) simulations, membrane conductance measurements, and site-directed mutagenesis.

Results

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.

Conclusion

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.

在棕色脂肪组织的非寒战产热过程中，线粒体能量可以以ATP的形式储存或通过解偶联蛋白1 （UCP1）以热量的形式释放。UCP1位于线粒体内膜内，在长链脂肪酸（FA）存在时降低质子梯度。FA是一种弱的、不依赖于蛋白质的解偶联剂，FA阴离子在膜上的转运是限速步骤。根据脂肪酸循环假说，UCP1通过一种尚未定义的机制催化这一步骤。方法采用计算和实验技术，包括全原子分子动力学（MD）模拟、膜电导测量和定点诱变。我们在UCP1蛋白-脂质界面上发现了两条新的脂肪酸阴离子转移（滑动）途径，它们在核苷酸结合区域的关键精氨酸残基R84和R183处结束。该区域与脂肪酸阴离子形成稳定的络合物，对阴离子运输至关重要。这两种精氨酸的突变降低了膜电导，与MD模拟预测一致，花生四烯酸阴离子在H2-H3和H4-H5螺旋之间滑动，终止于R84和R183。花生四烯酸阴离子的质子化预测了它从蛋白-脂质界面的释放，允许它移动到细胞膜的细胞质或基质小叶。我们提供了一种新的、详细的机制，UCP1促进脂肪酸阴离子运输，这是Skulachev最初提出的脂肪酸循环过程的一部分。参与这种转运的残基在其他SLC25蛋白中是保守的，这表明该机制可能超越UCP1延伸到超家族的其他成员。

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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 Q1 PHYSIOLOGY

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

Aim

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).

Methods

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.

Results

AQP3-KO mice exhibited a significantly increased daily urine output (6 times that in wild-type mice) and reduced urinary osmolality (< 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.

Conclusion

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.

本研究的目的是通过AQP3基因敲除（AQP3- ko）小鼠和AQP3基因编码区被AQP4 cDNA （AQP4- ki）取代的新型小鼠模型，确定水或溶质转运是否在AQP3介导的尿浓缩能力中起关键作用。方法采用Western blot和免疫荧光法检测AQP3- ko和AQP4- ki小鼠，证实AQP3缺失和AQP4原位替代。在不同条件下，包括缺水、急性尿素负荷和高蛋白摄入，测量小鼠模型的尿量、渗透压和尿素浓度。结果AQP3-KO小鼠的日尿量显著增加（是野生型小鼠的6倍），尿渗透压显著降低（1000 mOsm/kg），在缺水、尿素负荷或高蛋白摄入的情况下，尿渗透压和尿素浓缩能力明显下降。相比之下，AQP4-KI小鼠显示尿量、尿渗透压和尿素浓度恢复，接近野生型水平。结论原位用AQP4替代AQP3可恢复AQP3介导的肾集管水通透性，挽救AQP3缺陷小鼠肾源性尿崩症（NDI）表型。本研究证明了aqp3介导的水渗透性在肾尿浓缩机制中起着至关重要的作用。

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引用次数: 0