The classical renin angiotensin aldosterone system (RAAS), as well as the recently described counter-regulatory or non-canonical RAAS have been well characterized for their role in cardiovascular homeostasis. Moreover, extensive research has been conducted over the past decades on both paracrine and the endocrine roles of local RAAS in various metabolic regulations and in chronic diseases. Clinical evidence from patients on RAAS blockers as well as pre-clinical studies using rodent models of genetic manipulations of RAAS genes documented that this system may play important roles in the interplay between metabolic diseases and cancer, namely breast cancer. Some of these studies suggest potential therapeutic applications and repurposing of RAAS inhibitors for these diseases. In this review, we discuss the mechanisms by which RAAS is involved in the pathogenesis of metabolic diseases such as obesity and type-2 diabetes as well as the role of this system in the initiation, expansion and/or progression of breast cancer, especially in the context of metabolic diseases.
{"title":"Beyond blood pressure, fluid and electrolyte homeostasis – Role of the renin angiotensin aldosterone system in the interplay between metabolic diseases and breast cancer","authors":"Nishan Sudheera Kalupahana, Naima Moustaid-Moussa","doi":"10.1111/apha.14164","DOIUrl":"10.1111/apha.14164","url":null,"abstract":"<p>The classical renin angiotensin aldosterone system (RAAS), as well as the recently described counter-regulatory or non-canonical RAAS have been well characterized for their role in cardiovascular homeostasis. Moreover, extensive research has been conducted over the past decades on both paracrine and the endocrine roles of local RAAS in various metabolic regulations and in chronic diseases. Clinical evidence from patients on RAAS blockers as well as pre-clinical studies using rodent models of genetic manipulations of RAAS genes documented that this system may play important roles in the interplay between metabolic diseases and cancer, namely breast cancer. Some of these studies suggest potential therapeutic applications and repurposing of RAAS inhibitors for these diseases. In this review, we discuss the mechanisms by which RAAS is involved in the pathogenesis of metabolic diseases such as obesity and type-2 diabetes as well as the role of this system in the initiation, expansion and/or progression of breast cancer, especially in the context of metabolic diseases.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 7","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141069840","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}
Ferroptosis is a novel type of programmed cell death that performs a critical function in diabetic nephropathy (DN). Augmenter of liver regeneration (ALR) exists in the inner membrane of mitochondria, and inhibits inflammation, apoptosis, and oxidative stress in acute kidney injury; however, its role in DN remains unexplored. Here, we aimed to identify the role of ALR in ferroptosis induction and macrophage activation in DN.
Methods
The expression of ALR was examined in DN patients, db/db DN mice, and HK-2 cells treated with high glucose (HG). The effects of ALR on ferroptosis and macrophage activation were investigated with ALR conditional knockout, lentivirus transfection, transmission electron microscopy, qRT-PCR and western blotting assay. Mass spectrometry and rescue experiments were conducted to determine the mechanism of ALR.
Results
ALR expression was reduced in the kidney tissues of DN patients and mice, serum of DN patients, and HG-HK-2 cells. Moreover, the inhibition of ALR promoted ferroptosis, macrophage activation, and DN progression. Mechanistically, ALR can directly bind to carnitine palmitoyltransferase-1A (CPT1A), the key rate-limiting enzyme of fatty acid oxidation (FAO), and inhibit the expression of CPT1A to regulate lipid metabolism involving FAO and lipid droplet-mitochondrial coupling in DN.
Conclusion
Taken together, our findings revealed a crucial protective role of ALR in ferroptosis induction and macrophage activation in DN and identified it as an alternative diagnostic marker and therapeutic target for DN.
{"title":"Augmenter of liver regeneration knockout aggravates tubular ferroptosis and macrophage activation by regulating carnitine palmitoyltransferase-1A-induced lipid metabolism in diabetic nephropathy","authors":"Yuanyuan Zhang, Zheng Zhang, Lili Huang, Chunxia Wang, Pengfei Yang, Ling Zhang, Xiaohui Liao","doi":"10.1111/apha.14159","DOIUrl":"10.1111/apha.14159","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Ferroptosis is a novel type of programmed cell death that performs a critical function in diabetic nephropathy (DN). Augmenter of liver regeneration (ALR) exists in the inner membrane of mitochondria, and inhibits inflammation, apoptosis, and oxidative stress in acute kidney injury; however, its role in DN remains unexplored. Here, we aimed to identify the role of ALR in ferroptosis induction and macrophage activation in DN.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The expression of ALR was examined in DN patients, db/db DN mice, and HK-2 cells treated with high glucose (HG). The effects of ALR on ferroptosis and macrophage activation were investigated with ALR conditional knockout, lentivirus transfection, transmission electron microscopy, qRT-PCR and western blotting assay. Mass spectrometry and rescue experiments were conducted to determine the mechanism of ALR.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>ALR expression was reduced in the kidney tissues of DN patients and mice, serum of DN patients, and HG-HK-2 cells. Moreover, the inhibition of ALR promoted ferroptosis, macrophage activation, and DN progression. Mechanistically, ALR can directly bind to carnitine palmitoyltransferase-1A (CPT1A), the key rate-limiting enzyme of fatty acid oxidation (FAO), and inhibit the expression of CPT1A to regulate lipid metabolism involving FAO and lipid droplet-mitochondrial coupling in DN.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Taken together, our findings revealed a crucial protective role of ALR in ferroptosis induction and macrophage activation in DN and identified it as an alternative diagnostic marker and therapeutic target for DN.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 7","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14159","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141066686","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}
<p>Smoking is associated with increased morbidity and mortality and can harm almost every organ in the body. The risk reduction for cardiovascular diseases with smoking cessation is well documented by numerous clinical studies,<span><sup>1</sup></span> but long-term adverse consequences persist. For instance, the risk for cardiovascular complications remains high for ex-smokers, and former heavy smokers have a higher incidence of left ventricular systolic dysfunction, coronary artery and peripheral arterial diseases, and type 2 diabetes. Surprisingly, little is known about the adverse effects that persist in the heart following smoking cessation.</p><p>In this issue, Dr. Wüst and colleagues investigated what happens in the heart following smoking cessation on the metabolic, lipidomic, and structural remodeling seen with smoking (Table 1).<span><sup>2</sup></span> It is well established that smoking stimulates cardiovascular remodeling by interdependent pathways involving inflammation, oxidative stress, mitochondrial dysfunction, and hyperlipidemia.<span><sup>3</sup></span> Using mice, the study conducted by Wüst and colleagues revealed both the reversible and durable effects of smoking on the heart after a cessation period of up to 2 weeks.<span><sup>2</sup></span> Provoked local inflammation and cardiac fibrosis were among the consequences that are not mitigated by short-term cessation. Their findings suggest that a persistent infiltration of macrophages induced by smoking may foster a profibrotic milieu, which increases the risk of a proatherogenic response and cardiovascular complications, such as diastolic dysfunction and arrhythmias.</p><p>Quitting smoking may often lead to weight gain, which is a primary concern for contributing to insulin resistance and increasing the inflammatory response and metabolic burden. The study discussed found that smoking exposure causes weight loss and increases long and very long-chain fatty acids in the heart. Upon cessation, mice experienced weight gain and a further increase in their lipid profile. Direct and indirect mechanisms mediated by nicotine or smoking-induced insulin resistance can lead to smoking-induced high lipid profiles. However, weight gain might become an important regulator of metabolism following cessation. Some clinical studies suggest that these effects are typically temporary and tend to reverse after 6 months in humans.<span><sup>4</sup></span> Conversely, there have been reports that suggest a correlation between weight gain and attenuation in the benefit of cessation on the risk of cardiovascular disease.<span><sup>5</sup></span></p><p>In addition to the well-known connection between obesity and lipid buildup, Wüst and colleagues discovered evidence of a possible shift in metabolism from fatty acids to glucose after 2 weeks of cessation.<span><sup>2</sup></span> This shift was indicated by higher levels of long-chain fatty acids and increased glycolytic intermediates, suggesting a po
吸烟与发病率和死亡率的增加有关，几乎会伤害人体的每一个器官。大量临床研究证明，戒烟可降低心血管疾病的风险1 ，但长期的不良后果依然存在。例如，戒烟者患心血管并发症的风险仍然很高，曾经大量吸烟者左心室收缩功能障碍、冠状动脉和外周动脉疾病以及 2 型糖尿病的发病率更高。本期，Wüst 博士及其同事研究了戒烟后心脏在代谢、脂质组和结构重塑方面发生的变化（表 1）。Wüst 及其同事利用小鼠进行的研究显示，戒烟 2 周后，吸烟对心脏的影响既有可逆的，也有持久的。他们的研究结果表明，吸烟诱导的巨噬细胞持续浸润可能会形成一种促纤维化环境，从而增加促动脉粥样硬化反应和心血管并发症（如舒张功能障碍和心律失常）的风险。这项研究发现，吸烟会导致体重减轻，并增加心脏中的长链和超长链脂肪酸。戒烟后，小鼠体重增加，血脂进一步升高。尼古丁或吸烟引起的胰岛素抵抗所介导的直接和间接机制可导致吸烟引起的高血脂。然而，体重增加可能成为戒烟后新陈代谢的重要调节因素。一些临床研究表明，这些影响通常是暂时的，在人体中 6 个月后往往会逆转。4 相反，也有报告表明，体重增加与戒烟对心血管疾病风险的益处减弱之间存在相关性。除了众所周知的肥胖与脂质堆积之间的关系外，Wüst 及其同事还发现有证据表明，戒烟 2 周后，新陈代谢可能会从脂肪酸转向葡萄糖2 。通过富集通路分析确定了这一过程中的主要参与者，包括增加的糖酵解、磷酸戊糖代谢和葡萄糖生成。有趣的是，研究发现，葡萄糖摄取的增加可能是通过 GLUT4 受体向膜的转位增强实现的。然而，由于该研究没有测量胰岛素敏感性或葡萄糖摄取量，因此戒烟对胰岛素平衡和心脏葡萄糖代谢的总体影响仍未确定。6 此外，值得注意的是，Wüst 及其同事2 发现戒烟后嘌呤和嘧啶的分解增加，这与肥厚型心肌病和其他心血管疾病的代谢特征相吻合，因此非常有趣。7 另一方面，戒烟可促进血管生成，改善线粒体呼吸和生物能（表 1）。戒烟可使线粒体氧化磷酸化能力恢复到对照组的正常水平，增加线粒体超级复合物的组装，并丰富 NAD+ 池。这些反应被认为是戒烟后抵消吸烟对线粒体功能和氧化应激不利影响的适应机制。8 除了在氧化还原反应中的作用外，NAD+ 还是参与能量产生、新陈代谢和 DNA 修复的酶的重要辅助因子。戒烟是心血管健康管理的关键。鉴于戒烟具有多方面的动态影响，监测戒烟后的生理变化有助于深入了解戒烟的直接影响，并为努力戒烟者确定最佳支持策略。 虽然长期效益值得注意，但重要的是要找出能够预测或对降低风险产生重大影响的关键机制。这就需要确定后果的可逆性和相关时机。9 值得注意的是，选择适当的戒烟治疗干预取决于与戒烟相关的时间模式。Wüst 及其同事的研究存在一些局限性。2 没有进行心脏功能分析以确定纤维化的增加是否与心脏僵化有关。此外，为了更好地了解胰岛素敏感性或葡萄糖耐量等新陈代谢效应，没有测量戒烟对全身的影响。总之，Wüst 及其同事的研究提供了戒烟后心脏纤维化和巨噬细胞浸润的证据，而代谢改变在 2 周后可部分逆转（图 1）2。2 纤维化很可能仍是长期的并发症因素，有必要进行更多的研究，在持续一段时间内进行重复测量，以调查这一问题。GA 提供了初稿。所有作者都参与了手稿的撰写和图表的制作。GWB和FAZ对最终稿件进行了编辑。GWB部分获得了美国国立卫生研究院国家普通医学科学研究所（National Institute of General Medical Sciences of the National Institutes of Health）的资助，奖励号为P20GM121334。FAZ得到了贝鲁特美国大学医学院（MPP-320145；URB-103949）、法国国家科学研究中心（CNRS）（资助编号104230）以及法国国家研究署（ANR）和法国开发署（AFD）（ANICOV-HF）的资助。内容仅代表作者个人观点，不代表美国国立卫生研究院的官方观点。
{"title":"Lasting consequences of cigarette smoking on the heart","authors":"Ghadir Amin, George W. Booz, Fouad A. Zouein","doi":"10.1111/apha.14166","DOIUrl":"10.1111/apha.14166","url":null,"abstract":"<p>Smoking is associated with increased morbidity and mortality and can harm almost every organ in the body. The risk reduction for cardiovascular diseases with smoking cessation is well documented by numerous clinical studies,<span><sup>1</sup></span> but long-term adverse consequences persist. For instance, the risk for cardiovascular complications remains high for ex-smokers, and former heavy smokers have a higher incidence of left ventricular systolic dysfunction, coronary artery and peripheral arterial diseases, and type 2 diabetes. Surprisingly, little is known about the adverse effects that persist in the heart following smoking cessation.</p><p>In this issue, Dr. Wüst and colleagues investigated what happens in the heart following smoking cessation on the metabolic, lipidomic, and structural remodeling seen with smoking (Table 1).<span><sup>2</sup></span> It is well established that smoking stimulates cardiovascular remodeling by interdependent pathways involving inflammation, oxidative stress, mitochondrial dysfunction, and hyperlipidemia.<span><sup>3</sup></span> Using mice, the study conducted by Wüst and colleagues revealed both the reversible and durable effects of smoking on the heart after a cessation period of up to 2 weeks.<span><sup>2</sup></span> Provoked local inflammation and cardiac fibrosis were among the consequences that are not mitigated by short-term cessation. Their findings suggest that a persistent infiltration of macrophages induced by smoking may foster a profibrotic milieu, which increases the risk of a proatherogenic response and cardiovascular complications, such as diastolic dysfunction and arrhythmias.</p><p>Quitting smoking may often lead to weight gain, which is a primary concern for contributing to insulin resistance and increasing the inflammatory response and metabolic burden. The study discussed found that smoking exposure causes weight loss and increases long and very long-chain fatty acids in the heart. Upon cessation, mice experienced weight gain and a further increase in their lipid profile. Direct and indirect mechanisms mediated by nicotine or smoking-induced insulin resistance can lead to smoking-induced high lipid profiles. However, weight gain might become an important regulator of metabolism following cessation. Some clinical studies suggest that these effects are typically temporary and tend to reverse after 6 months in humans.<span><sup>4</sup></span> Conversely, there have been reports that suggest a correlation between weight gain and attenuation in the benefit of cessation on the risk of cardiovascular disease.<span><sup>5</sup></span></p><p>In addition to the well-known connection between obesity and lipid buildup, Wüst and colleagues discovered evidence of a possible shift in metabolism from fatty acids to glucose after 2 weeks of cessation.<span><sup>2</sup></span> This shift was indicated by higher levels of long-chain fatty acids and increased glycolytic intermediates, suggesting a po","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 7","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14166","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140955236","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}
To reveal the contribution of Irisin in the beneficial effects of resistance exercise on myocardial fibrosis (MF) and cardiac function in the mice with myocardial infarction (MI).
Methods
The MI model was built by ligating the left anterior descending coronary artery in Fndc5 knockout mice (Fndc5−/−). Resistance exercise was started one week after surgery and continued for four weeks. In addition, H2O2, AICAR, recombinant human Irisin protein (rhIRISIN), and Sirt1 shRNA lentivirus (LV-Sirt1 shRNA) were used to intervene primary isolated cardiac fibroblasts (CFs). MF was observed through Masson staining, and apoptosis was assessed using TUNEL staining. MDA and T-SOD contents were detected by biochemical kits. The expression of proteins and genes was detected by Western blotting and RT-qPCR.
Results
Resistance exercise increased Fndc5 mRNA level, inhibited the activation of TGFβ1-TGFβR2-Smad2/3 pathway, activated AMPK-Sirt1 pathway, reduced the levels of oxidative stress, apoptosis, and MF in the infarcted heart, and promoted cardiac function. However, Fndc5 knockout attenuated the protective effects of resistance exercise on the MI heart. Results of the in vitro experiments showed that AICAR and rhIRISIN intervention activated the AMPK-Sirt1 pathway and inactivated the TGFβ1-Smad2/3 pathway, and promoted apoptosis in H2O2-treated CFs. Notably, these effects of rhIRISIN intervention, except for the TGFβR2 expression, were attenuated by LV-Sirt1 shRNA.
Conclusion
Resistance exercise upregulates Fndc5 expression, activates AMPK-Sirt1 pathway, inhibits the activation of TGFβ1-Smad2/3 pathway, attenuates MF, and promotes cardiac function after MI.
{"title":"Resistance exercise upregulates Irisin expression and suppresses myocardial fibrosis following myocardial infarction via activating AMPK-Sirt1 and inactivating TGFβ1-Smad2/3","authors":"Hangzhuo Li, Shuguang Qin, Jie Tang, Tao Wang, Wujing Ren, Lingyun Di, Wenyan Bo, Yixuan Ma, Fangnan Wu, Zujie Xu, Wei Song, Mengxin Cai, Yue Xi, Zhenjun Tian","doi":"10.1111/apha.14163","DOIUrl":"10.1111/apha.14163","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>To reveal the contribution of Irisin in the beneficial effects of resistance exercise on myocardial fibrosis (MF) and cardiac function in the mice with myocardial infarction (MI).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The MI model was built by ligating the left anterior descending coronary artery in <i>Fndc5</i> knockout mice (<i>Fndc5</i><sup>−/−</sup>). Resistance exercise was started one week after surgery and continued for four weeks. In addition, H<sub>2</sub>O<sub>2</sub>, AICAR, recombinant human Irisin protein (rhIRISIN), and Sirt1 shRNA lentivirus (LV-<i>Sirt1</i> shRNA) were used to intervene primary isolated cardiac fibroblasts (CFs). MF was observed through Masson staining, and apoptosis was assessed using TUNEL staining. MDA and T-SOD contents were detected by biochemical kits. The expression of proteins and genes was detected by Western blotting and RT-qPCR.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Resistance exercise increased <i>Fndc5</i> mRNA level, inhibited the activation of TGFβ1-TGFβR2-Smad2/3 pathway, activated AMPK-Sirt1 pathway, reduced the levels of oxidative stress, apoptosis, and MF in the infarcted heart, and promoted cardiac function. However, <i>Fndc5</i> knockout attenuated the protective effects of resistance exercise on the MI heart. Results of the <i>in vitro</i> experiments showed that AICAR and rhIRISIN intervention activated the AMPK-Sirt1 pathway and inactivated the TGFβ1-Smad2/3 pathway, and promoted apoptosis in H<sub>2</sub>O<sub>2</sub>-treated CFs. Notably, these effects of rhIRISIN intervention, except for the TGFβR2 expression, were attenuated by LV-<i>Sirt1</i> shRNA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Resistance exercise upregulates <i>Fndc5</i> expression, activates AMPK-Sirt1 pathway, inhibits the activation of TGFβ1-Smad2/3 pathway, attenuates MF, and promotes cardiac function after MI.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 7","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140943286","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}
Kitti Thiankhaw, Nipon Chattipakorn, Siripron C. Chattipakorn
Aims
With a focus on the discrepancy between preclinical and clinical findings, this review will gather comprehensive information about the effects of calcineurin inhibitors (CNI) on cognitive function and related brain pathology from in vitro, in vivo, and clinical studies. We also summarize the potential mechanisms that underlie the pathways related to CNI-induced cognitive impairment.
Methods
We systematically searched articles in PubMed using keywords ‘calcineurin inhibitor*’ and ‘cognition’ to identify related articles, which the final list pertaining to underlying mechanisms of CNI on cognition.
Results
Several studies have reported an association between calcineurin and the neuropathology of Alzheimer’s disease (AD). AD is the most common neurocognitive disorder associated with amyloid plaques and neurofibrillary tangles in the brain, leading to cognitive impairment. CNI, including tacrolimus and cyclosporin A, are commonly prescribed for patients with transplantation of solid organs such as kidney, liver, or heart, those drugs are currently being used as long-term immunosuppressive therapy. Although preclinical models emphasize the favorable effects of CNI on the restoration of brain pathology due to the impacts of calcineurin on the alleviation of amyloid-beta deposition and tau hyperphosphorylation, or rescuing synaptic and mitochondrial functions, treatment-related neurotoxicity, resulting in cognitive dysfunctions has been observed in clinical settings of patients who received CNI.
Conclusion
Inconsistent results of CNI on cognition from clinical studies have been observed due to impairment of the blood-brain barrier, neuroinflammation mediated by reactive oxygen species, and alteration in mitochondrial fission, and extended research is required to confirm its promising use in cognitive impairment.
目的：本综述重点关注临床前研究结果与临床研究结果之间的差异，将从体外、体内和临床研究中收集有关钙神经蛋白抑制剂（CNI）对认知功能和相关脑病理学影响的全面信息。我们还总结了钙神经蛋白抑制剂诱发认知障碍相关途径的潜在机制：我们使用关键词 "钙神经蛋白酶抑制剂*"和 "认知 "在PubMed上系统地搜索了相关文章，最后列出了与CNI对认知的潜在机制有关的文章：多项研究报告了钙调磷酸酶与阿尔茨海默病（AD）神经病理学之间的关联。阿尔茨海默病是最常见的神经认知障碍，与大脑中的淀粉样斑块和神经纤维缠结有关，会导致认知障碍。包括他克莫司和环孢素 A 在内的 CNI 是肾脏、肝脏或心脏等实体器官移植患者的常用处方药，这些药物目前被用作长期免疫抑制疗法。尽管临床前模型强调了 CNI 对恢复大脑病理学的有利影响，因为钙神经蛋白可减轻淀粉样蛋白-β沉积和 tau 过度磷酸化，或挽救突触和线粒体功能，但在接受 CNI 治疗的患者的临床环境中观察到了与治疗相关的神经毒性，导致认知功能障碍：结论：由于血脑屏障受损、活性氧介导的神经炎症以及线粒体裂变的改变，临床研究发现 CNI 对认知功能的影响结果并不一致，因此需要进行更多的研究来证实其在认知障碍方面的应用前景。
{"title":"How calcineurin inhibitors affect cognition","authors":"Kitti Thiankhaw, Nipon Chattipakorn, Siripron C. Chattipakorn","doi":"10.1111/apha.14161","DOIUrl":"10.1111/apha.14161","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>With a focus on the discrepancy between preclinical and clinical findings, this review will gather comprehensive information about the effects of calcineurin inhibitors (CNI) on cognitive function and related brain pathology from <i>in vitro</i>, <i>in vivo</i>, and clinical studies. We also summarize the potential mechanisms that underlie the pathways related to CNI-induced cognitive impairment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We systematically searched articles in PubMed using keywords ‘calcineurin inhibitor*’ and ‘cognition’ to identify related articles, which the final list pertaining to underlying mechanisms of CNI on cognition.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Several studies have reported an association between calcineurin and the neuropathology of Alzheimer’s disease (AD). AD is the most common neurocognitive disorder associated with amyloid plaques and neurofibrillary tangles in the brain, leading to cognitive impairment. CNI, including tacrolimus and cyclosporin A, are commonly prescribed for patients with transplantation of solid organs such as kidney, liver, or heart, those drugs are currently being used as long-term immunosuppressive therapy. Although preclinical models emphasize the favorable effects of CNI on the restoration of brain pathology due to the impacts of calcineurin on the alleviation of amyloid-beta deposition and tau hyperphosphorylation, or rescuing synaptic and mitochondrial functions, treatment-related neurotoxicity, resulting in cognitive dysfunctions has been observed in clinical settings of patients who received CNI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Inconsistent results of CNI on cognition from clinical studies have been observed due to impairment of the blood-brain barrier, neuroinflammation mediated by reactive oxygen species, and alteration in mitochondrial fission, and extended research is required to confirm its promising use in cognitive impairment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 7","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140920144","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}
Emilie Passerieux, Elodie Desplanche, Laurie Alburquerque, Quentin Wynands, Axel Bellanger, Anne Virsolvy, Farés Gouzi, Olivier Cazorla, Arnaud Bourdin, Maurice Hayot, Pascal Pomiès
Aim
Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow obstruction and development of emphysema. Among the comorbidities associated with COPD, skeletal muscle dysfunction is known to affect exercise capacity and the survival rate of patients. Pulmonary rehabilitation (PR), via exercise training, is essential for COPD patients. However, the response to PR is most often moderate. An animal model that recapitulates critical features of chronic human disease and provides access to muscle function should therefore be useful to improve PR benefits.
Methods
We used a rat model of induced emphysema based on pulmonary instillations of elastase (ELA) and lipopolysaccharides (LPS). We assessed the long-term effects of ELA/LPS and the potential effectiveness of endurance training on the skeletal muscle function. In vivo strength of the animals, and ex vivo contractility, endurance, type 1 fiber proportion, fiber cross-sectional area, and capillarization of both soleus and extensor digitorum longus (EDL) were assessed.
Results
An impaired overall muscle strength with decreased force, reduced capillarization, and atrophy of type 1 fiber of EDL was observed in ELA/LPS rats. Soleus was not affected. Endurance training was able to reduce fatigability, and increase type 1 fiber proportion and capillarization of soleus, and improve force, endurance, and capillarization of EDL in control and ELA/LPS rats.
Conclusion
Our rat model of induced emphysema, which shares some features with the phenotype present in patients with COPD, could represent a suitable model to study skeletal muscle dysfunction and the effects of exercise training on muscle function in patients.
{"title":"Altered skeletal muscle function and beneficial effects of exercise training in a rat model of induced pulmonary emphysema","authors":"Emilie Passerieux, Elodie Desplanche, Laurie Alburquerque, Quentin Wynands, Axel Bellanger, Anne Virsolvy, Farés Gouzi, Olivier Cazorla, Arnaud Bourdin, Maurice Hayot, Pascal Pomiès","doi":"10.1111/apha.14165","DOIUrl":"10.1111/apha.14165","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow obstruction and development of emphysema. Among the comorbidities associated with COPD, skeletal muscle dysfunction is known to affect exercise capacity and the survival rate of patients. Pulmonary rehabilitation (PR), via exercise training, is essential for COPD patients. However, the response to PR is most often moderate. An animal model that recapitulates critical features of chronic human disease and provides access to muscle function should therefore be useful to improve PR benefits.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used a rat model of induced emphysema based on pulmonary instillations of elastase (ELA) and lipopolysaccharides (LPS). We assessed the long-term effects of ELA/LPS and the potential effectiveness of endurance training on the skeletal muscle function. In vivo strength of the animals, and ex vivo contractility, endurance, type 1 fiber proportion, fiber cross-sectional area, and capillarization of both soleus and extensor digitorum longus (EDL) were assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>An impaired overall muscle strength with decreased force, reduced capillarization, and atrophy of type 1 fiber of EDL was observed in ELA/LPS rats. Soleus was not affected. Endurance training was able to reduce fatigability, and increase type 1 fiber proportion and capillarization of soleus, and improve force, endurance, and capillarization of EDL in control and ELA/LPS rats.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our rat model of induced emphysema, which shares some features with the phenotype present in patients with COPD, could represent a suitable model to study skeletal muscle dysfunction and the effects of exercise training on muscle function in patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 7","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14165","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140920143","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}
P. Benzoni, M. Arici, F. Giannetti, A. Cospito, R. Prevostini, C. Volani, L. Fassina, M. D. Rosato-Siri, A. Metallo, L. Gennaccaro, S. Suffredini, L. Foco, S. Mazzetti, A. Calogero, G. Cappelletti, A. Leibbrandt, U. Elling, F. Broso, J. M. Penninger, P. P. Pramstaller, C. Piubelli, A. Bucchi, M. Baruscotti, A. Rossini, M. Rocchetti, A. Barbuti
Aim
Striatin (Strn) is a scaffold protein expressed in cardiomyocytes (CMs) and alteration of its expression are described in various cardiac diseases. However, the alteration underlying its pathogenicity have been poorly investigated.
Methods
We studied the role(s) of cardiac Strn gene (STRN) by comparing the functional properties of CMs, generated from Strn-KO and isogenic WT mouse embryonic stem cell lines.
Results
The spontaneous beating rate of Strn-KO CMs was faster than WT cells, and this correlated with a larger fast INa conductance and no changes in If. Paced (2–8 Hz) Strn-KO CMs showed prolonged action potential (AP) duration in comparison with WT CMs and this was not associated with changes in ICaL and IKr. Motion video tracking analysis highlighted an altered contraction in Strn-KO CMs; this was associated with a global increase in intracellular Ca2+, caused by an enhanced late Na+ current density (INaL) and a reduced Na+/Ca2+ exchanger (NCX) activity and expression. Immunofluorescence analysis confirmed the higher Na+ channel expression and a more dynamic microtubule network in Strn-KO CMs than in WT. Indeed, incubation of Strn-KO CMs with the microtubule stabilizer taxol, induced a rescue (downregulation) of INa conductance toward WT levels.
Conclusion
Loss of STRN alters CMs electrical and contractile profiles and affects cell functionality by a disarrangement of Strn-related multi-protein complexes. This leads to impaired microtubules dynamics and Na+ channels trafficking to the plasma membrane, causing a global Na+ and Ca2+ enhancement.
{"title":"Striatin knock out induces a gain of function of INa and impaired Ca2+ handling in mESC-derived cardiomyocytes","authors":"P. Benzoni, M. Arici, F. Giannetti, A. Cospito, R. Prevostini, C. Volani, L. Fassina, M. D. Rosato-Siri, A. Metallo, L. Gennaccaro, S. Suffredini, L. Foco, S. Mazzetti, A. Calogero, G. Cappelletti, A. Leibbrandt, U. Elling, F. Broso, J. M. Penninger, P. P. Pramstaller, C. Piubelli, A. Bucchi, M. Baruscotti, A. Rossini, M. Rocchetti, A. Barbuti","doi":"10.1111/apha.14160","DOIUrl":"10.1111/apha.14160","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Striatin (Strn) is a scaffold protein expressed in cardiomyocytes (CMs) and alteration of its expression are described in various cardiac diseases. However, the alteration underlying its pathogenicity have been poorly investigated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We studied the role(s) of cardiac Strn gene (<i>STRN</i>) by comparing the functional properties of CMs, generated from Strn-KO and isogenic WT mouse embryonic stem cell lines.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The spontaneous beating rate of Strn-KO CMs was faster than WT cells, and this correlated with a larger fast I<sub>Na</sub> conductance and no changes in I<sub>f</sub>. Paced (2–8 Hz) Strn-KO CMs showed prolonged action potential (AP) duration in comparison with WT CMs and this was not associated with changes in I<sub>CaL</sub> and I<sub>Kr</sub>. Motion video tracking analysis highlighted an altered contraction in Strn-KO CMs; this was associated with a global increase in intracellular Ca<sup>2+</sup>, caused by an enhanced late Na<sup>+</sup> current density (I<sub>NaL</sub>) and a reduced Na<sup>+</sup>/Ca<sup>2+</sup> exchanger (NCX) activity and expression. Immunofluorescence analysis confirmed the higher Na<sup>+</sup> channel expression and a more dynamic microtubule network in Strn-KO CMs than in WT. Indeed, incubation of Strn-KO CMs with the microtubule stabilizer taxol, induced a rescue (downregulation) of I<sub>Na</sub> conductance toward WT levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Loss of <i>STRN</i> alters CMs electrical and contractile profiles and affects cell functionality by a disarrangement of Strn-related multi-protein complexes. This leads to impaired microtubules dynamics and Na<sup>+</sup> channels trafficking to the plasma membrane, causing a global Na<sup>+</sup> and Ca<sup>2+</sup> enhancement.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14160","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140920145","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}
Livia Saccani Hervas, Lara do Amaral-Silva, Marina Rincon Sartori, Ane Guadalupe-Silva, Luciane H. Gargaglioni, Johannes Lerchner, Marcos Túlio Oliveira, Kênia Cardoso Bícego
Aim
In cyclic climate variations, including seasonal changes, many animals regulate their energy demands to overcome critical transitory moments, restricting their high-demand activities to phases of resource abundance, enabling rapid growth and reproduction. Tegu lizards (Salvator merianae) are ectotherms with a robust annual cycle, being active during summer, hibernating during winter, and presenting a remarkable endothermy during reproduction in spring. Here, we evaluated whether changes in mitochondrial respiratory physiology in skeletal muscle could serve as a mechanism for the increased thermogenesis observed during the tegu's reproductive endothermy.
Methods
We performed high-resolution respirometry and calorimetry in permeabilized red and white muscle fibers, sampled during summer (activity) and spring (high activity and reproduction), in association with citrate synthase measurements.
Results
During spring, the muscle fibers exhibited increased oxidative phosphorylation. They also enhanced uncoupled respiration and heat production via adenine nucleotide translocase (ANT), but not via uncoupling proteins (UCP). Citrate synthase activity was higher during the spring, suggesting greater mitochondrial density compared to the summer. These findings were consistent across both sexes and muscle types (red and white).
Conclusion
The current results highlight potential cellular thermogenic mechanisms in an ectothermic reptile that contribute to transient endothermy. Our study indicates that the unique feature of transitioning to endothermy through nonshivering thermogenesis during the reproductive phase may be facilitated by higher mitochondrial density, function, and uncoupling within the skeletal muscle. This knowledge contributes significant elements to the broader picture of models for the evolution of endothermy, particularly in relation to the enhancement of aerobic capacity.
{"title":"Mitochondrial function in skeletal muscle contributes to reproductive endothermy in tegu lizards (Salvator merianae)","authors":"Livia Saccani Hervas, Lara do Amaral-Silva, Marina Rincon Sartori, Ane Guadalupe-Silva, Luciane H. Gargaglioni, Johannes Lerchner, Marcos Túlio Oliveira, Kênia Cardoso Bícego","doi":"10.1111/apha.14162","DOIUrl":"10.1111/apha.14162","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>In cyclic climate variations, including seasonal changes, many animals regulate their energy demands to overcome critical transitory moments, restricting their high-demand activities to phases of resource abundance, enabling rapid growth and reproduction. Tegu lizards (<i>Salvator merianae</i>) are ectotherms with a robust annual cycle, being active during summer, hibernating during winter, and presenting a remarkable endothermy during reproduction in spring. Here, we evaluated whether changes in mitochondrial respiratory physiology in skeletal muscle could serve as a mechanism for the increased thermogenesis observed during the tegu's reproductive endothermy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed high-resolution respirometry and calorimetry in permeabilized red and white muscle fibers, sampled during summer (activity) and spring (high activity and reproduction), in association with citrate synthase measurements.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>During spring, the muscle fibers exhibited increased oxidative phosphorylation. They also enhanced uncoupled respiration and heat production via adenine nucleotide translocase (ANT), but not via uncoupling proteins (UCP). Citrate synthase activity was higher during the spring, suggesting greater mitochondrial density compared to the summer. These findings were consistent across both sexes and muscle types (red and white).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The current results highlight potential cellular thermogenic mechanisms in an ectothermic reptile that contribute to transient endothermy. Our study indicates that the unique feature of transitioning to endothermy through nonshivering thermogenesis during the reproductive phase may be facilitated by higher mitochondrial density, function, and uncoupling within the skeletal muscle. This knowledge contributes significant elements to the broader picture of models for the evolution of endothermy, particularly in relation to the enhancement of aerobic capacity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 7","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140915472","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}
Stanislava Stevanovic, Andrea Dalmao-Fernandez, Derya Mohamed, Tuula A. Nyman, Emil Kostovski, Per Ole Iversen, Mladen Savikj, Natasa Nikolic, Arild C. Rustan, G. Hege Thoresen, Eili T. Kase
Background
Skeletal muscle adapts in reaction to contractile activity to efficiently utilize energy substrates, primarily glucose and free fatty acids (FA). Inactivity leads to atrophy and a change in energy utilization in individuals with spinal cord injury (SCI). The present study aimed to characterize possible inactivity-related differences in the energy metabolism between skeletal muscle cells cultured from satellite cells isolated 1- and 12-months post-SCI.
Methods
To characterize inactivity-related disturbances in spinal cord injury, we studied skeletal muscle cells isolated from SCI subjects. Cell cultures were established from biopsy samples from musculus vastus lateralis from subjects with SCI 1 and 12 months after the injury. The myoblasts were proliferated and differentiated into myotubes before fatty acid and glucose metabolism were assessed and gene and protein expressions were measured.
Results
The results showed that glucose uptake was increased, while oleic acid oxidation was reduced at 12 months compared to 1 month. mRNA expressions of PPARGC1α, the master regulator of mitochondrial biogenesis, and MYH2, a determinant of muscle fiber type, were significantly reduced at 12 months. Proteomic analysis showed reduced expression of several mitochondrial proteins.
Conclusion
In conclusion, skeletal muscle cells isolated from immobilized subjects 12 months compared to 1 month after SCI showed reduced fatty acid metabolism and reduced expression of mitochondrial proteins, indicating an increased loss of oxidative capacity with time after injury.
{"title":"Time-dependent reduction in oxidative capacity among cultured myotubes from spinal cord injured individuals","authors":"Stanislava Stevanovic, Andrea Dalmao-Fernandez, Derya Mohamed, Tuula A. Nyman, Emil Kostovski, Per Ole Iversen, Mladen Savikj, Natasa Nikolic, Arild C. Rustan, G. Hege Thoresen, Eili T. Kase","doi":"10.1111/apha.14156","DOIUrl":"10.1111/apha.14156","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Skeletal muscle adapts in reaction to contractile activity to efficiently utilize energy substrates, primarily glucose and free fatty acids (FA). Inactivity leads to atrophy and a change in energy utilization in individuals with spinal cord injury (SCI). The present study aimed to characterize possible inactivity-related differences in the energy metabolism between skeletal muscle cells cultured from satellite cells isolated 1- and 12-months post-SCI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To characterize inactivity-related disturbances in spinal cord injury, we studied skeletal muscle cells isolated from SCI subjects. Cell cultures were established from biopsy samples from <i>musculus vastus lateralis</i> from subjects with SCI 1 and 12 months after the injury. The myoblasts were proliferated and differentiated into myotubes before fatty acid and glucose metabolism were assessed and gene and protein expressions were measured.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The results showed that glucose uptake was increased, while oleic acid oxidation was reduced at 12 months compared to 1 month. mRNA expressions of <i>PPARGC1α</i>, the master regulator of mitochondrial biogenesis, and <i>MYH2</i>, a determinant of muscle fiber type, were significantly reduced at 12 months. Proteomic analysis showed reduced expression of several mitochondrial proteins.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In conclusion, skeletal muscle cells isolated from immobilized subjects 12 months compared to 1 month after SCI showed reduced fatty acid metabolism and reduced expression of mitochondrial proteins, indicating an increased loss of oxidative capacity with time after injury.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 7","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14156","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140848906","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}
Hiroshi Shimada, Theresa L. Powell, Thomas Jansson
Abnormal fetal growth, i.e., intrauterine growth restriction (IUGR) or fetal growth restriction (FGR) and fetal overgrowth, is associated with increased perinatal morbidity and mortality and is strongly linked to the development of metabolic and cardiovascular disease in childhood and later in life. Emerging evidence suggests that changes in placental amino acid transport may contribute to abnormal fetal growth. This review is focused on amino acid transport in the human placenta, however, relevant animal models will be discussed to add mechanistic insights. At least 25 distinct amino acid transporters with different characteristics and substrate preferences have been identified in the human placenta. Of these, System A, transporting neutral nonessential amino acids, and System L, mediating the transport of essential amino acids, have been studied in some detail. Importantly, decreased placental Systems A and L transporter activity is strongly associated with IUGR and increased placental activity of these two amino acid transporters has been linked to fetal overgrowth in human pregnancy. An array of factors in the maternal circulation, including insulin, IGF-1, and adiponectin, and placental signaling pathways such as mTOR, have been identified as key regulators of placental Systems A and L. Studies using trophoblast-specific gene targeting in mice have provided compelling evidence that changes in placental Systems A and L are mechanistically linked to altered fetal growth. It is possible that targeting specific placental amino acid transporters or their upstream regulators represents a novel intervention to alleviate the short- and long-term consequences of abnormal fetal growth in the future.
胎儿发育异常，即宫内生长受限（IUGR）或胎儿生长受限（FGR）和胎儿过度生长，与围产期发病率和死亡率的增加有关，并与儿童期和日后代谢性疾病和心血管疾病的发生密切相关。新的证据表明，胎盘氨基酸转运的变化可能会导致胎儿发育异常。本综述侧重于人类胎盘的氨基酸转运，但也会讨论相关的动物模型，以增加对机理的了解。在人类胎盘中至少发现了 25 种不同的氨基酸转运体，它们具有不同的特性和底物偏好。其中，运输中性非必需氨基酸的 A 系统和介导必需氨基酸运输的 L 系统已被详细研究。重要的是，胎盘 A 系统和 L 系统转运体活性的降低与 IUGR 密切相关，而这两种氨基酸转运体活性的增加与人类妊娠中胎儿的过度生长有关。母体循环中的一系列因子，包括胰岛素、IGF-1、脂肪连素和胎盘信号通路，如 mTOR，已被确定为胎盘 A 系统和 L 系统的关键调节因子。以特定的胎盘氨基酸转运体或其上游调节因子为靶点可能是一种新的干预方法，可在未来减轻胎儿生长异常的短期和长期后果。
{"title":"Regulation of placental amino acid transport in health and disease","authors":"Hiroshi Shimada, Theresa L. Powell, Thomas Jansson","doi":"10.1111/apha.14157","DOIUrl":"10.1111/apha.14157","url":null,"abstract":"<p>Abnormal fetal growth, i.e., intrauterine growth restriction (IUGR) or fetal growth restriction (FGR) and fetal overgrowth, is associated with increased perinatal morbidity and mortality and is strongly linked to the development of metabolic and cardiovascular disease in childhood and later in life. Emerging evidence suggests that changes in placental amino acid transport may contribute to abnormal fetal growth. This review is focused on amino acid transport in the human placenta, however, relevant animal models will be discussed to add mechanistic insights. At least 25 distinct amino acid transporters with different characteristics and substrate preferences have been identified in the human placenta. Of these, System A, transporting neutral nonessential amino acids, and System L, mediating the transport of essential amino acids, have been studied in some detail. Importantly, decreased placental Systems A and L transporter activity is strongly associated with IUGR and increased placental activity of these two amino acid transporters has been linked to fetal overgrowth in human pregnancy. An array of factors in the maternal circulation, including insulin, IGF-1, and adiponectin, and placental signaling pathways such as mTOR, have been identified as key regulators of placental Systems A and L. Studies using trophoblast-specific gene targeting in mice have provided compelling evidence that changes in placental Systems A and L are mechanistically linked to altered fetal growth. It is possible that targeting specific placental amino acid transporters or their upstream regulators represents a novel intervention to alleviate the short- and long-term consequences of abnormal fetal growth in the future.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 7","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140848324","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}
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