Animals exhibit physiological changes designed to eliminate the perceived danger, provoking similar symptoms of fever. However, a high-grade fever indicates poor clinical outcomes. Caspase11 (Casp11) is involved in many inflammatory diseases. Whether Casp11 leads to fever remains unclear. In this study, we investigate the role of the preoptic area of the hypothalamus (PO/AH) microglia Casp11 in fever.
Methods
We perform experiments using a rat model of LPS-induced fever. We measure body temperature and explore the functions of peripheral macrophages and PO/AH microglia in fever signaling by ELISA, immunohistochemistry, immunofluorescence, flow cytometry, macrophage depletion, protein blotting, and RNA-seq. Then, the effects of macrophages on microglia in a hyperthermic environment are observed in vitro. Finally, adeno-associated viruses are used to knockdown or overexpress microglia Casp11 in PO/AH to determine the role of Casp11 in fever.
Results
We find peripheral macrophages and PO/AH microglia play important roles in the process of fever, which is proved by macrophage and microglia depletion. By RNA-seq analysis, we find Casp11 expression in PO/AH is significantly increased during fever. Co-culture and conditioned-culture simulate the induction of microglia Casp11 activation by macrophages in a non-contact manner. Microglia Casp11 knockdown decreases body temperature, pyrogenic factors, and inflammasome, and vice versa.
Conclusion
We report that Casp11 drives fever. Mechanistically, peripheral macrophages transmit immune signals via cytokines to microglia in PO/AH, which activate the Casp11 non-canonical inflammasome. Our findings identify a novel player, the microglia Casp11, in the control of fever, providing an explanation for the transmission and amplification of fever immune signaling.
{"title":"Microglia Caspase11 non-canonical inflammasome drives fever","authors":"Ping Yu, Yuangeng Li, Wenwen Fu, Xiaofeng Yu, Dayun Sui, Huali Xu, Weilun Sun","doi":"10.1111/apha.14187","DOIUrl":"10.1111/apha.14187","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Animals exhibit physiological changes designed to eliminate the perceived danger, provoking similar symptoms of fever. However, a high-grade fever indicates poor clinical outcomes. Caspase11 (Casp11) is involved in many inflammatory diseases. Whether Casp11 leads to fever remains unclear. In this study, we investigate the role of the preoptic area of the hypothalamus (PO/AH) microglia Casp11 in fever.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We perform experiments using a rat model of LPS-induced fever. We measure body temperature and explore the functions of peripheral macrophages and PO/AH microglia in fever signaling by ELISA, immunohistochemistry, immunofluorescence, flow cytometry, macrophage depletion, protein blotting, and RNA-seq. Then, the effects of macrophages on microglia in a hyperthermic environment are observed in vitro. Finally, adeno-associated viruses are used to knockdown or overexpress microglia Casp11 in PO/AH to determine the role of Casp11 in fever.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We find peripheral macrophages and PO/AH microglia play important roles in the process of fever, which is proved by macrophage and microglia depletion. By RNA-seq analysis, we find Casp11 expression in PO/AH is significantly increased during fever. Co-culture and conditioned-culture simulate the induction of microglia Casp11 activation by macrophages in a non-contact manner. Microglia Casp11 knockdown decreases body temperature, pyrogenic factors, and inflammasome, and vice versa.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We report that Casp11 drives fever. Mechanistically, peripheral macrophages transmit immune signals via cytokines to microglia in PO/AH, which activate the Casp11 non-canonical inflammasome. Our findings identify a novel player, the microglia Casp11, in the control of fever, providing an explanation for the transmission and amplification of fever immune signaling.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141304923","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}
Xin-Peng Duan, Cheng-Biao Zhang, Wen-Hui Wang, Dao-Hong Lin
Calcineurin, protein phosphatase 2B (PP2B) or protein phosphatase 3 (PP3), is a calcium-dependent serine/threonine protein phosphatase. Calcineurin is widely expressed in the kidney and regulates renal Na+ and K+ transport. In the thick ascending limb, calcineurin plays a role in inhibiting NKCC2 function by promoting the dephosphorylation of the cotransporter and an intracellular sorting receptor, called sorting-related-receptor-with-A-type repeats (SORLA), is involved in modulating the effect of calcineurin on NKCC2. Calcineurin also participates in regulating thiazide-sensitive NaCl-cotransporter (NCC) in the distal convoluted tubule. The mechanisms by which calcineurin regulates NCC include directly dephosphorylation of NCC, regulating Kelch-like-3/CUL3 E3 ubiquitin–ligase complex, which is responsible for WNK (with-no-lysin-kinases) ubiquitination, and inhibiting Kir4.1/Kir5.1, which determines NCC expression/activity. Finally, calcineurin is also involved in regulating ROMK (Kir1.1) channels in the cortical collecting duct and Cyp11 2 expression in adrenal zona glomerulosa. In summary, calcineurin is involved in the regulation of NKCC2, NCC, and inwardly rectifying K+ channels in the kidney, and it also plays a role in modulating aldosterone synthesis in adrenal gland, which regulates epithelial-Na+-channel expression/activity. Thus, application of calcineurin inhibitors (CNIs) is expected to abrupt calcineurin-mediated regulation of transepithelial Na+ and K+ transport in the kidney. Consequently, CNIs cause hypertension, compromise renal K+ excretion, and induce hyperkalemia.
{"title":"Role of calcineurin in regulating renal potassium (K+) excretion: Mechanisms of calcineurin inhibitor-induced hyperkalemia","authors":"Xin-Peng Duan, Cheng-Biao Zhang, Wen-Hui Wang, Dao-Hong Lin","doi":"10.1111/apha.14189","DOIUrl":"10.1111/apha.14189","url":null,"abstract":"<p>Calcineurin, protein phosphatase 2B (PP2B) or protein phosphatase 3 (PP3), is a calcium-dependent serine/threonine protein phosphatase. Calcineurin is widely expressed in the kidney and regulates renal Na<sup>+</sup> and K<sup>+</sup> transport. In the thick ascending limb, calcineurin plays a role in inhibiting NKCC2 function by promoting the dephosphorylation of the cotransporter and an intracellular sorting receptor, called sorting-related-receptor-with-A-type repeats (SORLA), is involved in modulating the effect of calcineurin on NKCC2. Calcineurin also participates in regulating thiazide-sensitive NaCl-cotransporter (NCC) in the distal convoluted tubule. The mechanisms by which calcineurin regulates NCC include directly dephosphorylation of NCC, regulating Kelch-like-3/CUL3 E3 ubiquitin–ligase complex, which is responsible for WNK (with-no-lysin-kinases) ubiquitination, and inhibiting Kir4.1/Kir5.1, which determines NCC expression/activity. Finally, calcineurin is also involved in regulating ROMK (Kir1.1) channels in the cortical collecting duct and Cyp11 2 expression in adrenal zona glomerulosa. In summary, calcineurin is involved in the regulation of NKCC2, NCC, and inwardly rectifying K<sup>+</sup> channels in the kidney, and it also plays a role in modulating aldosterone synthesis in adrenal gland, which regulates epithelial-Na<sup>+</sup>-channel expression/activity. Thus, application of calcineurin inhibitors (CNIs) is expected to abrupt calcineurin-mediated regulation of transepithelial Na<sup>+</sup> and K<sup>+</sup> transport in the kidney. Consequently, CNIs cause hypertension, compromise renal K<sup>+</sup> excretion, and induce hyperkalemia.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141299458","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}
Maureen A. Walsh, Amanda S. Latham, Qian Zhang, Robert A. Jacobs, Robert V. Musci, Thomas J. LaRocca, Julie A. Moreno, Kelly S. Santangelo, Karyn L. Hamilton
Aim
Alzheimer’s disease (AD) is the most common form of dementia. However, while 150+ animal models of AD exist, drug translation from preclinical models to humans for treatment usually fails. One factor contributing to low translation is likely the absence of neurodegenerative models that also encompass the multi-morbidities of human aging. We previously demonstrated that, in comparison to the PigmEnTed (PET) guinea pig strain which models “typical” brain aging, the Hartley strain develops hallmarks of AD like aging humans. Hartleys also exhibit age-related impairments in cartilage and skeletal muscle. Impaired mitochondrial respiration is one driver of both cellular aging and AD. In humans with cognitive decline, diminished skeletal muscle and brain respiratory control occurs in parallel. We previously reported age-related declines in skeletal muscle mitochondrial respiration in Hartleys. It is unknown if there is concomitant mitochondrial dysfunction in the brain.
Methods
Therefore, we assessed hippocampal mitochondrial respiration in 5- and 12-month Hartley and PET guinea pigs using high-resolution respirometry.
Results
At 12 months, PETs had higher complex I supported mitochondrial respiration paralleling their increase in body mass compared to 5 months PETs. Hartleys were also heavier at 12 months compared to 5 months but did not have higher complex I respiration. Compared to 5 months Hartleys, 12 months Hartleys had lower complex I mitochondrial efficiency and compensatory increases in mitochondrial proteins collectively suggesting mitochondrial dysfunction with age.
Conclusions
Therefore, Hartleys might be a relevant model to test promising therapies targeting mitochondria to slow brain aging and AD progression.
目的：阿尔茨海默病（AD）是最常见的痴呆症。然而，虽然目前已有 150 多种阿尔茨海默病动物模型，但将药物从临床前模型转化为人类治疗方法的工作通常都以失败告终。导致转化率低的一个因素可能是缺乏同时包含人类衰老过程中多种疾病的神经退行性模型。我们以前曾证实，与模拟 "典型 "脑衰老的 PigmEnTed（PET）豚鼠品系相比，哈特里品系会像衰老的人类一样出现注意力缺失症的特征。哈特里也表现出与年龄相关的软骨和骨骼肌损伤。线粒体呼吸受损是细胞衰老和注意力缺失症的驱动因素之一。在认知能力下降的人类中，骨骼肌和大脑呼吸控制的减弱也同时发生。我们以前曾报道过哈特莱人骨骼肌线粒体呼吸与年龄相关的下降。目前尚不清楚大脑中是否同时存在线粒体功能障碍：因此，我们使用高分辨率呼吸测定法评估了 5 个月和 12 个月哈特利豚鼠和 PET 豚鼠的海马线粒体呼吸：与 5 个月的 PET 相比，12 个月的 PET 具有更高的复合物 I 支持线粒体呼吸，这与其体重的增加相一致。与 5 个月的哈特里犬相比，12 个月的哈特里犬体重也有所增加，但复合 I 呼吸量却没有增加。与 5 个月大的哈特莱人相比，12 个月大的哈特莱人的复合 I 线粒体效率较低，线粒体蛋白质则呈代偿性增加，这共同表明随着年龄的增长，线粒体功能会出现障碍：因此，哈特莱可能是一种相关的模型，可用于测试针对线粒体的有前途的疗法，以延缓大脑衰老和注意力缺失症的进展。
{"title":"Non-transgenic guinea pig strains exhibit divergent age-related changes in hippocampal mitochondrial respiration","authors":"Maureen A. Walsh, Amanda S. Latham, Qian Zhang, Robert A. Jacobs, Robert V. Musci, Thomas J. LaRocca, Julie A. Moreno, Kelly S. Santangelo, Karyn L. Hamilton","doi":"10.1111/apha.14185","DOIUrl":"10.1111/apha.14185","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Alzheimer’s disease (AD) is the most common form of dementia. However, while 150+ animal models of AD exist, drug translation from preclinical models to humans for treatment usually fails. One factor contributing to low translation is likely the absence of neurodegenerative models that also encompass the multi-morbidities of human aging. We previously demonstrated that, in comparison to the PigmEnTed (PET) guinea pig strain which models “typical” brain aging, the Hartley strain develops hallmarks of AD like aging humans. Hartleys also exhibit age-related impairments in cartilage and skeletal muscle. Impaired mitochondrial respiration is one driver of both cellular aging and AD. In humans with cognitive decline, diminished skeletal muscle and brain respiratory control occurs in parallel. We previously reported age-related declines in skeletal muscle mitochondrial respiration in Hartleys. It is unknown if there is concomitant mitochondrial dysfunction in the brain.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Therefore, we assessed hippocampal mitochondrial respiration in 5- and 12-month Hartley and PET guinea pigs using high-resolution respirometry.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>At 12 months, PETs had higher complex I supported mitochondrial respiration paralleling their increase in body mass compared to 5 months PETs. Hartleys were also heavier at 12 months compared to 5 months but did not have higher complex I respiration. Compared to 5 months Hartleys, 12 months Hartleys had lower complex I mitochondrial efficiency and compensatory increases in mitochondrial proteins collectively suggesting mitochondrial dysfunction with age.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Therefore, Hartleys might be a relevant model to test promising therapies targeting mitochondria to slow brain aging and AD progression.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14185","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141299457","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}
Alessandro Esposito, Sara Pepe, Maria Sabina Cerullo, Katia Cortese, Hanako Tsushima Semini, Silvia Giovedì, Renzo Guerrini, Fabio Benfenati, Antonio Falace, Anna Fassio
Aim
Understanding the physiological role of ATP6V1A, a component of the cytosolic V1 domain of the proton pump vacuolar ATPase, in regulating neuronal development and function.
Methods
Modeling loss of function of Atp6v1a in primary murine hippocampal neurons and studying neuronal morphology and function by immunoimaging, electrophysiological recordings and electron microscopy.
Results
Atp6v1a depletion affects neurite elongation, stabilization, and function of excitatory synapses and prevents synaptic rearrangement upon induction of plasticity. These phenotypes are due to an overall decreased expression of the V1 subunits, that leads to impairment of lysosomal pH-regulation and autophagy progression with accumulation of aberrant lysosomes at neuronal soma and of enlarged vacuoles at synaptic boutons.
Conclusions
These data suggest a physiological role of ATP6V1A in the surveillance of synaptic integrity and plasticity and highlight the pathophysiological significance of ATP6V1A loss in the alteration of synaptic function that is associated with neurodevelopmental and neurodegenerative diseases. The data further support the pivotal involvement of lysosomal function and autophagy flux in maintaining proper synaptic connectivity and adaptive neuronal properties.
{"title":"ATP6V1A is required for synaptic rearrangements and plasticity in murine hippocampal neurons","authors":"Alessandro Esposito, Sara Pepe, Maria Sabina Cerullo, Katia Cortese, Hanako Tsushima Semini, Silvia Giovedì, Renzo Guerrini, Fabio Benfenati, Antonio Falace, Anna Fassio","doi":"10.1111/apha.14186","DOIUrl":"10.1111/apha.14186","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Understanding the physiological role of ATP6V1A, a component of the cytosolic V<sub>1</sub> domain of the proton pump vacuolar ATPase, in regulating neuronal development and function.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Modeling loss of function of <i>Atp6v1a</i> in primary murine hippocampal neurons and studying neuronal morphology and function by immunoimaging, electrophysiological recordings and electron microscopy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p><i>Atp6v1a</i> depletion affects neurite elongation, stabilization, and function of excitatory synapses and prevents synaptic rearrangement upon induction of plasticity. These phenotypes are due to an overall decreased expression of the V<sub>1</sub> subunits, that leads to impairment of lysosomal pH-regulation and autophagy progression with accumulation of aberrant lysosomes at neuronal soma and of enlarged vacuoles at synaptic boutons.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These data suggest a physiological role of ATP6V1A in the surveillance of synaptic integrity and plasticity and highlight the pathophysiological significance of ATP6V1A loss in the alteration of synaptic function that is associated with neurodevelopmental and neurodegenerative diseases. The data further support the pivotal involvement of lysosomal function and autophagy flux in maintaining proper synaptic connectivity and adaptive neuronal properties.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14186","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141263700","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}
Anja Schork, Elisabeth Vogel, Bernhard N. Bohnert, Daniel Essigke, Matthias Wörn, Imma Fischer, Nils Heyne, Andreas L. Birkenfeld, Ferruh Artunc
Aim
In rodent models of nephrotic syndrome (NS), edema formation was prevented by blockade of the epithelial sodium channel ENaC with amiloride. However, apart from case reports, there is no evidence favoring ENaC blockade in patients with NS.
Methods
The monocentric randomized controlled AMILOR study investigated the antiedematous effect of amiloride (starting dose 5 mg/day, max. 15 mg/day) in comparison to standard therapy with the loop diuretic furosemide (40 mg/day, max. 120 mg/day) over 16 days. Overhydration (OH) was measured by bioimpedance spectroscopy (BCM, Fresenius). Depending on the OH response, diuretic dose was adjusted on days 2, 5, 8 and 12, and if necessary, hydrochlorothiazide (HCT) was added from d8 (12.5 mg/day, max. 25 mg/day). The primary endpoint was the decrease in OH on d8. The study was terminated prematurely due to insufficient recruitment and a low statistical power due to a low actual effect size.
Results
Median baseline OH was +26.4 (interquartile range 15.5–35.1)% extracellular water (ECW) in the amiloride arm and + 27.9 (24.1–29.4)% ECW in the furosemide arm and decreased by 1.95 (0.80–6.40) and 5.15 (0.90–8.30)% ECW after 8 days, respectively, and by 10.10 (1.30–14.40) and 7.40 (2.80–10.10)% ECW after 16 days, respectively. OH decrease on d8 and d16 was not significantly different between both arms.
Conclusion
The AMILOR study is the first randomized controlled pilot study suggesting a similar antiedematous effect as furosemide. Further studies are required to better define the role of amiloride in NS (EudraCT 2019-002607-18).
{"title":"Amiloride versus furosemide for the treatment of edema in patients with nephrotic syndrome: A pilot study (AMILOR)","authors":"Anja Schork, Elisabeth Vogel, Bernhard N. Bohnert, Daniel Essigke, Matthias Wörn, Imma Fischer, Nils Heyne, Andreas L. Birkenfeld, Ferruh Artunc","doi":"10.1111/apha.14183","DOIUrl":"10.1111/apha.14183","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>In rodent models of nephrotic syndrome (NS), edema formation was prevented by blockade of the epithelial sodium channel ENaC with amiloride. However, apart from case reports, there is no evidence favoring ENaC blockade in patients with NS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The monocentric randomized controlled AMILOR study investigated the antiedematous effect of amiloride (starting dose 5 mg/day, max. 15 mg/day) in comparison to standard therapy with the loop diuretic furosemide (40 mg/day, max. 120 mg/day) over 16 days. Overhydration (OH) was measured by bioimpedance spectroscopy (BCM, Fresenius). Depending on the OH response, diuretic dose was adjusted on days 2, 5, 8 and 12, and if necessary, hydrochlorothiazide (HCT) was added from d8 (12.5 mg/day, max. 25 mg/day). The primary endpoint was the decrease in OH on d8. The study was terminated prematurely due to insufficient recruitment and a low statistical power due to a low actual effect size.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Median baseline OH was +26.4 (interquartile range 15.5–35.1)% extracellular water (ECW) in the amiloride arm and + 27.9 (24.1–29.4)% ECW in the furosemide arm and decreased by 1.95 (0.80–6.40) and 5.15 (0.90–8.30)% ECW after 8 days, respectively, and by 10.10 (1.30–14.40) and 7.40 (2.80–10.10)% ECW after 16 days, respectively. OH decrease on d8 and d16 was not significantly different between both arms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The AMILOR study is the first randomized controlled pilot study suggesting a similar antiedematous effect as furosemide. Further studies are required to better define the role of amiloride in NS (EudraCT 2019-002607-18).</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14183","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141185527","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}
Sepsis-induced myocardial injury (SIMI) may be associated with insufficient mitophagy in cardiomyocytes, but the exact mechanism involved remains unknown. Sirtuin 3 (Sirt3) is mainly found in the mitochondrial matrix and is involved in repairing mitochondrial function through means such as the activation of autophagy. Previously, we demonstrated that the annexin-A1 small peptide (ANXA1sp) can promote Sirt3 expression in mitochondria. In this study, we hypothesized that the activation of Sirt3 by ANXA1sp induces mitophagy, thereby providing a protective effect against SIMI in mice.
Methods
A mouse model of SIMI was established via cecal ligation and puncture. Intraperitoneal injections of ANXA1sp, 3TYP, and 3MA were administered prior to modeling. After successful modeling, IL-6, TNF-α, CK-MB, and CTn-I levels were measured; cardiac function was assessed using echocardiography; myocardial mitochondrial membrane potential, ROS, and ATP production were determined; myocardial mitochondrial ultrastructure was observed using transmission electron microscopy; and the expression levels of Sirt3 and autophagy-related proteins were detected using western blotting.
Results
ANXA1sp significantly reduced serum IL-6, TNF-α, CK-MB, and CTn-I levels; decreased myocardial ROS production; increased mitochondrial membrane potential and ATP synthesis; and improved myocardial mitochondrial ultrastructure in septic mice. Furthermore, ANXA1sp promoted Sirt3 expression and activated the AMPK-mTOR pathway to induce myocardial mitophagy. These protective effects of ANXA1sp were reversed upon treatment with the Sirt3 blocker, 3-TYP.
Conclusion
ANXA1sp can reverse SIMI, and the underlying mechanism may be related to the activation of the AMPK-mTOR pathway following upregulation of Sirt3 by ANXA1sp, which, in turn, induces autophagy.
{"title":"ANXA1sp modulates the protective effect of Sirt3-induced mitophagy against sepsis-induced myocardial injury in mice","authors":"Wanyu Ma, Zhijia Huang, Yanmei Miao, Xinglong Ma, Zhiquan Zhang, Wenjie Liu, Peng Xie","doi":"10.1111/apha.14184","DOIUrl":"10.1111/apha.14184","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Sepsis-induced myocardial injury (SIMI) may be associated with insufficient mitophagy in cardiomyocytes, but the exact mechanism involved remains unknown. Sirtuin 3 (Sirt3) is mainly found in the mitochondrial matrix and is involved in repairing mitochondrial function through means such as the activation of autophagy. Previously, we demonstrated that the annexin-A1 small peptide (ANXA1sp) can promote Sirt3 expression in mitochondria. In this study, we hypothesized that the activation of Sirt3 by ANXA1sp induces mitophagy, thereby providing a protective effect against SIMI in mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A mouse model of SIMI was established via cecal ligation and puncture. Intraperitoneal injections of ANXA1sp, 3TYP, and 3MA were administered prior to modeling. After successful modeling, IL-6, TNF-α, CK-MB, and CTn-I levels were measured; cardiac function was assessed using echocardiography; myocardial mitochondrial membrane potential, ROS, and ATP production were determined; myocardial mitochondrial ultrastructure was observed using transmission electron microscopy; and the expression levels of Sirt3 and autophagy-related proteins were detected using western blotting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>ANXA1sp significantly reduced serum IL-6, TNF-α, CK-MB, and CTn-I levels; decreased myocardial ROS production; increased mitochondrial membrane potential and ATP synthesis; and improved myocardial mitochondrial ultrastructure in septic mice. Furthermore, ANXA1sp promoted Sirt3 expression and activated the AMPK-mTOR pathway to induce myocardial mitophagy. These protective effects of ANXA1sp were reversed upon treatment with the Sirt3 blocker, 3-TYP.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>ANXA1sp can reverse SIMI, and the underlying mechanism may be related to the activation of the AMPK-mTOR pathway following upregulation of Sirt3 by ANXA1sp, which, in turn, induces autophagy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141185528","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}
Neil G. Docherty, Christian Delles, Francisco J. López-Hernández
Surrogate measures of glomerular filtration rate (GFR) continue to serve as pivotal determinants of the incidence, severity, and management of acute kidney injury (AKI), as well as the primary reference point underpinning knowledge of its pathophysiology. However, several clinically important deficits in aspects of renal excretory function during AKI other than GFR decline, including acid–base regulation, electrolyte and water balance, and urinary concentrating capacity, can evade detection when diagnostic criteria are built around purely GFR-based assessments. The use of putative markers of tubular injury to detect “sub-clinical” AKI has been proposed to expand the definition and diagnostic criteria for AKI, but their diagnostic performance is curtailed by ambiguity with respect to their biological meaning and context specificity. Efforts to devise new holistic assessments of overall renal functional compromise in AKI would foster the capacity to better personalize patient care by replacing biomarker threshold-based diagnostic criteria with a shift to assessment of compromise along a pathophysiological continuum. The term AKI refers to a syndrome of sudden renal deterioration, the severity of which is classified by precise diagnostic criteria that have unquestionable utility in patient management as well as blatant limitations. Particularly, the absence of an explicit pathophysiological definition of AKI curtails further scientific development and clinical handling, entrapping the field within its present narrow GFR-based view. A refreshed approach based on a more holistic consideration of renal functional impairment in AKI as the basis for a new diagnostic concept that reaches beyond the boundaries imposed by the current GFR threshold-based classification of AKI, capturing broader aspects of pathogenesis, could enhance AKI prevention strategies and improve AKI patient outcome and prognosis.
肾小球滤过率（GFR）的替代指标仍然是决定急性肾损伤（AKI）发病率、严重程度和管理的关键因素，也是了解其病理生理学的主要参考点。然而，在 AKI 期间，除了肾小球滤过率下降以外，肾脏排泄功能还存在一些临床上重要的缺陷，包括酸碱调节、电解质和水平衡以及尿浓缩能力，而这些缺陷在诊断标准建立在单纯的肾小球滤过率评估基础上时可能会被忽略。有人建议使用肾小管损伤的假定标志物来检测 "亚临床 "AKI，以扩大 AKI 的定义和诊断标准，但由于这些标志物的生物学意义和背景特异性不明确，其诊断性能受到限制。对 AKI 中的整体肾功能损害进行新的整体评估，可取代基于生物标志物阈值的诊断标准，转而评估病理生理学连续体的损害情况，从而提高对患者进行个性化治疗的能力。AKI 一词指的是肾功能突然恶化的综合征，其严重程度由精确的诊断标准来划分，这些标准在患者管理中的作用毋庸置疑，但也有明显的局限性。特别是，由于缺乏明确的病理生理学定义，AKI 的进一步科学发展和临床处理受到限制，使该领域陷入目前基于 GFR 的狭隘观点。以更全面地考虑 AKI 中的肾功能损伤为基础，更新诊断方法，超越目前基于 GFR 临界值的 AKI 分类所强加的界限，捕捉更广泛的发病机制，可以加强 AKI 预防策略，改善 AKI 患者的预后。
{"title":"Reframing acute kidney injury as a pathophysiological continuum of disrupted renal excretory function","authors":"Neil G. Docherty, Christian Delles, Francisco J. López-Hernández","doi":"10.1111/apha.14181","DOIUrl":"10.1111/apha.14181","url":null,"abstract":"<p>Surrogate measures of glomerular filtration rate (GFR) continue to serve as pivotal determinants of the incidence, severity, and management of acute kidney injury (AKI), as well as the primary reference point underpinning knowledge of its pathophysiology. However, several clinically important deficits in aspects of renal excretory function during AKI other than GFR decline, including acid–base regulation, electrolyte and water balance, and urinary concentrating capacity, can evade detection when diagnostic criteria are built around purely GFR-based assessments. The use of putative markers of tubular injury to detect “sub-clinical” AKI has been proposed to expand the definition and diagnostic criteria for AKI, but their diagnostic performance is curtailed by ambiguity with respect to their biological meaning and context specificity. Efforts to devise new holistic assessments of overall renal functional compromise in AKI would foster the capacity to better personalize patient care by replacing biomarker threshold-based diagnostic criteria with a shift to assessment of compromise along a pathophysiological continuum. The term AKI refers to a syndrome of sudden renal deterioration, the severity of which is classified by precise diagnostic criteria that have unquestionable utility in patient management as well as blatant limitations. Particularly, the absence of an explicit pathophysiological definition of AKI curtails further scientific development and clinical handling, entrapping the field within its present narrow GFR-based view. A refreshed approach based on a more holistic consideration of renal functional impairment in AKI as the basis for a new diagnostic concept that reaches beyond the boundaries imposed by the current GFR threshold-based classification of AKI, capturing broader aspects of pathogenesis, could enhance AKI prevention strategies and improve AKI patient outcome and prognosis.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141159882","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}
E. Cowan, J. Sun, A. Hamilton, S. Ruhrmann, A. Karagiannopoulos, E. Westholm, J. K. Ofori, C. Luan, E. Zhang, H. Mulder, L. Eliasson
Aim
MicroRNAs (miRNAs) regulate β-cell function, and β-cell mitochondria and insulin secretion are perturbed in diabetes. We aimed to identify key miRNAs regulating β-cell mitochondrial metabolism and novel β-cell miRNA-mitochondrial pathways.
Methods
TargetScan (http://www.targetscan.org/) was used to predict if 16 miRNAs implicated in β-cell function target 27 cis-eGenes implicated in mitochondrial activity. The expression of candidate miRNAs and insulin secretion after 24 and 1 h pre-incubation in 2.8, 11.1- and 16.7-mM glucose was measured in clonal INS-1 832/13 β-cells. MiR-29 silenced INS-1 832/13 cells were assessed for insulin secretion (glucose, pyruvate, and K+), target cis-eGene expression (Ndufv3 and Ndufa10 components of mitochondrial complex I (CI)), OXPHOS (CI-V) protein expression, and mitochondrial OXPHOS respiration/activity. The expression of differentially expressed miR-29 miRNAs was evaluated in Goto-Kakizaki (GK) rat, db/db mouse and type 2 diabetic (T2D) human islets, as well as NMRI mouse islets cultured under glucolipotoxic conditions.
Results
MiR-29, miR-15 and miR-124 were predicted to regulate ~20 cis-eGenes, while miR-29 alone was predicted to regulate ≥12 of these in rat and human species. MiR-29 expression and insulin secretion were reduced in INS-1 832/13 cells after 24 h in elevated glucose. MiR-29 knockdown increased all tested insulin secretory responses, Nudfv3, Ndufa10, complex I and II expression, and cellular mitochondrial OXPHOS. MiR-29 expression was reduced in db/db islets but increased in GK rat and T2D human islets.
Conclusion
We conclude miR-29 is a key miRNA in regulating β-cell mitochondrial metabolism and insulin secretion via underlying miR-29-OXPHOS complex pathways. Furthermore, we infer reduced miR-29 expression compensatorily enhances insulin secretion under glucotoxicity.
{"title":"MicroRNA 29 modulates β-cell mitochondrial metabolism and insulin secretion via underlying miR-29-OXPHOS complex pathways","authors":"E. Cowan, J. Sun, A. Hamilton, S. Ruhrmann, A. Karagiannopoulos, E. Westholm, J. K. Ofori, C. Luan, E. Zhang, H. Mulder, L. Eliasson","doi":"10.1111/apha.14180","DOIUrl":"10.1111/apha.14180","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>MicroRNAs (miRNAs) regulate β-cell function, and β-cell mitochondria and insulin secretion are perturbed in diabetes. We aimed to identify key miRNAs regulating β-cell mitochondrial metabolism and novel β-cell miRNA-mitochondrial pathways.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>TargetScan (http://www.targetscan.org/) was used to predict if 16 miRNAs implicated in β-cell function target 27 cis-eGenes implicated in mitochondrial activity. The expression of candidate miRNAs and insulin secretion after 24 and 1 h pre-incubation in 2.8, 11.1- and 16.7-mM glucose was measured in clonal INS-1 832/13 β-cells. MiR-29 silenced INS-1 832/13 cells were assessed for insulin secretion (glucose, pyruvate, and K<sup>+</sup>), target cis-eGene expression (<i>Ndufv3</i> and <i>Ndufa10</i> components of mitochondrial complex I (CI)), OXPHOS (CI-V) protein expression, and mitochondrial OXPHOS respiration/activity. The expression of differentially expressed miR-29 miRNAs was evaluated in Goto-Kakizaki (GK) rat, db/db mouse and type 2 diabetic (T2D) human islets, as well as NMRI mouse islets cultured under glucolipotoxic conditions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>MiR-29, miR-15 and miR-124 were predicted to regulate ~20 cis-eGenes, while miR-29 alone was predicted to regulate ≥12 of these in rat and human species. MiR-29 expression and insulin secretion were reduced in INS-1 832/13 cells after 24 h in elevated glucose. MiR-29 knockdown increased all tested insulin secretory responses, <i>Nudfv3</i>, <i>Ndufa10</i>, complex I and II expression, and cellular mitochondrial OXPHOS. MiR-29 expression was reduced in db/db islets but increased in GK rat and T2D human islets.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We conclude miR-29 is a key miRNA in regulating β-cell mitochondrial metabolism and insulin secretion via underlying miR-29-OXPHOS complex pathways. Furthermore, we infer reduced miR-29 expression compensatorily enhances insulin secretion under glucotoxicity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14180","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141154126","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>As humans, we detect and process external stimuli through sensory perception.<span><sup>1</sup></span> Vision, scent, touch, sound, and taste, often in combination and/or simultaneously, help us interpret and adequately react to our environments. Sensory and perceptual alterations in humans occur on a wide spectrum,<span><sup>2</sup></span> ranging from physiological phenomena in response to everyday environmental<span><sup>3</sup></span> or hormonal<span><sup>4</sup></span> influences, to the aura symptoms in migraine patients, to severe, prolonged alterations that qualify as hallucinations.<span><sup>5</sup></span></p><p>Color perception is a fundamental aspect of the human experience. Colors, manifestations of different wavelengths of light, influence human emotions, behaviors and physiological responses.<span><sup>6</sup></span> From the vibrant hues of a sunset to the subtle shades of a painting, the way we perceive color plays a huge role in shaping our understanding of the world around us. In recent years, scientific inquiry into the details of the mechanisms behind visual perception have deepened our comprehension of how our visual system processes and interprets the rich array of colors in our environment. Recent insights into visual perception and signal interpretation include for example the role of pacsin proteins in vision, a novel function of these regulators of the actin cytoskeleton and cellular transport processes.<span><sup>7</sup></span> Also, in the context of visual perception and the role of visual stimuli in maintaining healthy circadian rhythms, the influence of an impaired eyesight<span><sup>8</sup></span> and the role of the eye as not only a light- but also temperature-sensitive organ<span><sup>9, 10</sup></span> have been described.</p><p>Aside from human perception and interpretation of light of different wavelenghths as color, colored light has become an indispensable methodological tool for physiologists to precisely manipulate light to activate or inhibit intracerebral neural circuits to selectively stimulate or suppress neuronal activity with high temporal and spatial precision, to e.g. analyze complex neural networks and elucidate causal relationships between neuronal activity and behavior.<span><sup>11-13</sup></span></p><p>However, color is also a multifaceted communicative tool across various domains, encompassing fields from biology to design. In nature, colors often act as a visual language, signaling vital information, for example survival and reproduction. From the vibrant hues of flowers attracting pollinators to the warning colors of venomous creatures, organisms utilize color to convey messages efficiently. Beyond biology, humans harness color as a potent means of expression and communication. Color plays, for example, a pivotal role in branding, where shades become synonymous with companies and products and influence consumer perception and behavior. Color choices evoke emotions, convey cultural sig
{"title":"Color in physiology","authors":"Pontus B. Persson, Anja Bondke Persson","doi":"10.1111/apha.14182","DOIUrl":"10.1111/apha.14182","url":null,"abstract":"<p>As humans, we detect and process external stimuli through sensory perception.<span><sup>1</sup></span> Vision, scent, touch, sound, and taste, often in combination and/or simultaneously, help us interpret and adequately react to our environments. Sensory and perceptual alterations in humans occur on a wide spectrum,<span><sup>2</sup></span> ranging from physiological phenomena in response to everyday environmental<span><sup>3</sup></span> or hormonal<span><sup>4</sup></span> influences, to the aura symptoms in migraine patients, to severe, prolonged alterations that qualify as hallucinations.<span><sup>5</sup></span></p><p>Color perception is a fundamental aspect of the human experience. Colors, manifestations of different wavelengths of light, influence human emotions, behaviors and physiological responses.<span><sup>6</sup></span> From the vibrant hues of a sunset to the subtle shades of a painting, the way we perceive color plays a huge role in shaping our understanding of the world around us. In recent years, scientific inquiry into the details of the mechanisms behind visual perception have deepened our comprehension of how our visual system processes and interprets the rich array of colors in our environment. Recent insights into visual perception and signal interpretation include for example the role of pacsin proteins in vision, a novel function of these regulators of the actin cytoskeleton and cellular transport processes.<span><sup>7</sup></span> Also, in the context of visual perception and the role of visual stimuli in maintaining healthy circadian rhythms, the influence of an impaired eyesight<span><sup>8</sup></span> and the role of the eye as not only a light- but also temperature-sensitive organ<span><sup>9, 10</sup></span> have been described.</p><p>Aside from human perception and interpretation of light of different wavelenghths as color, colored light has become an indispensable methodological tool for physiologists to precisely manipulate light to activate or inhibit intracerebral neural circuits to selectively stimulate or suppress neuronal activity with high temporal and spatial precision, to e.g. analyze complex neural networks and elucidate causal relationships between neuronal activity and behavior.<span><sup>11-13</sup></span></p><p>However, color is also a multifaceted communicative tool across various domains, encompassing fields from biology to design. In nature, colors often act as a visual language, signaling vital information, for example survival and reproduction. From the vibrant hues of flowers attracting pollinators to the warning colors of venomous creatures, organisms utilize color to convey messages efficiently. Beyond biology, humans harness color as a potent means of expression and communication. Color plays, for example, a pivotal role in branding, where shades become synonymous with companies and products and influence consumer perception and behavior. Color choices evoke emotions, convey cultural sig","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14182","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086207","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}
Henning Tim Langer, Shakti Ramsamooj, Ezequiel Dantas, Anirudh Murthy, Mujmmail Ahmed, Tanvir Ahmed, Seo-Kyoung Hwang, Rahul Grover, Rita Pozovskiy, Roger J. Liang, Andre Lima Queiroz, Justin C. Brown, Eileen P. White, Tobias Janowitz, Marcus D. Goncalves
Aim
To investigate systemic regulators of the cancer-associated cachexia syndrome (CACS) in a pre-clinical model for lung cancer with the goal to identify therapeutic targets for tissue wasting.
Methods
Using the Kras/Lkb1 (KL) mouse model, we found that CACS is associated with white adipose tissue (WAT) dysfunction that directly affects skeletal muscle homeostasis. WAT transcriptomes showed evidence of reduced adipogenesis, and, in agreement, we found low levels of circulating adiponectin. To preserve adipogenesis and restore adiponectin levels, we treated mice with the PPAR-γ agonist, rosiglitazone.
Results
Rosiglitazone treatment increased serum adiponectin levels, delayed weight loss, and preserved skeletal muscle and adipose tissue mass, as compared to vehicle-treated mice. The preservation of muscle mass with rosiglitazone was associated with increases in AMPK and AKT activity. Similarly, activation of the adiponectin receptors in muscle cells increased AMPK activity, anabolic signaling, and protein synthesis.
Conclusion
Our data suggest that PPAR-γ agonists may be a useful adjuvant therapy to preserve tissue mass in lung cancer.
{"title":"Restoring adiponectin via rosiglitazone ameliorates tissue wasting in mice with lung cancer","authors":"Henning Tim Langer, Shakti Ramsamooj, Ezequiel Dantas, Anirudh Murthy, Mujmmail Ahmed, Tanvir Ahmed, Seo-Kyoung Hwang, Rahul Grover, Rita Pozovskiy, Roger J. Liang, Andre Lima Queiroz, Justin C. Brown, Eileen P. White, Tobias Janowitz, Marcus D. Goncalves","doi":"10.1111/apha.14167","DOIUrl":"10.1111/apha.14167","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>To investigate systemic regulators of the cancer-associated cachexia syndrome (CACS) in a pre-clinical model for lung cancer with the goal to identify therapeutic targets for tissue wasting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using the Kras/Lkb1 (KL) mouse model, we found that CACS is associated with white adipose tissue (WAT) dysfunction that directly affects skeletal muscle homeostasis. WAT transcriptomes showed evidence of reduced adipogenesis, and, in agreement, we found low levels of circulating adiponectin. To preserve adipogenesis and restore adiponectin levels, we treated mice with the PPAR-γ agonist, rosiglitazone.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Rosiglitazone treatment increased serum adiponectin levels, delayed weight loss, and preserved skeletal muscle and adipose tissue mass, as compared to vehicle-treated mice. The preservation of muscle mass with rosiglitazone was associated with increases in AMPK and AKT activity. Similarly, activation of the adiponectin receptors in muscle cells increased AMPK activity, anabolic signaling, and protein synthesis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our data suggest that PPAR-γ agonists may be a useful adjuvant therapy to preserve tissue mass in lung cancer.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14167","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141079904","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}
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