Teodora V. Grigore, Malou Zuidscherwoude, Hannes Olauson, Joost G. Hoenderop
Aim
Klotho, a key component of the endocrine fibroblast growth factor receptor—fibroblast growth factor axis, is a multi-functional protein that impacts renal electrolyte handling. The physiological significance of Klotho will be highlighted in the regulation of calcium, phosphate, and potassium metabolism.
Methods
In this review, we compare several murine models with different renal targeted deletions of Klotho and the insights into the molecular and physiological function that these models offer.
Results
In vivo, Klotho deficiency is associated with severely impaired mineral metabolism, with consequences on growth, longevity and disease development. Additionally, we explore the perspectives of Klotho in renal pathology and vascular events, as well as potential Klotho treatment options.
Conclusion
This comprehensive review emphasizes the use of Klotho to shed light on deciphering the renal molecular in vivo mechanisms in electrolyte handling, as well as novel therapeutic interventions.
{"title":"Lessons from Klotho mouse models to understand mineral homeostasis","authors":"Teodora V. Grigore, Malou Zuidscherwoude, Hannes Olauson, Joost G. Hoenderop","doi":"10.1111/apha.14220","DOIUrl":"10.1111/apha.14220","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Klotho, a key component of the endocrine fibroblast growth factor receptor—fibroblast growth factor axis, is a multi-functional protein that impacts renal electrolyte handling. The physiological significance of Klotho will be highlighted in the regulation of calcium, phosphate, and potassium metabolism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this review, we compare several murine models with different renal targeted deletions of Klotho and the insights into the molecular and physiological function that these models offer.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In vivo, Klotho deficiency is associated with severely impaired mineral metabolism, with consequences on growth, longevity and disease development. Additionally, we explore the perspectives of Klotho in renal pathology and vascular events, as well as potential Klotho treatment options.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This comprehensive review emphasizes the use of Klotho to shed light on deciphering the renal molecular in vivo mechanisms in electrolyte handling, as well as novel therapeutic interventions.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 10","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14220","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142034617","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}
Nicolas O. Eskesen, Rasmus Kjøbsted, Jesper Bratz Birk, Nicolai S. Henriksen, Nicoline R. Andersen, Stine Ringholm, Henriette Pilegaard, Jørgen F. P. Wojtaszewski
Aim
AMP-activated protein kinase (AMPK) is activated during cellular energy perturbation. AMPK complexes are composed of three subunits and several variants of AMPK are expressed in skeletal muscle. The regulatory AMPKγ3 subunit is predominantly expressed in fast-twitch muscle fibers. A human AMPKγ3 R225W mutation has been described. The mutation increases the total pool of AMPK activity in cells cultured from R225W carrier muscle and is associated with increased glycogen levels in mature skeletal muscle. This led to the idea of AMPKγ3 being involved in the regulation of skeletal muscle glycogen levels. Evidence for this causative link remains to be provided.
Methods
We studied muscle biopsies from human carriers of the AMPKγ3 R225W mutation and we developed a novel AMPKγ3 R225W knock-in mouse model (KI HOM). Through in vitro, in situ, and ex vivo techniques, we investigated AMPK activity, AMPK function, and glycogen levels in skeletal muscle of humans and mice.
Results
In human carriers, the basal AMPKγ3-associated activity was reduced when assayed in the absence of exogenous AMP. No difference was observed when assayed under AMP saturation, which was supported by findings in muscle of KI HOM mice. Furthermore, effects of AICAR/muscle contraction on AMPKγ3-associated activity were absent in KI HOM muscle. Muscle glycogen levels were not affected by the mutation in human carriers or in KI HOM mice.
Conclusions
The AMPKγ3 R225W mutation does not impact the AMPK-associated activity in human skeletal muscle and the mutation is not linked to glycogen accumulation. The R225W mutation ablates the AMPKγ3-associated activation by AICAR/muscle contractions, presumably due to loss of nucleotide binding in the CBS 1 domain of AMPKγ3.
目的：AMP-活化蛋白激酶（AMPK）在细胞能量扰动时被激活。AMPK 复合物由三个亚基组成，在骨骼肌中表达多种 AMPK 变体。调节性 AMPKγ3 亚基主要在快肌纤维中表达。人类 AMPKγ3 R225W 突变已被描述。该突变增加了从 R225W 载体肌肉中培养的细胞中 AMPK 活性的总库，并与成熟骨骼肌中糖原水平的增加有关。这导致了 AMPKγ3 参与调节骨骼肌糖原水平的想法。这种因果关系的证据仍有待提供：我们研究了 AMPKγ3 R225W 突变人类携带者的肌肉活检组织，并开发了一种新型 AMPKγ3 R225W 基因敲入小鼠模型（KI HOM）。通过体外、原位和体外技术，我们研究了人和小鼠骨骼肌中的 AMPK 活性、AMPK 功能和糖原水平：结果：在人类载体中，在没有外源 AMP 的情况下，基础 AMPKγ3 相关活性降低。在 AMP 饱和状态下进行测定时未观察到差异，KI HOM 小鼠肌肉中的研究结果也证实了这一点。此外，在 KI HOM 肌肉中，AICAR/肌肉收缩对 AMPKγ3 相关活性没有影响。人类携带者和 KI HOM 小鼠的肌肉糖原水平不受突变的影响：结论：AMPKγ3 R225W突变不会影响人类骨骼肌中的AMPK相关活性，且该突变与糖原累积无关。R225W突变消除了AMPKγ3与AICAR/肌肉收缩相关的激活作用，这可能是由于AMPKγ3的CBS 1结构域失去了核苷酸结合。
{"title":"The human AMPKγ3 R225W mutation negatively impacts site-1 nucleotide binding and does not enhance basal AMPKγ3-associated activity nor glycogen production in human or mouse skeletal muscle","authors":"Nicolas O. Eskesen, Rasmus Kjøbsted, Jesper Bratz Birk, Nicolai S. Henriksen, Nicoline R. Andersen, Stine Ringholm, Henriette Pilegaard, Jørgen F. P. Wojtaszewski","doi":"10.1111/apha.14213","DOIUrl":"10.1111/apha.14213","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>AMP-activated protein kinase (AMPK) is activated during cellular energy perturbation. AMPK complexes are composed of three subunits and several variants of AMPK are expressed in skeletal muscle. The regulatory AMPKγ3 subunit is predominantly expressed in fast-twitch muscle fibers. A human AMPKγ3 R225W mutation has been described. The mutation increases the total pool of AMPK activity in cells cultured from R225W carrier muscle and is associated with increased glycogen levels in mature skeletal muscle. This led to the idea of AMPKγ3 being involved in the regulation of skeletal muscle glycogen levels. Evidence for this causative link remains to be provided.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We studied muscle biopsies from human carriers of the AMPKγ3 R225W mutation and we developed a novel AMPKγ3 R225W knock-in mouse model (KI HOM). Through in vitro, in situ, and ex vivo techniques, we investigated AMPK activity, AMPK function, and glycogen levels in skeletal muscle of humans and mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In human carriers, the basal AMPKγ3-associated activity was reduced when assayed in the absence of exogenous AMP. No difference was observed when assayed under AMP saturation, which was supported by findings in muscle of KI HOM mice. Furthermore, effects of AICAR/muscle contraction on AMPKγ3-associated activity were absent in KI HOM muscle. Muscle glycogen levels were not affected by the mutation in human carriers or in KI HOM mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The AMPKγ3 R225W mutation does not impact the AMPK-associated activity in human skeletal muscle and the mutation is not linked to glycogen accumulation. The R225W mutation ablates the AMPKγ3-associated activation by AICAR/muscle contractions, presumably due to loss of nucleotide binding in the CBS 1 domain of AMPKγ3.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 10","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14213","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142015654","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>Recently, a colleague asked after a lecture about a fancy diagram where the axis designation was not clear to him and the discussion about that raised a few interesting thoughts about that specific matter. Physiological knowledge is often taught at university seminars and in textbooks with the help of diagrams. A very important first step when discussing diagrams is to clarify which physical, physiological variable at what scale and unit is represented on which axis. Examples of typical classical low dimensional diagrams in physiology publications in Acta Physiologica might be blood pressure over time,<span><sup>1</sup></span> infarct size as percentage of Left ventricular mass depending on genotype<span><sup>2</sup></span> or urine excretion in volume per time depending on diet.<span><sup>3</sup></span> Not knowing the axes of the classical diagrams, they might as well be “just” pieces of fancy modern art.</p><p>We strongly believe that graphical representation of complex data—for example, as diagrams—is essential in communicating them. However, for specific types of diagrams, the understanding and interpretation of their content is more complex, and requires more explanation than classical diagrams. Specifically, we refer to the graphical representation of high-dimensional data, which have, in recent years, played an increasing role in new understandings of physiological processes.</p><p>To visualize data a reduction of dimensionality is often applied. A simple example is a black/white photograph of a colorful moving three dimensional object. The snapshot “eliminated” the dimension time and the optical projection on a plane in the camera eliminated one dimension in space and the gray values just reduced the spectral information to an intensity value on the photograph. Although the photograph does not represent the compete “dataset” it gives us in most cases a good impression about the situation captured by the photographer.</p><p>Times have changed.</p><p>To describe the “amount” of data obtained for a study in the 1960s one physiologist for example referred to the length of the paper of plots of curved of blood pressure measurements he was analyzing for one particular study. Compared with that amount of data back then we are nowadays faced with a completely new situation. With the development of technology we have to handle a huge amount of data today. For example, in recent studies with single RNAseq data scientists obtained with thousands of expression values for single genes for each of thousands of single cells at multiple experimental points and possibly for multiple interventions. Obviously you cannot produce a meaningful simple classical plot with thousands of dimensions.</p><p>In order to make sense out of the hugely dimensional data, researches can employ methods for the reduction of dimensionality. One classical methods would be to employ the so called principal component analysis (PCA). This linear method projects the data onto a
{"title":"How to visualize high-dimensional data","authors":"Ralf Mrowka, Ralf Schmauder","doi":"10.1111/apha.14219","DOIUrl":"10.1111/apha.14219","url":null,"abstract":"<p>Recently, a colleague asked after a lecture about a fancy diagram where the axis designation was not clear to him and the discussion about that raised a few interesting thoughts about that specific matter. Physiological knowledge is often taught at university seminars and in textbooks with the help of diagrams. A very important first step when discussing diagrams is to clarify which physical, physiological variable at what scale and unit is represented on which axis. Examples of typical classical low dimensional diagrams in physiology publications in Acta Physiologica might be blood pressure over time,<span><sup>1</sup></span> infarct size as percentage of Left ventricular mass depending on genotype<span><sup>2</sup></span> or urine excretion in volume per time depending on diet.<span><sup>3</sup></span> Not knowing the axes of the classical diagrams, they might as well be “just” pieces of fancy modern art.</p><p>We strongly believe that graphical representation of complex data—for example, as diagrams—is essential in communicating them. However, for specific types of diagrams, the understanding and interpretation of their content is more complex, and requires more explanation than classical diagrams. Specifically, we refer to the graphical representation of high-dimensional data, which have, in recent years, played an increasing role in new understandings of physiological processes.</p><p>To visualize data a reduction of dimensionality is often applied. A simple example is a black/white photograph of a colorful moving three dimensional object. The snapshot “eliminated” the dimension time and the optical projection on a plane in the camera eliminated one dimension in space and the gray values just reduced the spectral information to an intensity value on the photograph. Although the photograph does not represent the compete “dataset” it gives us in most cases a good impression about the situation captured by the photographer.</p><p>Times have changed.</p><p>To describe the “amount” of data obtained for a study in the 1960s one physiologist for example referred to the length of the paper of plots of curved of blood pressure measurements he was analyzing for one particular study. Compared with that amount of data back then we are nowadays faced with a completely new situation. With the development of technology we have to handle a huge amount of data today. For example, in recent studies with single RNAseq data scientists obtained with thousands of expression values for single genes for each of thousands of single cells at multiple experimental points and possibly for multiple interventions. Obviously you cannot produce a meaningful simple classical plot with thousands of dimensions.</p><p>In order to make sense out of the hugely dimensional data, researches can employ methods for the reduction of dimensionality. One classical methods would be to employ the so called principal component analysis (PCA). This linear method projects the data onto a","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 10","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14219","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141998964","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>In the current issue of <i>Acta Physiologica</i>, Harter et al.<span><sup>1</sup></span> provide novel evidence for soluble adenylyl cyclase (sAC), a ubiquitous regulatory enzyme present in the cytosol of almost all cells, acting as a sensor for intracellular pH (pHi) in fish red blood cells. Harter and coworkers also propose an acid–base sensing mechanism that acts to protect adequate oxygen delivery in face of alkalosis or acidosis, and therefore may be of considerable functional importance.</p><p>Erythrocytes are very specialized cells, packed with hemoglobin, that provide for oxygen delivery to the tissues. In humans and other mammals, the nucleus and mitochondria are lost as the erythrocytes mature, and ATP is mostly derived from glycolysis.<span><sup>2</sup></span> This is not the case in other vertebrates where the red blood cells from birds, reptiles, amphibians, and fish retain their nucleus and capacity for mitochondrial respiration. In contrast to the other vertebrates, the mammalian red blood cell is therefore often viewed as a simple cell, a bag of hemoglobin. However, there is mounting evidence that mammalian red blood cells can rapidly restore pHi upon acid–base disturbances by activating the chloride-bicarbonate exchanger (or anion exchanger, AE1).<span><sup>3</sup></span> In addition to safeguarding the metabolic processes within the erythrocyte, the protection of pHi has important implications for oxygen delivery as oxygen affinity of the hemoglobin is sensitive to pHi through the Bohr effect.<span><sup>4</sup></span> This is the case for all vertebrates, but perhaps particularly so in fish. In addition to having rather large Bohr effects, fish are endowed with the so-called Root effect, named after its discoverer Raymond W. Root, who demonstrated that acidosis not only right-shifts the blood oxygen equilibrium curve, that is, lowers oxygen affinity, but also reduces the capacity for oxygen binding, such that part of the hemoglobin is unable to bind oxygen.<span><sup>5</sup></span></p><p>The Root effect may, at least at first, seem maladaptive, but provides for the possibility of creating very high partial pressures of oxygen when local acidification forces the oxygen to separate from the hemoglobin. This is exploited in the swim bladder of many fish species where local acidification of the blood in a specialized gas gland with a <i>rete mirabile</i> elicits extraordinarily high partial pressures of oxygen that then fills the swim-bladder and enables exquisite control of buoyancy.<span><sup>6</sup></span> Moreover, the Root effect also plays an important role in delivering oxygen to the eyes of numerous groups of fishes.<span><sup>6</sup></span> Here, specialized mechanisms for acidification provide partial pressures of oxygen in excess of 500 mmHg that enable diffusion into the avascular retina.<span><sup>7</sup></span> To allow fish to exploit the Root effect in these specialized structures, it is essential that the acidifi
{"title":"Rapid restoration of intracellular pH in erythrocytes protects oxygen transport","authors":"Tobias Wang, Michael Berenbrink","doi":"10.1111/apha.14218","DOIUrl":"10.1111/apha.14218","url":null,"abstract":"<p>In the current issue of <i>Acta Physiologica</i>, Harter et al.<span><sup>1</sup></span> provide novel evidence for soluble adenylyl cyclase (sAC), a ubiquitous regulatory enzyme present in the cytosol of almost all cells, acting as a sensor for intracellular pH (pHi) in fish red blood cells. Harter and coworkers also propose an acid–base sensing mechanism that acts to protect adequate oxygen delivery in face of alkalosis or acidosis, and therefore may be of considerable functional importance.</p><p>Erythrocytes are very specialized cells, packed with hemoglobin, that provide for oxygen delivery to the tissues. In humans and other mammals, the nucleus and mitochondria are lost as the erythrocytes mature, and ATP is mostly derived from glycolysis.<span><sup>2</sup></span> This is not the case in other vertebrates where the red blood cells from birds, reptiles, amphibians, and fish retain their nucleus and capacity for mitochondrial respiration. In contrast to the other vertebrates, the mammalian red blood cell is therefore often viewed as a simple cell, a bag of hemoglobin. However, there is mounting evidence that mammalian red blood cells can rapidly restore pHi upon acid–base disturbances by activating the chloride-bicarbonate exchanger (or anion exchanger, AE1).<span><sup>3</sup></span> In addition to safeguarding the metabolic processes within the erythrocyte, the protection of pHi has important implications for oxygen delivery as oxygen affinity of the hemoglobin is sensitive to pHi through the Bohr effect.<span><sup>4</sup></span> This is the case for all vertebrates, but perhaps particularly so in fish. In addition to having rather large Bohr effects, fish are endowed with the so-called Root effect, named after its discoverer Raymond W. Root, who demonstrated that acidosis not only right-shifts the blood oxygen equilibrium curve, that is, lowers oxygen affinity, but also reduces the capacity for oxygen binding, such that part of the hemoglobin is unable to bind oxygen.<span><sup>5</sup></span></p><p>The Root effect may, at least at first, seem maladaptive, but provides for the possibility of creating very high partial pressures of oxygen when local acidification forces the oxygen to separate from the hemoglobin. This is exploited in the swim bladder of many fish species where local acidification of the blood in a specialized gas gland with a <i>rete mirabile</i> elicits extraordinarily high partial pressures of oxygen that then fills the swim-bladder and enables exquisite control of buoyancy.<span><sup>6</sup></span> Moreover, the Root effect also plays an important role in delivering oxygen to the eyes of numerous groups of fishes.<span><sup>6</sup></span> Here, specialized mechanisms for acidification provide partial pressures of oxygen in excess of 500 mmHg that enable diffusion into the avascular retina.<span><sup>7</sup></span> To allow fish to exploit the Root effect in these specialized structures, it is essential that the acidifi","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 10","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14218","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141986836","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}
Mingyan Zhou, Catherine Li, Frances L. Byrne, Calum S. Vancuylenburg, Ellen M. Olzomer, Adam Hargreaves, Lindsay E. Wu, Nicholas A. Shackel, Webster L. Santos, Kyle L. Hoehn
Background and Aim
Metabolic dysfunction-associated steatohepatitis (MASH) is a metabolic disorder with limited treatment options. The thyroid hormone receptor (THR)-β agonist resmetirom/MGL-3196 (MGL) increases liver fat oxidation and has been approved for treating adult MASH. However, over 60% of patients receiving MGL treatment do not achieve MASH resolution. Therefore, we investigated the potential for combination therapy of MGL with the mitochondrial uncoupler BAM15 to improve fatty liver disease outcomes in the GAN mouse model of MASH.
Methods
C57BL/6J male mice were fed GAN diet for 38 weeks before stratification and randomization to treatments including MGL, BAM15, MGL + BAM15, or no drug control for 8 weeks. Treatments were admixed in diet and mice were pair-fed to control for drug intake. Treatment effectiveness was assessed by body weight, body composition, energy expenditure, glucose tolerance, tissue lipid content, and histological analyses.
Results
MGL + BAM15 treatment resulted in better efficacy versus GAN control mice than either monotherapy in the context of energy expenditure, liver fat loss, glucose control, and fatty liver disease activity score. Improvements in ALT, liver mass, and plasma cholesterol were primarily driven by MGL, while improvements in body fat were primarily driven by BAM15. No treatments altered liver fibrosis.
Conclusions
MGL + BAM15 treatment had overall better efficacy to improve metabolic outcomes in mice fed GAN diet than either monotherapy alone. These data warrant further investigation into combination therapies of THR-β agonists and mitochondrial uncouplers for the potential treatment of disorders related to fatty liver, obesity, and insulin resistance.
{"title":"Beneficial effects of MGL-3196 and BAM15 combination in a mouse model of fatty liver disease","authors":"Mingyan Zhou, Catherine Li, Frances L. Byrne, Calum S. Vancuylenburg, Ellen M. Olzomer, Adam Hargreaves, Lindsay E. Wu, Nicholas A. Shackel, Webster L. Santos, Kyle L. Hoehn","doi":"10.1111/apha.14217","DOIUrl":"10.1111/apha.14217","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aim</h3>\u0000 \u0000 <p>Metabolic dysfunction-associated steatohepatitis (MASH) is a metabolic disorder with limited treatment options. The thyroid hormone receptor (THR)-β agonist resmetirom/MGL-3196 (MGL) increases liver fat oxidation and has been approved for treating adult MASH. However, over 60% of patients receiving MGL treatment do not achieve MASH resolution. Therefore, we investigated the potential for combination therapy of MGL with the mitochondrial uncoupler BAM15 to improve fatty liver disease outcomes in the GAN mouse model of MASH.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>C57BL/6J male mice were fed GAN diet for 38 weeks before stratification and randomization to treatments including MGL, BAM15, MGL + BAM15, or no drug control for 8 weeks. Treatments were admixed in diet and mice were pair-fed to control for drug intake. Treatment effectiveness was assessed by body weight, body composition, energy expenditure, glucose tolerance, tissue lipid content, and histological analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>MGL + BAM15 treatment resulted in better efficacy versus GAN control mice than either monotherapy in the context of energy expenditure, liver fat loss, glucose control, and fatty liver disease activity score. Improvements in ALT, liver mass, and plasma cholesterol were primarily driven by MGL, while improvements in body fat were primarily driven by BAM15. No treatments altered liver fibrosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>MGL + BAM15 treatment had overall better efficacy to improve metabolic outcomes in mice fed GAN diet than either monotherapy alone. These data warrant further investigation into combination therapies of THR-β agonists and mitochondrial uncouplers for the potential treatment of disorders related to fatty liver, obesity, and insulin resistance.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 10","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14217","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141994829","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>In the current issue of <i>Acta Physiologica</i>, Hamilton et al. investigate in a mouse model of urinary tract infection (UTI) the therapeutic value of elevated fluid intake for the risk of ascension to pyelonephritis, after cystitis has been established.<span><sup>1</sup></span> Urinary tract infection is considered the most common bacterial infection causing immense burden to affected patients and healthcare systems.<span><sup>2</sup></span> Women are more frequently affected than men. It is estimated that 50% of women will be affected at least once during their lifetime, and 30%–40% suffer from recurrent UTI. Costs are estimated to reach $2 billion per year in the USA.<span><sup>2</sup></span> Confinement to the lower urinary tract (cystitis) is considered a benign disease; however, the infection may ascend to the kidney (pyelonephritis) or in the worst case cause bacteremia and sepsis (urosepsis).<span><sup>2, 3</sup></span> The most effective therapy is antibiotic.<span><sup>4</sup></span> However, with regard to prevalence and further provocation of resistances, non-antibiotic treatment options are of growing importance.<span><sup>4</sup></span> Major non-antibiotic recommendations are cranberry products and elevated fluid intake.<span><sup>4</sup></span> While there is evidence and recommendation for increased fluid intake for prevention of recurrent UTI, it is unclear, whether this also helps to reduce the risk of ascension to pyelonephritis once cystitis is established. The latter question has been investigated by Hamilton et al.<span><sup>1</sup></span> The authors found that increasing fluid intake and thereby urine production, not only failed to reduce the risk for ascension but substantially augmented the occurrence and severity of pyelonephritis.</p><p>The urinary tract is not only open to the body surface, but the orifice anatomically close to the microbiotic reservoir of the gastrointestinal tract. Accordingly, UTI is a constant battlefield between bacteria and host, featuring a wide array of mechanisms on both the side of bacterial virulence and host defense.<span><sup>3, 5</sup></span> By far (80%) the most common pathogens causing UTI are uropathogenic <i>Escherichia coli</i> (UPEC).<span><sup>3, 5</sup></span> Most virulence factors of UPEC are genetically clustered in pathogenicity-associated islands<span><sup>3</sup></span> and include mechanisms for attachment to the urinary epithelium (adhesins), for survival and immune escape, as well as pathogenic toxins. The most important adhesins are fimbriae or pili,<span><sup>3, 5</sup></span> multimeric proteins assembled to form hair-like structures protruding from the outer membrane of the bacterium. Several types have been described (Type-1-, P-, FIC-, S-, curli-fimbria, and Dr-adhesin). Type-1-fimbria attach to mannose-rich polysaccharides on the surface of the urothelium, allowing attachment to and possibly invasion of the bladder wall and accordingly are important for cys
{"title":"Elevated fluid intake and the risk for pyelonephritis in urinary tract infection","authors":"Armin Just","doi":"10.1111/apha.14216","DOIUrl":"10.1111/apha.14216","url":null,"abstract":"<p>In the current issue of <i>Acta Physiologica</i>, Hamilton et al. investigate in a mouse model of urinary tract infection (UTI) the therapeutic value of elevated fluid intake for the risk of ascension to pyelonephritis, after cystitis has been established.<span><sup>1</sup></span> Urinary tract infection is considered the most common bacterial infection causing immense burden to affected patients and healthcare systems.<span><sup>2</sup></span> Women are more frequently affected than men. It is estimated that 50% of women will be affected at least once during their lifetime, and 30%–40% suffer from recurrent UTI. Costs are estimated to reach $2 billion per year in the USA.<span><sup>2</sup></span> Confinement to the lower urinary tract (cystitis) is considered a benign disease; however, the infection may ascend to the kidney (pyelonephritis) or in the worst case cause bacteremia and sepsis (urosepsis).<span><sup>2, 3</sup></span> The most effective therapy is antibiotic.<span><sup>4</sup></span> However, with regard to prevalence and further provocation of resistances, non-antibiotic treatment options are of growing importance.<span><sup>4</sup></span> Major non-antibiotic recommendations are cranberry products and elevated fluid intake.<span><sup>4</sup></span> While there is evidence and recommendation for increased fluid intake for prevention of recurrent UTI, it is unclear, whether this also helps to reduce the risk of ascension to pyelonephritis once cystitis is established. The latter question has been investigated by Hamilton et al.<span><sup>1</sup></span> The authors found that increasing fluid intake and thereby urine production, not only failed to reduce the risk for ascension but substantially augmented the occurrence and severity of pyelonephritis.</p><p>The urinary tract is not only open to the body surface, but the orifice anatomically close to the microbiotic reservoir of the gastrointestinal tract. Accordingly, UTI is a constant battlefield between bacteria and host, featuring a wide array of mechanisms on both the side of bacterial virulence and host defense.<span><sup>3, 5</sup></span> By far (80%) the most common pathogens causing UTI are uropathogenic <i>Escherichia coli</i> (UPEC).<span><sup>3, 5</sup></span> Most virulence factors of UPEC are genetically clustered in pathogenicity-associated islands<span><sup>3</sup></span> and include mechanisms for attachment to the urinary epithelium (adhesins), for survival and immune escape, as well as pathogenic toxins. The most important adhesins are fimbriae or pili,<span><sup>3, 5</sup></span> multimeric proteins assembled to form hair-like structures protruding from the outer membrane of the bacterium. Several types have been described (Type-1-, P-, FIC-, S-, curli-fimbria, and Dr-adhesin). Type-1-fimbria attach to mannose-rich polysaccharides on the surface of the urothelium, allowing attachment to and possibly invasion of the bladder wall and accordingly are important for cys","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14216","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141905103","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}
Osvaldo Rivera-Gonzalez, Megumi F. Mills, Bridget D. Konadu, Natalie A. Wilson, Hayley A. Murphy, Madison K. Newberry, Kelly A. Hyndman, Michael R. Garrett, David J. Webb, Joshua S. Speed
Aims
Endothelin-1 (ET-1) is elevated in patients with obesity and adipose tissue of obese mice fed high-fat diet (HFD); however, its contribution to the pathophysiology of obesity is not fully understood. Genetic loss of endothelin type B receptors (ETB) improves insulin sensitivity in rats and leads to increased circulating adiponectin, suggesting that ETB activation on adipocytes may contribute to obesity pathophysiology. We hypothesized that elevated ET-1 in obesity promotes insulin resistance by reducing the secretion of insulin sensitizing adipokines, via ETB receptor.
Methods
Male adipocyte-specific ETB receptor knockout (adETBKO), overexpression (adETBOX), or control littermates were fed either normal diet (NMD) or high-fat diet (HFD) for 8 weeks.
Results
RNA-sequencing of epididymal adipose (eWAT) indicated differential expression of over 5500 genes (p < 0.05) in HFD compared to NMD controls, and changes in 1077 of these genes were attenuated in HFD adETBKO mice. KEGG analysis indicated significant increase in metabolic signaling pathway. HFD adETBKO mice had significantly improved glucose and insulin tolerance compared to HFD control. In addition, adETBKO attenuated changes in plasma adiponectin, insulin, and leptin that is observed in HFD versus NMD control mice. Treatment of primary adipocytes with ET-1 caused a reduction in adiponectin production that was attenuated in cells pretreated with an ETB antagonist.
Conclusion
These data indicate elevated ET-1 in adipose tissue of mice fed HFD inhibits adiponectin production and causes insulin resistance through activation of the ETB receptor on adipocytes.
{"title":"Adipocyte endothelin B receptor activation inhibits adiponectin production and causes insulin resistance in obese mice","authors":"Osvaldo Rivera-Gonzalez, Megumi F. Mills, Bridget D. Konadu, Natalie A. Wilson, Hayley A. Murphy, Madison K. Newberry, Kelly A. Hyndman, Michael R. Garrett, David J. Webb, Joshua S. Speed","doi":"10.1111/apha.14214","DOIUrl":"10.1111/apha.14214","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Endothelin-1 (ET-1) is elevated in patients with obesity and adipose tissue of obese mice fed high-fat diet (HFD); however, its contribution to the pathophysiology of obesity is not fully understood. Genetic loss of endothelin type B receptors (ET<sub>B</sub>) improves insulin sensitivity in rats and leads to increased circulating adiponectin, suggesting that ET<sub>B</sub> activation on adipocytes may contribute to obesity pathophysiology. We hypothesized that elevated ET-1 in obesity promotes insulin resistance by reducing the secretion of insulin sensitizing adipokines, via ET<sub>B</sub> receptor.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Male adipocyte-specific ET<sub>B</sub> receptor knockout (adET<sub>B</sub>KO), overexpression (adET<sub>B</sub>OX), or control littermates were fed either normal diet (NMD) or high-fat diet (HFD) for 8 weeks.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>RNA-sequencing of epididymal adipose (eWAT) indicated differential expression of over 5500 genes (<i>p</i> < 0.05) in HFD compared to NMD controls, and changes in 1077 of these genes were attenuated in HFD adET<sub>B</sub>KO mice. KEGG analysis indicated significant increase in metabolic signaling pathway. HFD adET<sub>B</sub>KO mice had significantly improved glucose and insulin tolerance compared to HFD control. In addition, adET<sub>B</sub>KO attenuated changes in plasma adiponectin, insulin, and leptin that is observed in HFD versus NMD control mice. Treatment of primary adipocytes with ET-1 caused a reduction in adiponectin production that was attenuated in cells pretreated with an ET<sub>B</sub> antagonist.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These data indicate elevated ET-1 in adipose tissue of mice fed HFD inhibits adiponectin production and causes insulin resistance through activation of the ET<sub>B</sub> receptor on adipocytes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 10","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878045","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}
<p>Sir Isaac Newton's 1686 “Philosophiae Naturalis Principia Mathematica”<span><sup>1</sup></span> has repeatedly, and notably by biomedical scientists, been cited as the most influential single piece of scientific writing ever produced<span><sup>2</sup></span>: Movement, the laws pertaining to which are laid down in this work, is a fundamental characteristic of life, and as such, essential for various biological functions. Thus, life scientists across disciplines study processes that involve changes in location, from a molecular level to that of groups of complex organisms.</p><p>Most complex organisms move from one place to another—in search for nutrition, new habitats, mates or to escape predators. Importantly, humans can convey complex information through speech, while animals must often also move their bodies to communicate. This is highly relevant for animal models with respect to translational physiology and has inspired numerous creative solutions by bioscientists to enable the study of, for example, the brain during movement.<span><sup>3</sup></span> Translational biomedical research—still so, and across disciplines—relies on animal models.<span><sup>4, 5</sup></span> When cognitive processes are studied, free movement is, despite the additional challenge of controlling or monitoring sensory input in a mobile subject, a prerequisite, as, for example, crucial behavioral patterns can only be observed and studied during free movement.<span><sup>3</sup></span> Nevertheless, telemetry-based studies in freely moving animals are extremely valuable for many more areas of application in physiology, for example in cardiovascular research,<span><sup>6</sup></span> studies of vegetative function and cardiovascular reflex responses<span><sup>7</sup></span> or renal function.<span><sup>8</sup></span> This is exemplified in recent studies: Wu et al. show the relevance of VIP+ miRNAs in sensory processing, olfactory neural activity, and “successful” olfactory function in rodents.<span><sup>9</sup></span> Toledo et al<span><sup>10</sup></span> did not primarily observe behavioral changes; however, the modulating effects of RVLM-C1 neurons on cardiorespiratory function at rest had never before studied in conscious, adult animals able to move freely, which adds great relevance to their results. As Pilowsky remarks, one crucial advantage of this study in awake animals, with reflexes intact, is the possibility to study changes in the sleep–wake cycle and normal breathing patterns, while, however, the effects of reflexes on the phenomena observed confounds the results and need to be taken into account critically.<span><sup>11</sup></span> Baseline heart rate recordings at rest in freely moving animals<span><sup>12</sup></span> are of particular value from a translational perspective, as they more closely resemble the natural situation.</p><p>At the cellular level, movement occurs during cell division, intracellular transport, and the functioning of immune cel
{"title":"Mobility, motion, and exercise","authors":"Pontus B. Persson, Anja Bondke Persson","doi":"10.1111/apha.14210","DOIUrl":"10.1111/apha.14210","url":null,"abstract":"<p>Sir Isaac Newton's 1686 “Philosophiae Naturalis Principia Mathematica”<span><sup>1</sup></span> has repeatedly, and notably by biomedical scientists, been cited as the most influential single piece of scientific writing ever produced<span><sup>2</sup></span>: Movement, the laws pertaining to which are laid down in this work, is a fundamental characteristic of life, and as such, essential for various biological functions. Thus, life scientists across disciplines study processes that involve changes in location, from a molecular level to that of groups of complex organisms.</p><p>Most complex organisms move from one place to another—in search for nutrition, new habitats, mates or to escape predators. Importantly, humans can convey complex information through speech, while animals must often also move their bodies to communicate. This is highly relevant for animal models with respect to translational physiology and has inspired numerous creative solutions by bioscientists to enable the study of, for example, the brain during movement.<span><sup>3</sup></span> Translational biomedical research—still so, and across disciplines—relies on animal models.<span><sup>4, 5</sup></span> When cognitive processes are studied, free movement is, despite the additional challenge of controlling or monitoring sensory input in a mobile subject, a prerequisite, as, for example, crucial behavioral patterns can only be observed and studied during free movement.<span><sup>3</sup></span> Nevertheless, telemetry-based studies in freely moving animals are extremely valuable for many more areas of application in physiology, for example in cardiovascular research,<span><sup>6</sup></span> studies of vegetative function and cardiovascular reflex responses<span><sup>7</sup></span> or renal function.<span><sup>8</sup></span> This is exemplified in recent studies: Wu et al. show the relevance of VIP+ miRNAs in sensory processing, olfactory neural activity, and “successful” olfactory function in rodents.<span><sup>9</sup></span> Toledo et al<span><sup>10</sup></span> did not primarily observe behavioral changes; however, the modulating effects of RVLM-C1 neurons on cardiorespiratory function at rest had never before studied in conscious, adult animals able to move freely, which adds great relevance to their results. As Pilowsky remarks, one crucial advantage of this study in awake animals, with reflexes intact, is the possibility to study changes in the sleep–wake cycle and normal breathing patterns, while, however, the effects of reflexes on the phenomena observed confounds the results and need to be taken into account critically.<span><sup>11</sup></span> Baseline heart rate recordings at rest in freely moving animals<span><sup>12</sup></span> are of particular value from a translational perspective, as they more closely resemble the natural situation.</p><p>At the cellular level, movement occurs during cell division, intracellular transport, and the functioning of immune cel","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14210","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858372","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}
Lorenzo Marcucci, Leonardo Nogara, Marta Canato, Elena Germinario, Anna Raffaello, Michela Carraro, Paolo Bernardi, Laura Pietrangelo, Simona Boncompagni, Feliciano Protasi, Nazareno Paolocci, Carlo Reggiani
Aim
Parvalbumin (PV) is a primary calcium buffer in mouse fast skeletal muscle fibers. Previous work showed that PV ablation has a limited impact on cytosolic Ca2+ ([Ca2+]cyto) transients and contractile response, while it enhances mitochondrial density and mitochondrial matrix-free calcium concentration ([Ca2+]mito). Here, we aimed to quantitatively test the hypothesis that mitochondria act to compensate for PV deficiency.
Methods
We determined the free Ca2+ redistribution during a 2 s 60 Hz tetanic stimulation in the sarcoplasmic reticulum, cytosol, and mitochondria. Via a reaction–diffusion Ca2+ model, we quantitatively evaluated mitochondrial uptake and storage capacity requirements to compensate for PV lack and analyzed possible extracellular export.
Results
[Ca2+]mito during tetanic stimulation is greater in knock-out (KO) (1362 ± 392 nM) than in wild-type (WT) (855 ± 392 nM), p < 0.05. Under the assumption of a non-linear intramitochondrial buffering, the model predicts an accumulation of 725 μmoles/Lfiber (buffering ratio 1:11 000) in KO, much higher than in WT (137 μmoles/Lfiber, ratio 1:4500). The required transport rate via mitochondrial calcium uniporter (MCU) reaches 3 mM/s, compatible with available literature. TEM images of calcium entry units and Mn2+ quenching showed a greater capacity of store-operated calcium entry in KO compared to WT. However, levels of [Ca2+]cyto during tetanic stimulation were not modulated to variations of extracellular calcium.
Conclusions
The model-based analysis of experimentally determined calcium distribution during tetanic stimulation showed that mitochondria can act as a buffer to compensate for the lack of PV. This result contributes to a better understanding of mitochondria's role in modulating [Ca2+]cyto in skeletal muscle fibers.
{"title":"Mitochondria can substitute for parvalbumin to lower cytosolic calcium levels in the murine fast skeletal muscle","authors":"Lorenzo Marcucci, Leonardo Nogara, Marta Canato, Elena Germinario, Anna Raffaello, Michela Carraro, Paolo Bernardi, Laura Pietrangelo, Simona Boncompagni, Feliciano Protasi, Nazareno Paolocci, Carlo Reggiani","doi":"10.1111/apha.14208","DOIUrl":"10.1111/apha.14208","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Parvalbumin (PV) is a primary calcium buffer in mouse fast skeletal muscle fibers. Previous work showed that PV ablation has a limited impact on cytosolic Ca<sup>2+</sup> ([Ca<sup>2+</sup>]<sub>cyto</sub>) transients and contractile response, while it enhances mitochondrial density and mitochondrial matrix-free calcium concentration ([Ca<sup>2+</sup>]<sub>mito</sub>). Here, we aimed to quantitatively test the hypothesis that mitochondria act to compensate for PV deficiency.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We determined the free Ca<sup>2+</sup> redistribution during a 2 s 60 Hz tetanic stimulation in the sarcoplasmic reticulum, cytosol, and mitochondria. Via a reaction–diffusion Ca<sup>2+</sup> model, we quantitatively evaluated mitochondrial uptake and storage capacity requirements to compensate for PV lack and analyzed possible extracellular export.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>[Ca<sup>2+</sup>]<sub>mito</sub> during tetanic stimulation is greater in knock-out (KO) (1362 ± 392 nM) than in wild-type (WT) (855 ± 392 nM), <i>p</i> < 0.05. Under the assumption of a non-linear intramitochondrial buffering, the model predicts an accumulation of 725 μmoles/<i>L</i>\u0000 <sub>fiber</sub> (buffering ratio 1:11 000) in KO, much higher than in WT (137 μmoles/<i>L</i>\u0000 <sub>fiber</sub>, ratio 1:4500). The required transport rate via mitochondrial calcium uniporter (MCU) reaches 3 mM/s, compatible with available literature. TEM images of calcium entry units and Mn<sup>2+</sup> quenching showed a greater capacity of store-operated calcium entry in KO compared to WT. However, levels of [Ca<sup>2+</sup>]<sub>cyto</sub> during tetanic stimulation were not modulated to variations of extracellular calcium.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The model-based analysis of experimentally determined calcium distribution during tetanic stimulation showed that mitochondria can act as a buffer to compensate for the lack of PV. This result contributes to a better understanding of mitochondria's role in modulating [Ca<sup>2+</sup>]<sub>cyto</sub> in skeletal muscle fibers.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14208","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141791377","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}
Eva Musiol, Tobias Fromme, Julia Hau, Antonella Di Pizio, Martin Klingenspor
Aim
Mitochondrial uncoupling protein 1 (UCP1) is a unique protein of brown adipose tissue. Upon activation by free fatty acids, UCP1 facilitates a thermogenic net proton flux across the mitochondrial inner membrane. Non-complexed purine nucleotides inhibit this fatty acid-induced activity of UCP1. The most available data have been generated from rodent model systems. In light of its role as a putative pharmacological target for treating metabolic disease, in-depth analyses of human UCP1 activity, regulation, and structural features are essential.
Methods
In the present study, we established a doxycycline-regulated cell model with inducible human or murine UCP1 expression and conducted functional studies using respirometry comparing wild-type and mutant variants of human UCP1.
Results
We demonstrate that human and mouse UCP1 exhibit similar specific fatty acid-induced activity but a different inhibitory potential of purine nucleotides. Mutagenesis of non-conserved residues in human UCP1 revealed structural components in α-helix 56 and α-helix 6 crucial for uncoupling function.
Conclusion
Comparative studies of human UCP1 with other orthologs can provide new insights into the structure–function relationship for this mitochondrial carrier and will be instrumental in searching for new activators.
{"title":"Comparative functional analysis reveals differential nucleotide sensitivity between human and mouse UCP1","authors":"Eva Musiol, Tobias Fromme, Julia Hau, Antonella Di Pizio, Martin Klingenspor","doi":"10.1111/apha.14209","DOIUrl":"10.1111/apha.14209","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Mitochondrial uncoupling protein 1 (UCP1) is a unique protein of brown adipose tissue. Upon activation by free fatty acids, UCP1 facilitates a thermogenic net proton flux across the mitochondrial inner membrane. Non-complexed purine nucleotides inhibit this fatty acid-induced activity of UCP1. The most available data have been generated from rodent model systems. In light of its role as a putative pharmacological target for treating metabolic disease, in-depth analyses of human UCP1 activity, regulation, and structural features are essential.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In the present study, we established a doxycycline-regulated cell model with inducible human or murine UCP1 expression and conducted functional studies using respirometry comparing wild-type and mutant variants of human UCP1.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We demonstrate that human and mouse UCP1 exhibit similar specific fatty acid-induced activity but a different inhibitory potential of purine nucleotides. Mutagenesis of non-conserved residues in human UCP1 revealed structural components in α-helix 56 and α-helix 6 crucial for uncoupling function.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Comparative studies of human UCP1 with other orthologs can provide new insights into the structure–function relationship for this mitochondrial carrier and will be instrumental in searching for new activators.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14209","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141786470","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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