Journal of Physiology-London最新文献

{"title":"Inducible deletion of endothelial cell Efnb2 delays capillary regeneration and attenuates myofibre reinnervation following myotoxin injury in mice.","authors":"Aaron B Morton, Nicole L Jacobsen, Alexandra R Diller, Jacob A Kendra, Shadi Golpasandi, D D W Cornelison, Steven S Segal","doi":"10.1113/JP285402","DOIUrl":"https://doi.org/10.1113/JP285402","url":null,"abstract":"<p><p>Acute injury of skeletal muscle disrupts myofibres, microvessels and motor innervation. Myofibre regeneration is well characterized, however its relationship with the regeneration of microvessels and motor nerves is undefined. Endothelial cell (EC) ephrin-B2 (Efnb2) is required for angiogenesis during embryonic development and promotes neurovascular regeneration in the adult. We hypothesized that, following acute injury to skeletal muscle, loss of EC Efnb2 would impair microvascular regeneration and the recovery of neuromuscular junction (NMJ) integrity. Mice (aged 3-6 months) were bred for EC-specific conditional knockout (CKO) of Efnb2 following tamoxifen injection with non-injected CKO mice as controls (CON). The gluteus maximus, tibialis anterior or extensor digitorum longus muscle was then injured with local injection of BaCl₂. Intravascular staining with wheat germ agglutinin revealed diminished capillary area in the gluteus maximus of CKO vs. CON at 5 days post-injury (dpi); both recovered to uninjured (0 dpi) level by 10 dpi. At 0 dpi, tibialis anterior isometric force of CKO was less than CON. At 10 dpi, isometric force was reduced by half in both groups. During intermittent contractions (75 Hz, 330 ms s^-1, 120 s), isometric force fell during indirect (sciatic nerve) stimulation whereas force was maintained during direct (electrical field) stimulation of myofibres. Neuromuscular transmission failure correlated with perturbed presynaptic (terminal Schwann cells) and postsynaptic (nicotinic acetylcholine receptors) NMJ morphology in CKO. Resident satellite cell number on extensor digitorum longus myofibres did not differ between groups. Following acute injury of skeletal muscle, loss of Efnb2 in ECs delays capillary regeneration and attenuates recovery of NMJ structure and function. KEY POINTS: The relationship between microvascular regeneration and motor nerve regeneration following skeletal muscle injury is undefined. Expression of Efnb2 in endothelial cells (ECs) is essential to vascular development and promotes neurovascular regeneration in the adult. To test the hypothesis that EfnB2 in ECs is required for microvascular regeneration and myofibre reinnervation, we induced conditional knockout of Efnb2 in ECs of mice. Acute injury was then induced by BaCl₂ injection into gluteus maximus, tibialis anterior or extensor digitorum longus (EDL) muscle. Capillary regeneration was reduced at 5 days post-injury (dpi) in gluteus maximus of conditional knockout vs. controls; at 10 dpi, neither differed from uninjured. Nerve stimulation revealed neuromuscular transmission failure in tibialis anterior with perturbed neuromuscular junction structure. Resident satellite cell number on EDL myofibres did not differ between groups. Conditional knockout of EC Efnb2 delays capillary regeneration and attenuates recovery of neuromuscular junction structure and function.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142086395","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}

{"title":"Reinventing the renin-angiotensin-aldosterone system based on experience from the COVID-19 pandemic.","authors":"Sven Kurbel","doi":"10.1113/JP287202","DOIUrl":"https://doi.org/10.1113/JP287202","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142086398","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}

{"title":"Loss of the alpha subunit distal furin cleavage site blunts ENaC activation following Na+ restriction","authors":"Andrew J. Nickerson,&nbsp;Shaohu Sheng,&nbsp;Natalie A. Cox,&nbsp;Kennedy G. Szekely,&nbsp;Allison L. Marciszyn,&nbsp;Tracey Lam,&nbsp;Jingxin Chen,&nbsp;Sebastien Gingras,&nbsp;Ossama B. Kashlan,&nbsp;Annet Kirabo,&nbsp;Rebecca P. Hughey,&nbsp;Evan C. Ray,&nbsp;Thomas R. Kleyman","doi":"10.1113/JP286559","DOIUrl":"10.1113/JP286559","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;Epithelial Na&lt;sup&gt;+&lt;/sup&gt; channels (ENaCs) are activated by proteolysis of the α and γ subunits at specific sites flanking embedded inhibitory tracts. To examine the role of α subunit proteolysis in channel activation &lt;i&gt;in vivo&lt;/i&gt;, we generated mice lacking the distal furin cleavage site in the α subunit (α&lt;sup&gt;F2M&lt;/sup&gt; mice). On a normal Na&lt;sup&gt;+&lt;/sup&gt; control diet, no differences in ENaC protein abundance in kidney or distal colon were noted between wild-type (WT) and α&lt;sup&gt;F2M&lt;/sup&gt; mice. Patch-clamp analyses revealed similar levels of ENaC activity in kidney tubules, while no physiologically relevant differences in blood chemistry or aldosterone levels were detected. Male α&lt;sup&gt;F2M&lt;/sup&gt; mice did exhibit diminished ENaC activity in the distal colon, as measured by amiloride-sensitive short-circuit current (&lt;i&gt;I&lt;/i&gt;&lt;sub&gt;SC&lt;/sub&gt;). Following dietary Na&lt;sup&gt;+&lt;/sup&gt; restriction, WT and α&lt;sup&gt;F2M&lt;/sup&gt; mice had similar natriuretic and colonic &lt;i&gt;I&lt;/i&gt;&lt;sub&gt;SC&lt;/sub&gt; responses to amiloride. However, single-channel activity was significantly lower in kidney tubules from Na&lt;sup&gt;+&lt;/sup&gt;-restricted α&lt;sup&gt;F2M&lt;/sup&gt; mice compared with WT littermates. ENaC α and γ subunit expression in kidney and distal colon were also enhanced in Na&lt;sup&gt;+&lt;/sup&gt;-restricted α&lt;sup&gt;F2M&lt;/sup&gt; &lt;i&gt;vs&lt;/i&gt;. WT mice, in association with higher aldosterone levels. These data provide evidence that disrupting α subunit proteolysis impairs ENaC activity &lt;i&gt;in vivo&lt;/i&gt;, requiring compensation in response to Na&lt;sup&gt;+&lt;/sup&gt; restriction.\u0000\u0000 &lt;figure&gt;\u0000 &lt;div&gt;&lt;picture&gt;\u0000 &lt;source&gt;&lt;/source&gt;&lt;/picture&gt;&lt;p&gt;&lt;/p&gt;\u0000 &lt;/div&gt;\u0000 &lt;/figure&gt;\u0000 &lt;/div&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;The epithelial Na&lt;sup&gt;+&lt;/sup&gt; channel (ENaC) is activated by proteolytic cleavage &lt;i&gt;in vitro&lt;/i&gt;, but key questions regarding the role of ENaC proteolysis in terms of whole-animal physiology remain to be addressed.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;We studied the &lt;i&gt;in vivo&lt;/i&gt; importance of this mechanism by generating a mouse model with a genetic disruption to a key cleavage site in the ENaC's α subunit (α&lt;sup&gt;F2M&lt;/sup&gt; mice).&lt;/li&gt;\u0000 \u0000 &lt;li&gt;We found that α&lt;sup&gt;F2M&lt;/sup&gt; mice did not exhibit a physiologically relevant phenotype under normal dietary conditions, but have impaired ENaC activation (channel open probability) in the kidney during salt restriction.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;ENaC function at the organ level was preserved in salt-restricted α&lt;sup&gt;F2M&lt;/sup&gt; mice, but this was associated with higher aldosterone levels and increased expression of ENaC subun","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP286559","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142086397","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}

{"title":"Differential effect of lead and cadmium on mitochondrial function and NLRP3 inflammasome activation in human trophoblast.","authors":"Yifeng Dai, Xijin Xu, Xia Huo, Joost H N Schuitemaker, Marijke M Faas","doi":"10.1113/JP286755","DOIUrl":"https://doi.org/10.1113/JP286755","url":null,"abstract":"<p><p>Heavy metals disrupt mitochondrial function and activate the NOD-like receptor pyrin-containing 3 (NLRP3) inflammasome. We investigated the effect of lead (Pb)/cadmium (Cd) on mitochondrial function and NLRP3 inflammasome activation in human trophoblast under normoxic, hypoxic and pro-inflammatory conditions. JEG-3, BeWo and HTR-8/SVneo cells were exposed to Pb or Cd for 24 h in the absence or presence of hypoxia or pro-inflammatory lipopolysaccharide (LPS) or poly(I:C). Then, we evaluated cell viability, apoptosis, mitochondrial DNA copy number (mtDNAcn), mitochondrial membrane potential (ΔΨ), NLRP3 inflammasome proteins and interleukin (IL)-1β secretion. Although our data showed that Pb, Cd, hypoxia, poly(I:C) and LPS decreased mtDNAcn in the three cell lines, the effects of these treatments on other biomarkers were different in the different cell lines. We found that hypoxia decreased ΔΨ and promoted apoptosis in JEG-3 cells, increased ΔΨ and prevented apoptosis in BeWo cells, and did not change ΔΨ and apoptosis in HTR-8/SVneo cells. Moreover, Pb under hypoxic conditions reduced ΔΨ and promoted apoptosis of BeWo cells. Exposure of BeWo and HTR-8/SVneo cells to hypoxia, Pb or Cd alone upregulated the expression of NLRP3 and pro-caspase 1 but did not activate the NLRP3 inflammasome since cleaved-caspase 1 and IL-1β were not increased. To conclude, Pb and Cd affected trophoblast mitochondrial function and NLRP3 proteins in trophoblast cell lines, but in a cell line-specific way. KEY POINTS: The objective of this work was an understanding of the effect of lead (Pb) and cadmium (Cd) on mitochondrial function and NLRP3 inflammasome activation in human trophoblast cell lines under normoxic, hypoxic and pro-inflammatory conditions. Apoptosis of JEG-3 cells was increased by hypoxia, while in BeWo cells, apoptosis was decreased by hypoxia, and in HTR-8/SVneo, apoptosis was not affected by hypoxic treatment. Exposure to either Pb or Cd decreased mtDNAcn in three human placental trophoblast cell lines. However, Pb under hypoxia induced a decrease of ΔΨ and promoted apoptosis of BeWo cells, but Cd did not induce a reduction in ΔΨ in the three trophoblast cell lines under any conditions. Exposure to hypoxia, Pb or Cd increased NLRP3 and pro-caspase 1 in BeWo and HTR-8/SVneo cells. Our findings highlight that Pb and Cd affected trophoblast mitochondrial function and NLRP3 proteins in trophoblast cell lines but in a cell line-specific way.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142086394","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}

{"title":"HFrEF and HFpEF: are mitochondria at the heart of the matter?","authors":"Amanda Groenewald, Liam Zhang, Amelia S Power","doi":"10.1113/JP287344","DOIUrl":"https://doi.org/10.1113/JP287344","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142082354","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}

{"title":"Madness or progress? The dilemma of standardizing exercise physiology thresholds.","authors":"Billy Sperlich, Thomas Gronwald","doi":"10.1113/JP287312","DOIUrl":"https://doi.org/10.1113/JP287312","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074408","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}

{"title":"Glycogen pools and utilization during exercise: future implication on glucose regulation.","authors":"Roderick E Sandilands, Alexis Marcotte-Chénard","doi":"10.1113/JP287294","DOIUrl":"https://doi.org/10.1113/JP287294","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074406","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}

{"title":"In Memoriam: Marcello Costa (1940-2024) - a pioneer of the enteric nervous system.","authors":"N J Spencer, S J H Brookes, D A Wattchow","doi":"10.1113/JP287066","DOIUrl":"https://doi.org/10.1113/JP287066","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074407","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}

{"title":"Presynaptic quantal size enhancement counteracts post-tetanic release depression.","authors":"Anu G Nair, Nasrin Bollmohr, Levin Schökle, Jennifer Keim, José María Mateos Melero, Martin Müller","doi":"10.1113/JP286176","DOIUrl":"https://doi.org/10.1113/JP286176","url":null,"abstract":"<p><p>Repetitive synaptic stimulation can induce different forms of synaptic plasticity but may also limit the robustness of synaptic transmission by exhausting key resources. Little is known about how synaptic transmission is stabilized after high-frequency stimulation. In the present study, we observed that tetanic stimulation of the Drosophila neuromuscular junction (NMJ) decreases quantal content, release-ready vesicle pool size and synaptic vesicle density for minutes after stimulation. This was accompanied by a pronounced increase in quantal size. Interestingly, action potential-evoked synaptic transmission remained largely unchanged. EPSC amplitude fluctuation analysis confirmed the post-tetanic increase in quantal size and the decrease in quantal content, suggesting that the quantal size increase counteracts release depression to maintain evoked transmission. The magnitude of the post-tetanic quantal size increase and release depression correlated with stimulation frequency and duration, indicating activity-dependent stabilization of synaptic transmission. The post-tetanic quantal size increase persisted after genetic ablation of the glutamate receptor subunits GluRIIA or GluRIIB, and glutamate receptor calcium permeability, as well as blockade of postsynaptic calcium channels. By contrast, it was strongly attenuated by pharmacological or presynaptic genetic perturbation of the GTPase dynamin. Similar observations were made after inhibition of the H⁺-ATPase, suggesting that the quantal size increase is presynaptically driven. Additionally, dynamin and H⁺-ATPase perturbation resulted in a post-tetanic decrease in evoked amplitudes. Finally, we observed an increase in synaptic vesicle diameter after tetanic stimulation. Thus, a presynaptically-driven quantal size increase, likely mediated by larger synaptic vesicles, counterbalances post-tetanic release depression, thereby conferring robustness to synaptic transmission on the minute time scale. KEY POINTS: Many synapses transmit robustly after sustained activity despite the limitation of key resources, such as release-ready synaptic vesicles. We report robust synaptic transmission after sustained high-frequency stimulation of the Drosophila neuromuscular junction despite a reduction in release-ready vesicle number. An increased postsynaptic response to individual vesicles, likely driven by an increase in vesicle size due to endocytosis defects, stabilizes synaptic efficacy for minutes after sustained activity. Our study provides novel insights into the mechanisms governing synaptic stability after sustained neural activity.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142057059","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}

{"title":"Shaping smell: chloride currents dictate the kinetics of olfactory transduction.","authors":"Zach Fyke, Kai Clane Belonio, Joseph D Zak","doi":"10.1113/JP287393","DOIUrl":"https://doi.org/10.1113/JP287393","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142057152","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}