Journal of Physiology-London最新文献

{"title":"Preface Editorial for Special Issue Dedicated to Jeffrey L. Ardell (1952–2025) Cardiac Neurobiology: Concepts to Clinic","authors":"David J Paterson, Kalyanam Shivkumar","doi":"10.1113/JP288209","DOIUrl":"10.1113/JP288209","url":null,"abstract":"<p>In 2016, we published a special issue concerned with cardiac autonomic control in health and disease (Shivkumar & Ardell, <span>2016</span>). Since then, there has been an explosion of scientific interest in the neurobiology of the cardiac autonomic nervous system (Herring et al., <span>2019</span>; Paton et al., <span>unpublished raw data</span>) aimed at understanding how neuromodulation can be used therapeutically to treat cardiac disease (La Rovere et al., <span>2020</span>; Hanna, Buch et al., <span>2021</span>; Hadaya & Ardell, <span>2020</span>). To bridge the areas of neurology and cardiology, the emerging field of neurocardiology and bioelectronic medicine or ‘neuroceutics’ is now receiving significant attention and funding as a priority area from NIH (National Institutes of Health, and Office of Strategic Coordination-The Common Fund. Stimulating Peripheral Activity to Relieve Conditions – SPARC; the University of Minnesota awarded $21 million to lead research revealing effects of vagus nerve stimulation in humans) and the Leducq Foundation (Paterson & Shivkumar, <span>2023</span>). The strategy is underpinned by the development of personalised site-specific targeting of the nervous system to treat end-organ function, in particular arrhythmia. What is becoming apparent is the importance of bidirectional communication between neurons and myocytes (Davis et al., <span>2022</span>) and the need to have a better understanding of the complex neural architecture (Hanna, Dacey et al., <span>2021</span>; Rajendran et al., <span>2019</span>) that underpins rhythm disturbance from the ‘little brain’ in the heart (Armour <span>2008</span>; Herring & Paterson, <span>2021</span>). Moreover, a deeper appreciation of neural circuits and the development of miniaturization of sensor technology has provided an opportunity to lay the foundations for the next generation of bioelectronics for closed loop neuromodulation (Lerman et al., <span>2025</span>).</p><p>In July 2024 <i>The Journal of Physiology</i> supported a focused meeting in Oxford that was associated with the <i>International Society for Autonomic Neuroscience</i> (ISAN 2024). This 2-day meeting provided a framework to assemble opinion leaders in the field and also facilitated the opportunity for younger investigators from the bioengineering, physiological and medical communities to interact. In this special issue, entitled <i>Cardiac Neurobiology: Concepts to Clinic</i>, we highlight the deliberations from this meeting. In particular, the issue starts with an update on the three white papers we published in 2016, which gather the opinions of 52 leading experts in the field as they review the major advances that have taken place in the past 8 years.</p><p>The first white paper by Habecker et al. (<span>2025</span>) addresses the molecular and cellular basis of neural cardiac interactions in heart disease. A particular focus on novel intracellular pathways and neuroplasticity ","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 7","pages":"1683-1686"},"PeriodicalIF":4.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP288209","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659603","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":"À la recherche du temps perdu: will AI and 150 years of human movement research drive the next Neuroscience revolution?","authors":"Alessandro D'Ausilio","doi":"10.1113/JP288605","DOIUrl":"https://doi.org/10.1113/JP288605","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143651790","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":"Interictal discharges spread along local recurrent networks between tubers and surrounding cortex.","authors":"Stasa Tumpa, Rachel Thornton, Martin M Tisdall, Torsten Baldeweg, Karl J Friston, Richard E Rosch","doi":"10.1113/JP288141","DOIUrl":"https://doi.org/10.1113/JP288141","url":null,"abstract":"<p><p>The presence of interictal epileptiform discharges on EEG may indicate increased epileptic seizure risk. In highly epileptogenic lesions, such as cortical tubers in tuberous sclerosis, these discharges can be recorded with intracranial stereotactic EEG as part of the evaluation for epilepsy surgery. Yet the network mechanisms that underwrite the generation and spread of these discharges remain poorly understood. Here, we investigate the dynamics of interictal epileptiform discharges using a combination of quantitative analysis of invasive EEG recordings and mesoscale neural mass modelling of cortical dynamics. We first characterise spatially organised local dynamics of discharges recorded from 36 separate tubers in eight patients with tuberous sclerosis. We characterise these dynamics with a set of competing explanatory network models using dynamic causal modelling. Bayesian model comparison of plausible network architectures suggests that the recurrent coupling between neuronal populations within, as well as adjacent to, the tuber core explains the travelling wave dynamics observed in these patient recordings. Our results indicate that tuber cores are the spatial sources of interictal discharges that behave like travelling waves with dynamics most probably explained by locally recurrent tuber-perituberal networks. This view integrates competing theories regarding the pathological organisation of epileptic foci and surrounding cortex in patients with tuberous sclerosis by through coupled oscillator dynamics. This recurrent coupling can explain the spread of ictal dynamics and also provide an explanation interictal discharge spread. In the future, we will explore the possible implications of our findings for epilepsy surgery approaches in tuberous sclerosis. KEY POINTS: Interictal epileptiform discharges (IEDs) are abnormal electrical patterns observed in the brains of people with epilepsy and may indicate seizure risk. In tuberous sclerosis, a condition causing epileptic lesions called cortical tubers, IEDs spread from the tuber core to surrounding brain tissue, forming travelling waves. This study used invasive EEG recordings and mathematical models to identify that recurrent connections between the tuber core and its surroundings explain this wave-like spread. Further in silico simulations demonstrate that this recurrent network architecture supports both interictal discharges and seizure-like dynamics under different levels of local inhibition.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143651792","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":"Neuromuscular junction instability with inactivity: morphological and functional changes after 10 days of bed rest in older adults.","authors":"Evgeniia Motanova, Fabio Sarto, Samuele Negro, Marco Pirazzini, Ornella Rossetto, Michela Rigoni, Daniel W Stashuk, Mladen Gasparini, Boštjan Šimunic, Rado Pišot, Marco V Narici","doi":"10.1113/JP288448","DOIUrl":"https://doi.org/10.1113/JP288448","url":null,"abstract":"<p><p>The neuromuscular junction (NMJ) plays a key role in modulating muscle contraction, but the impact of short-term disuse on NMJ structure and function, particularly in older humans, remains unclear. This study aimed to investigate NMJ alterations following 10 days of horizontal bed rest in 10 older males (68.5 ± 2.6 years). Before and after bed rest, vastus lateralis muscle biopsies were obtained to evaluate NMJ morphology, intramuscular EMG (iEMG) was recorded to assess NMJ function and blood samples were collected to determine circulating C-terminal agrin fragment (CAF) concentration, a biomarker of NMJ remodelling. In a sub-cohort of six participants who had NMJs in both pre- and post-bed rest biopsies, we observed altered NMJ morphology, including reduced overlap between NMJ terminals, as well as increased endplate area and perimeter. CAF concentration was elevated after bed rest, suggesting ongoing NMJ remodelling. iEMG analysis showed increased motor unit potential complexity and reduced firing rate. In addition, we observed impaired NMJ transmission, inferred from increased near-fibre jiggle and segment jitter. These findings suggest that older male individuals are susceptible to NMJ remodelling and impaired transmission with short-term disuse, providing valuable insights into the morphological and functional consequences of inactivity in an ageing population. Our study highlights the importance of developing interventions for mitigating the detrimental consequences of inactivity on neuromuscular health in older adults, which they frequently experience following injury, trauma, illness or surgery. KEY POINTS: The neuromuscular junction (NMJ) is crucial for signal transmission between the motoneuron and skeletal muscle, and NMJ alterations are linked to several neuromuscular disorders, as well as ageing. However, the impact of disuse on the structural and functional integrity of the NMJ, particularly in older humans, is largely unknown. We used the bed rest model to study the impact of inactivity on NMJ morphology and function in older men. We hypothesised that a 10 day bed rest period would lead to alterations in NMJ morphology and transmission. We show that 10 days of bed rest were sufficient to induce marked alterations in NMJ morphology, associated with an impaired NMJ transmission and with changes in motor unit potential properties. These findings suggest that older male individuals are vulnerable to NMJ dysfunction in response to inactivity and emphasise the importance of maintaining an active lifestyle for preserving neuromuscular health with ageing.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143651794","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":"Unlocking the full potential of high-density surface EMG: novel non-invasive high-yield motor unit decomposition.","authors":"Agnese Grison, Irene Mendez Guerra, Alexander Kenneth Clarke, Silvia Muceli, Jaime Ibáñez, Dario Farina","doi":"10.1113/JP287913","DOIUrl":"https://doi.org/10.1113/JP287913","url":null,"abstract":"<p><p>The decomposition of high-density surface electromyography (HD-sEMG) signals into motor unit discharge patterns has become a powerful tool for investigating the neural control of movement, providing insights into motor neuron recruitment and discharge behaviour. However, current algorithms, while effective under certain conditions, face significant challenges in complex scenarios, as their accuracy and motor unit yield are highly dependent on anatomical differences among individuals. To address this issue, we recently introduced Swarm-Contrastive Decomposition (SCD), which dynamically adjusts the contrast function based on the distribution of the data. Here, we demonstrate the ability of SCD in identifying low-amplitude motor unit action potentials and effectively handling complex decomposition scenarios. We validated SCD using simulated and experimental HD-sEMG recordings and compared it with current state-of-the-art decomposition methods under varying conditions, including different excitation levels, noise intensities, force profiles, sexes and muscle groups. The proposed method consistently outperformed existing techniques in both the quantity of decoded motor units and the precision of their firing time identification. Across different simulated excitation levels, SCD detected, on average, 25.9 ±5.8 motor units vs. 13.9 ± 2.7 found by a state-of-the-art baseline approach. Across noise levels, SCD detected 19.8 ± 13.5 motor units, compared to 11.9 ± 6.9 by the baseline method. In simulated conditions of high synchronisation levels, SCD detected approximately three times as many motor units compared to previous methods (31.2 ± 4.3 for SCD, 10.5 ± 1.7 for baseline), while also significantly improving accuracy. These advancements represent a step forward in non-invasive EMG technology for studying motor unit activity in complex scenarios. KEY POINTS: High-density surface electromyography (HD-sEMG) decomposition provides information on how the nervous system controls muscles, but current methods struggle in complex conditions. Swarm-Contrastive Decomposition (SCD) is a new approach that dynamically adjusts how signals are separated, improving accuracy and increasing the sample of detected motor units. SCD successfully identifies more motor units, including those with low-amplitude signals, and performs well even in challenging conditions such as high-interference signals. In simulated ballistic contractions, SCD detected three times more motor units than previous methods while improving accuracy. These advancements could improve non-invasive studies of muscle function in movement, fatigue and neurological disorders.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143651796","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":"Antiarrhythmic effects of mirabegron on ventricular fibrillation in Langendorff-perfused rabbit ventricles.","authors":"Xiao Liu, Yen-Ling Sung, Liyang Zhang, Shuai Guo, Minjing Yang, James E Tisdale, Zhenhui Chen, Joshua I Goldhaber, Michael Rubart, Xiaochun Li, Peng-Sheng Chen","doi":"10.1113/JP286901","DOIUrl":"https://doi.org/10.1113/JP286901","url":null,"abstract":"<p><p>β-3 adrenoceptor (AR) counteracts the β-1 and β-2 ARs and rescues the effects of excessive catecholamines. To test the hypothesis that a β-3 AR agonist (mirabegron) can reverse the effects of isoproterenol (ISO) on ventricular fibrillation (VF), we performed optical mapping studies in six male and six female Langendorff perfused rabbit hearts at baseline and after sequential administration of ISO (100 nm), mirabegron (1000 nm), apamin (100 nm) and washout (Study I). An additional six male and six female hearts were studied with mirabegron doses ranging between 250 and 1000 nm without ISO (Study II). Patch clamp studies in human embryonic kidney 293 cells were performed to determine the effect of mirabegron on the apamin-sensitive small conductance Ca²⁺ activated K⁺ current (I_KAS). Study I show that ISO increased phase singularities per VF episode (PSs/VF) in females and the dominant frequency (DF) in both sexes. Mirabegron significantly decreased PSs/VF in both sexes and significantly decreased DF in females. Study II showed no significant difference in PSs/VF between sexes at mirabegron concentrations of 250 nm and 500 nm. However, females showed significantly lower PSs/VF than males at mirabegron concentrations of 750 nm and 1000 nm. There were no differences in the DF profiles of dose-response between males and females. Mirabegron did not inhibit or activate I_KAS heterologously expressed in human embryonal kidney 293 cells. Reverse transcriptase-quantitative PCR showed no differences in β-3 AR expression between sexes. We conclude that mirabegron is antiarrhythmic, and its antiarrhythmic properties are more commonly observed in females than males. KEY POINTS: Sympathetic nerve activity activates β adrenoceptors to induce cardiac arrhythmia. Among the β adrenoceptors, β-3 counteracts the effects of β-1 and β-2. Mirabegron is an US Food and Drug Administration (FDA)-approved β-3 agonist that does not by itself block cardiac ionic currents or prolong the QT interval. We showed that mirabegron significantly prevents wave breaks and reduces the dominant frequency of ventricular fibrillation. These effects are more prominent in female than in male rabbit ventricles. Because the FDA approves mirabegron for human use, its antiarrhythmic effects can be readily tested in humans.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634804","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":"Methodological evaluation of muscle oxidative stress in normotensive and hypertensive individuals: Ageing-related.","authors":"João Pedro Floriano, Alisson Luiz da Rocha","doi":"10.1113/JP288551","DOIUrl":"https://doi.org/10.1113/JP288551","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625840","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":"Biophysical modelling of intrinsic cardiac nervous system neuronal electrophysiology based on single-cell transcriptomics","authors":"Suranjana Gupta,&nbsp;Michelle M. Gee,&nbsp;Adam J. H. Newton,&nbsp;Lakshmi Kuttippurathu,&nbsp;Alison Moss,&nbsp;John D. Tompkins,&nbsp;James S. Schwaber,&nbsp;Rajanikanth Vadigepalli,&nbsp;William W. Lytton","doi":"10.1113/JP287595","DOIUrl":"10.1113/JP287595","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;The intrinsic cardiac nervous system (ICNS), termed as the heart's ‘little brain’, is the final point of neural regulation of cardiac function. Studying the dynamic behaviour of these ICNS neurons via multiscale neuronal computer models has been limited by the sparsity of electrophysiological data. We developed and analysed a computational library of neuronal electrophysiological models based on single neuron transcriptomic data obtained from ICNS neurons. Each neuronal genotype was characterized by a unique combination of ion channels identified from the transcriptomic data, using a cycle threshold cutoff that ensured the electrical excitability of the neuronal models. The parameters of the ion channel models were grounded based on passive properties (resting membrane potential, input impedance and rheobase) to avoid biasing the dynamic behaviour of the model. Consistent with experimental observations, the emergent model dynamics showed phasic activity in response to the current clamp stimulus in a majority of neuronal genotypes (61%). Additionally, 24% of the ICNS neurons showed a tonic response, 11% were phasic-to-tonic with increasing current stimulation and 3% showed tonic-to-phasic behaviour. The computational approach and the library of models bridge the gap between widely available molecular-level gene expression and sparse cellular-level electrophysiology for studying the functional role of the ICNS in cardiac regulation and pathology.\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;Computational models were developed of neuron electrophysiology from single-cell transcriptomic data from neurons in the heart's ‘little brain’: the intrinsic cardiac nervous system.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;The single-cell transcriptomic data were thresholded to select the ion channel combinations in each neuronal model.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;The library of neuronal models was constrained by the passive electrical properties of the neurons and predicted a distribution of phasic and tonic responses that aligns with experimental observations.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;The ratios of model-predicted conductance values are correlated with the gene expression ratios from transcriptomic data.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;These neuron models are a first step towards connecting single-cell transcriptomic data to dynamic, predictive physiology-based models.&lt;/li&gt;\u0000 &lt;/ul&gt;\u0000 ","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 7","pages":"2119-2138"},"PeriodicalIF":4.7,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP287595","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143617687","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":"The physiology, anatomy and stimulation of the vagus nerve in epilepsy.","authors":"Mikaela Patros, Shobi Sivathamboo, Hugh D Simpson, Terence J O'Brien, Vaughan G Macefield","doi":"10.1113/JP287164","DOIUrl":"https://doi.org/10.1113/JP287164","url":null,"abstract":"<p><p>The vagus nerve is the longest cranial nerve, with much of its territory residing outside the head, in the neck, chest and abdomen. Although belonging to the parasympathetic division of the autonomic nervous system, it is dominated by sensory axons originating in the heart, lungs and airways and the gastrointestinal tract. Electrical stimulation of the cervical vagus nerve via surgically implanted cuff electrodes has been used clinically for the treatment of drug-resistant epilepsy for three decades but has also shown efficacy in the treatment of drug-resistant depression and certain gastrointestinal disorders. Through consideration of the anatomical composition of the vagus nerve, its physiology and its distribution throughout the body, we review the effects of vagus nerve stimulation in the context of drug-resistant epilepsy. This narrative review is divided into two sections: part one surveys the anatomy and physiology of the vagus nerve, and part two describes what we know about how vagus nerve stimulation works.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143587890","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":"Calciprotein particle-induced calcium overload triggers mitochondrial dysfunction in endothelial cells.","authors":"Lian Feenstra, Laurent Chatre, Benoit Bernay, Julien Pontin, Mirjam F Mastik, Azuwerus van Buiten, Dalibor Nakládal, Bastiaan S Star, Jan-Luuk Hillebrands, Guido Krenning","doi":"10.1113/JP287656","DOIUrl":"https://doi.org/10.1113/JP287656","url":null,"abstract":"<p><p>Calciprotein particles (CPPs) are calcium- and phosphate-containing nanoparticles numbers of which are increased in patients with chronic kidney disease (CKD). CPPs have been associated with the development of vascular disease, although the underlying mechanisms are unknown. We previously showed that CPPs induce endothelial cell (EC) dysfunction by reducing nitric oxide (NO) bioavailability and generating superoxide (O₂ ^.-). Here, we tested the hypothesis that CPPs induce mitochondrial calcium (Ca²⁺) overload, which may trigger mitochondrial dysfunction and, consequently, EC activation. Exposure of human umbilical vein ECs to CPPs resulted in significantly increased cytosolic and mitochondrial Ca²⁺ levels compared to vehicle-treated ECs. Proteome analysis demonstrated impaired endoplasmic reticulum calcium signalling, and decreased enrichment of proteins in the mitochondrial OXPHOS complexes I-III in CPP-exposed ECs. Respirometry data confirmed these findings and demonstrated decreased basal and maximal respiration in CPP-exposed ECs. This was accompanied by reduced mitochondrial membrane potential, reduced antioxidant capacity and loss of mitochondria. In the presence of cyclosporin A, a potent mitochondrial permeability transition pore inhibitor, CPP-induced EC activation and cell death were attenuated. Taken together, our data indicate that CPP-induced Ca²⁺ overload is an important trigger of mitochondrial dysfunction, and EC activation and cell loss, which eventually may contribute to the development of vascular diseases in CKD. Interventions that target CPP-induced mitochondrial dysfunction might preserve EC function and possibly alleviate the development of vascular diseases in CKD. KEY POINTS: Calciprotein particles (CPPs) are calcium- and phosphate-containing nanoparticles numbers of which are increased in patients with chronic kidney disease and which have been associated with the development of vascular disease. In this study, we tested the hypothesis that CPPs induce mitochondrial calcium (Ca²⁺) overload in endothelial cells, thereby triggering mitochondrial dysfunction and endothelial activation. We show that exposure of HUVECs (human umbilical vein endothelial cells) to CPPs results in increased cytosolic and mitochondrial Ca²⁺ levels, which is associated with alterations in mitochondrial processes (proteome analysis), cellular respiration, mitochondrial integrity and number. CPP-induced EC activation and cell death were attenuated in the presence of cyclosporin A, a potent mitochondrial permeability transition pore inhibitor. Our data indicate that CPP-induced Ca²⁺ overload triggers mitochondrial dysfunction, endothelial activation and cell loss. Interventions that target CPP-induced mitochondrial dysfunction might preserve EC function in chronic kidney disease.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143587842","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}