Journal of Physiology-London最新文献

{"title":"Potassium homeostasis during disease progression of Alzheimer's disease.","authors":"Evgeniia Samokhina, Armaan Mangat, Chandra S Malladi, Erika Gyengesi, John W Morley, Yossi Buskila","doi":"10.1113/JP287903","DOIUrl":"https://doi.org/10.1113/JP287903","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder characterized by neuronal loss leading to dementia and ultimately death. Whilst the loss of neurons is central to this disease, it is becoming clear that glia, specifically astrocytes, contribute to the onset and progression of neurodegeneration. The role of astrocytes in maintaining ion homeostasis in the extracellular milieu is fundamental for multiple brain functions, including synaptic plasticity and neuronal excitability, which are compromised during AD and affect neuronal signalling. In this study, we measured the astrocytic K⁺ clearance rate in the hippocampus and somatosensory cortex of a mouse model for AD during disease progression. Our results establish that astrocytic [K⁺]_o (extracellular K⁺ concentration) clearance in the hippocampus is reduced in symptomatic 5xFAD mice, and this decrease is region-specific, as no significant alterations were detected in the superficial layers of the somatosensory cortex. The decrease in the [K⁺]_o clearance rate correlated with a significant reduction in the expression and conductivity of Kir4.1 channels and a decline in the number of primary connected astrocytes. Moreover, astrocytes in the hippocampus of symptomatic 5xFAD mice demonstrated increased reactivity which was accompanied by an increased excitability and altered spiking profile of nearby neurons. These findings indicate that the supportive function astrocytes typically provide to nearby neurons is diminished during disease progression, which affects the neuronal circuit signalling in this area and provides a potential explanation for the increased vulnerability of neurons in AD. KEY POINTS: Astrocytic potassium clearance from the extracellular milleu is fundamental for multiple brain functions. Alterations in the clearance rate can affect the excitability and overall viability of neurons. A symptomatic mouse model for Alzheimer's disease (5xFAD) exhibits a significant decline in astrocytic K⁺ clearance at the hippocampus, but not the somatosensory cortex. The decrease in the clearance rate correlated with a reduction in the expression and conductivity of astrocytic Kir4.1 channels and a decrease in the number of primary connected astrocytes, specifically at the stratum lacunosum moleculare layer of the CA1 region. Astrocytes in the hippocampus of symptomatic 5xFAD mice displayed increased reactivity. The excitability profile and firing patterns of neurons at the hippocampus were affected by alterations in K⁺ homeostasis, indicating that the supportive function astrocytes typically provide to nearby neurons is diminished during progression of Alzheimer's disease.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144006281","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":"Varied ionic currents underlie functional diversity of hypoglossal motoneurons innervating the superior longitudinalis and genioglossus tongue muscles.","authors":"Michael Frazure, Emily Flanigan, Lila B Wollman, Ralph Fregosi","doi":"10.1113/JP288599","DOIUrl":"https://doi.org/10.1113/JP288599","url":null,"abstract":"<p><p>Hypoglossal motoneurons (XIIMNs) control tongue movement, which must be precisely coordinated for communication, swallowing and respiration. We previously found that XIIMNs innervating intrinsic and extrinsic tongue muscles exhibit diverse firing properties. Here we investigate the mechanisms behind functional differences of XIIMNs that control the superior longitudinalis (SL) and genioglossus (GG) muscles, which retract and protrude the tongue, respectively. We hypothesized that varied ionic currents drive muscle-specific firing properties in XIIMNs. We obtained whole-cell patch-clamp recordings from retrogradely labelled SL and GG XIIMNs obtained from male and female neonatal rats. SL and GG XIIMNs exhibited distinct firing patterns, and SL XIIMNs had higher intrinsic excitability than GG XIIMNs. Next, voltage-clamp studies aimed to determine the ionic mechanisms responsible for functional differences between SL and GG XIIMNs. While whole-cell K⁺ conductance was similar in both populations, SL XIIMNs exhibited a large, sustained Ca²⁺-sensitive K⁺ current that was not observed in GG XIIMNs. Subsequent current-clamp studies evaluated the influence of Ca²⁺-sensitive K⁺ currents on firing behaviour. Bath application of the Ca²⁺ channel antagonist CdCl₂ produced opposite effects on firing behaviour in SL and GG XIIMNs. Ca²⁺ blockade impaired repetitive firing in SL XIIMNs and increased firing frequency in GG XIIMNs. These data indicate that distinct ionic currents contribute to the functional specialization of XIIMNs that control different tongue muscles. KEY POINTS: Using retrograde labelling and electrophysiology, we found that hypoglossal motoneurons innervating the superior longitudinalis (SL) and genioglossus (GG) muscles exhibit distinct biophysical properties. Until recently, hypoglossal motoneurons have been considered functionally homogeneous. Motoneurons innervating the SL had depolarized resting membrane potentials, lower firing thresholds and steeper frequency-current curves than GG motoneurons. SL motoneurons exhibited a prominent calcium-sensitive potassium current that was not observed in GG motoneurons. Calcium channel blockade differentially affected firing behaviour in SL and GG motoneurons. While SL motoneurons exhibited impaired repetitive discharge, GG motoneurons displayed increased firing frequency. Our findings suggest that hypoglossal motoneurons exhibit functional specialization, with distinct intrinsic membrane properties tailored to the specific motor demands of the tongue muscles they innervate.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024501","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":"Elucidating the cellular determinants of the end-systolic pressure-volume relationship of the heart via computational modelling.","authors":"Francesco Regazzoni, Corrado Poggesi, Cecilia Ferrantini","doi":"10.1113/JP287282","DOIUrl":"https://doi.org/10.1113/JP287282","url":null,"abstract":"<p><p>The left ventricular end-systolic pressure-volume relationship (ESPVr) is a key indicator of cardiac contractility. Despite its established importance, several studies suggested that the mechanical mode of contraction, such as isovolumetric or ejecting contractions, may affect the ESPVr, challenging the traditional notion of a single, consistent relationship. Furthermore, it remains unclear whether the observed effects of ejection on force generation are inherent to the ventricular chamber itself or are a fundamental property of the myocardial tissue, with the underlying mechanisms remaining poorly understood. We investigated these aspects using a multiscale in silico model that allowed us to elucidate the links between subcellular mechanisms and organ-level function. Simulations of ejecting and isovolumetric beats with different preload and afterload resistance were performed by modulating calcium and cross-bridge kinetics. The results suggest that the ESPVr is not a fixed curve but depends on the mechanical history of the contraction, with potentially both positive and negative effects of ejection. Cell scale simulations suggest that these phenomena are intrinsic to the myocardial tissue, rather than properties of the ventricular chamber. Our results suggest that the ESPVr results from the balance between positive and negative effects of ejection, related to a memory effect of the increased apparent calcium sensitivity at high sarcomere length, and to the inverse relationship between force and velocity. Numerical simulations allowed us to reconcile conflicting results in the literature and suggest translational implications for clinical conditions such as hypertrophic cardiomyopathy, where altered calcium dynamics and cross-bridge kinetics may impact the ESPVr. KEY POINTS: The left ventricular end-systolic pressure-volume relationship (ESPVr) is a fundamental indicator of cardiac contractility, but the traditional notion of a single, consistent curve across different mechanical modes of contraction (isovolumetric vs. ejecting) has been challenged. Using multiscale computational simulations, our findings suggest that the ESPVr is not a fixed curve but depends on the mechanical history of the contraction, with both positive and negative inotropic effects during muscle shortening (ejection). Our results suggest that these phenomena are intrinsic to myocardial tissue properties, specifically involving calcium kinetics and cross-bridge cycling, rather than being due to ventricular chamber mechanics. Our study reconciles conflicting findings in the literature by providing a mechanistic explanation of how length-dependent activation and the force-velocity relationship influence ESPVr. This work has potential translational implications for clinical conditions such as hypertrophic cardiomyopathy, where altered calcium dynamics and enhanced cross-bridge kinetics may significantly affect cardiac contractility and the ESPVr.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144057128","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":"Tumour necrosis factor-alpha at the intersection of renal epithelial and immune cell function.","authors":"Sara Hubbi, Shoujin Hao, Jarred Epps, Nicholas R Ferreri","doi":"10.1113/JP286756","DOIUrl":"https://doi.org/10.1113/JP286756","url":null,"abstract":"<p><p>This review explores the roles of tumour necrosis factor-alpha (TNF) in kidney physiology and pathology. TNF, produced by renal epithelial cells, regulates glucose, electrolyte, water and urea transport by modulating key transporters such as sodium-glucose co-transporter-2 (SGLT2), sodium-potassium-chloride cotransporter 2 (NKCC2), sodium chloride cotransporter (NCC), epithelial sodium channel (ENaC), aquaporin-2 (AQP2) and urea transporters. Under non-inflammatory conditions, TNF functions as a regulatory 'brake' on water and solute transport, particularly by attenuating NKCC2 and AQP2 activity. Disruption of these actions, coupled with increased salt intake, shifts mice from being salt-resistant to salt-sensitive, thereby altering their blood pressure. In autoimmune diseases, chronic kidney disease (CKD), hypertension with renal inflammation, and sepsis, TNF drives immune responses and disease progression. Although mechanisms underlying tubular epithelial cell (TEC)-immune cell interactions remain unclear, emerging evidence indicates that the spatial organization of immune responses in the kidney is associated with distinct TEC signature phenotypes. Hypertonicity- and NFAT5 (i.e. nuclear factor of activated T cells 5)-driven TNF production in TECs and T lymphocytes may influence immune cell communication by affecting co-stimulatory molecule expression and ENaC activity on macrophages and dendritic cells. Although TNF is generally pathogenic in renal diseases, its inhibition does not always confer protection because its effects on endoplasmic reticulum stress, ion transport, vascular smooth muscle and immune cells are influenced by distinct cellular sources and signalling mechanisms through TNF receptors 1 and 2. Anti-TNF therapies are crucial for treating chronic inflammatory diseases and may also aid in preventing the progression of acute kidney injury to CKD. A more complete understanding of the role of TNF in immunophysiological responses may enable the development of more targeted therapeutic strategies.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144025222","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":"Hyperglycaemia-induced reactive oxygen species production in cardiac ventricular myocytes differs among mammals.","authors":"Shan Lu, Maria J Baier, Risto-Pekka Polonen, Zhandi Liao, Jody L Martin, Kenneth S Ginsburg, Julian Mustroph, Donald M Bers","doi":"10.1113/JP287886","DOIUrl":"https://doi.org/10.1113/JP287886","url":null,"abstract":"<p><strong>Background: </strong>Diabetic cardiomyopathy (DbCM) preclinical studies have used animal models from different species and implicated altered redox regulation and reactive oxygen species (ROS) in this disease. However hyperglycaemia-induced ROS signalling may differ in ventricular myocytes from different species, and here we compare mice, rats, rabbits and humans with respect to hyperglycaemia-induced ROS production.</p><p><strong>Methods: </strong>Using the chemical sensor H₂DCFDA and genetically encoded redox sensors, we measured time-dependent ROS signals in response to high glucose (HiGlu). Live cell confocal imaging was used to determine redox and glucose levels, contractility and Ca²⁺ transients in isolated cardiomyocytes. Western blotting and activity assays were used to evaluate superoxide dismutase (SOD) expression and activity.</p><p><strong>Results: </strong>Consistent with our prior mouse studies, HiGlu exposure in rat and human ventricular myocytes increased cytosolic (not mitochondrial) ROS production via a mechanism involving Ca-calmodulin-dependent protein kinase (CaMKII) O-GlcNAcylation (at Ser280) and NADPH oxidase 2 (NOX2) activation. However in rabbit ventricular myocytes HiGlu alone did not induce significant ROS production, unless complemented by low levels of angiotensin II and inhibition of the enzyme that reverses O-GlcNAcylation using 100 nM Thiamet G, where both cytosolic and mitochondrial ROS accumulation were involved by more complex signalling networks.</p><p><strong>Conclusion: </strong>Acute hyperglycaemia readily induces robust ROS production in mouse, rat and human ventricular myocytes, but rabbit myocytes are intrinsically better protected from this HiGlu-induced ROS responses. In most regards rabbit are much more human-like than rodents for many aspects of myocyte function, but this surprisingly is not the case for HiGlu-induced ROS production.</p><p><strong>Key points: </strong>In mouse ventricular myocytes we previously showed that acute hyperglycaemia (HiGlu) induced increase in reactive oxygen species (ROS) mediated by O-GlcNAcylation of Ca-calmodulin-dependent protein kinase at Ser280 and consequent NADPH oxidase 2 (NOX2) activation. Here we demonstrate that this same pathway is functional in human and rat ventricular myocytes but not in rabbit ventricular myocytes. In rat and human myocytes HiGlu induced an increase in cytosolic, but not mitochondrial, ROS production. In rabbit myocytes HiGlu only produced increased ROS (cytosolic and mitochondrial) only when it was accompanied by both low concentration angiotensin II and an O-GlcNAcylase inhibitor (that individually did not promote ROS production). This direct HiGlu-induced ROS production in cardiac myocytes may contribute to pathological signalling in diabetes.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143993934","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":"Adverse effects of high-fat diet consumption on contractile mechanics of isolated mouse skeletal muscle are reduced when supplemented with resveratrol","authors":"Sharn P. Shelley,&nbsp;Rob S. James,&nbsp;Steven J. Eustace,&nbsp;Mark C. Turner,&nbsp;Ryan Brett,&nbsp;Emma L. J. Eyre,&nbsp;Jason Tallis","doi":"10.1113/JP287056","DOIUrl":"https://doi.org/10.1113/JP287056","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;Increasing evidence indicates resveratrol (RES) supplementation evokes anti-obesogenic responses that could mitigate obesity-induced reductions in skeletal muscle (SkM) contractility. Contractile function is a key facet of SkM health that underpins whole body health. For the first time, the present study examines the effects of a high-fat diet and RES supplementation on isolated soleus (SOL) and extensor digitorum longus (EDL) contractile function. Female CD-1 mice, ∼6 weeks old (&lt;i&gt;n&lt;/i&gt; = 38), consumed a standard laboratory diet (SLD) or a high-fat diet (HFD), with or without RES (4 g kg&lt;sup&gt;−1&lt;/sup&gt; diet) for 12 weeks. SOL and EDL (&lt;i&gt;n&lt;/i&gt; = 8–10 per muscle, per group) were isolated and then absolute and normalised (to muscle size and body mass) isometric force and work loop power output (PO) were measured, and fatigue resistance was determined. Furthermore, sirtuin-1 expression was determined to provide mechanistic insight into any potential contractile changes. For SOL absolute force was higher in HFDRES compared to HFD (&lt;i&gt;P&lt;/i&gt; = 0.033), and PO normalised to body mass and cumulative work during fatigue were reduced in HFD groups (&lt;i&gt;P &lt;/i&gt;&lt; 0.014). EDL absolute and normalised PO and cumulative work during fatigue were lower in HFD compared to other groups (&lt;i&gt;P &lt;/i&gt;&lt; 0.019). RES negated most adverse effects of HFD consumption on EDL contractility, with HFDRES producing PO and cumulative work comparable to the SLD groups. Sirtuin-1 expression was not influenced by diet in either muscle (&lt;i&gt;P &lt;/i&gt;&gt; 0.165). This study uniquely demonstrates that RES attenuates HFD-induced reductions in contractile performance of EDL, but this response is not explained by altered sirtuin-1 expression. These results suggest RES may be an appropriate strategy to alleviate obesity-induced declines in SkM function.\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;Skeletal muscle health, a precursor for disease prevention, whole body health and quality of life, is substantially reduced because of obesity.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Growing evidence suggests that the anti-obesogenic effects of nutritional supplement resveratrol may mitigate against obesity-induced muscle pathology. However, the effect of resveratrol on skeletal muscle contractile performance, a primary marker of skeletal muscle health, is yet to be examined.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Our findings indicate that resveratrol reduces the adverse effects of high-fat diet consumption ","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 9","pages":"2675-2698"},"PeriodicalIF":4.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP287056","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143938916","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":"A polygenetic rat model of divergent aerobic capacity reveals a liver-brain interaction impacting Alzheimer's disease-like phenotypes.","authors":"Colton R Lysaker, Benjamin A Kugler, Vivien Csikos, Cole J Birky, Caleb A Gilmore, Madi Wenger, Edziu Franczak, Xin Davis, Brittany M Hauger, Julie A Allen, Benjamin R Troutwine, Laura Gonalez-Duran, Colin S McCoin, Munish Chauhan, Janna L Harris, Alexandria L Frazier, Michelle K Winter, Lauren G Koch, Steven L Britton, John P Thyfault, Heather M Wilkins","doi":"10.1113/JP286750","DOIUrl":"https://doi.org/10.1113/JP286750","url":null,"abstract":"<p><p>The interaction between liver and brain health is an emerging complex relationship implicated in Alzheimer's disease (AD). Divergence in aerobic capacity influences liver and brain health independently; however, whether these factors converge to influence AD risk is mechanistically unknown. Bile acid metabolism has been implicated as a link between liver and brain health and is modulated by aerobic capacity. Here, we examined rats selectively bred for high vs. low intrinsic aerobic capacity [high and low-capacity runner (HCR or LCR)] on indices of hepatic metabolism and brain health following a chronic low-fat, high-fat, or high-fat diet with bile acid sequestrant from 6 to 12 months of age. Pre- and post-diet measures included learning, memory, and brain volume metabolite levels. We additionally quantified brain and liver Aβ and proteins associated with Aβ production and clearance, as well as liver and brain mitochondrial energetics and liver bile acid species. We found that not only did aerobic capacity and diet influence mitochondrial function, but also it modified Aβ levels across the liver and brain. Additionally, aerobic capacity and diet altered bile acid profiles and brain hippocampal metabolite levels. The addition of bile acid sequestrant lowered brain Aβ levels in a sexually dimorphic manner. Aerobic capacity but not diet altered cognitive outcomes. Our results indicate that aerobic capacity and diet-induced liver health alterations modulate brain health with respect to metabolism and AD-like pathologies, whereas a stimulation of faecal bile acid loss could have positive effects on lowering brain Aβ. KEY POINTS: Aerobic capacity and diet-induced alterations to liver function alter liver bile acid species and faecal energy loss. Aerobic capacity and diet alter both brain and liver Aβ homeostasis. Aerobic capacity modulates brain and hippocampal volume in addition to brain metabolism. Aerobic capacity influences learning in middle-aged rats.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144006205","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":"Mechanisms of sympathetic excitation during cycling exercise in heart failure with reduced ejection fraction.","authors":"Catherine F Notarius, Mark B Badrov, Tomoyuki Tobushi, Daniel A Keir, Evan Keys, Dilafruz Hasanova, Paul Oh, John S Floras","doi":"10.1113/JP287491","DOIUrl":"https://doi.org/10.1113/JP287491","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Leg muscle sympathetic nerve activity (MSNA) diminishes in healthy (HC) individuals during mild dynamic exercise but not in age-matched patients with heart failure due to reduced ejection fraction (HFrEF). To elucidate the neural mechanisms responsible for such sympathetic excitation, we studied 20 stable HFrEF patients (6F; mean age 62 ± 8 SD years) and 15 age-matched HC (6F; mean age 59 ± 7). We quantified peak oxygen uptake ( &lt;math&gt; &lt;semantics&gt; &lt;msub&gt;&lt;mover&gt;&lt;mi&gt;V&lt;/mi&gt; &lt;mo&gt;̇&lt;/mo&gt;&lt;/mover&gt; &lt;msub&gt;&lt;mi&gt;O&lt;/mi&gt; &lt;mrow&gt;&lt;mn&gt;2&lt;/mn&gt; &lt;mi&gt;peak&lt;/mi&gt;&lt;/mrow&gt; &lt;/msub&gt; &lt;/msub&gt; &lt;annotation&gt;${{dot{V}}_{{{{mathrm{O}}}_{2{mathrm{peak}}}}}}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; ) and separately, fibular MSNA (microneurography) at rest and during one-leg cycling (2 min each, mild (unloaded) and moderate intensity (loaded = 30-40% &lt;math&gt; &lt;semantics&gt; &lt;msub&gt;&lt;mover&gt;&lt;mi&gt;V&lt;/mi&gt; &lt;mo&gt;̇&lt;/mo&gt;&lt;/mover&gt; &lt;msub&gt;&lt;mi&gt;O&lt;/mi&gt; &lt;mrow&gt;&lt;mn&gt;2&lt;/mn&gt; &lt;mi&gt;peak&lt;/mi&gt;&lt;/mrow&gt; &lt;/msub&gt; &lt;/msub&gt; &lt;annotation&gt;${{dot{V}}_{{{{mathrm{O}}}_{2{mathrm{peak}}}}}}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; )) throughout three interventions: (1) post-exercise circulatory occlusion (PECO), which isolates the leg muscle metaboreflex (MMR); (2) supine posture, which stimulates cardiopulmonary baroreceptors (CPB); and (3) 32% inspired oxygen, to supress the peripheral chemoreflex (PC). One-leg cycling increased MSNA and activated the leg MMR in patients with HFrEF but not HC. MSNA at rest and during mild exercise was lower when supine than seated in both cohorts. Breathing 32% oxygen lowered the MSNA of HC but not HFrEF. In both groups, hyperoxia decreased burst frequency during low-intensity cycling. Hyperoxia abolished the 'paradoxical' sympatho-excitation of HFrEF. Thirteen participants with HFrEF were reassessed after 4 months of conventional cardiopulmonary rehabilitation. Exercise training improved &lt;math&gt; &lt;semantics&gt; &lt;msub&gt;&lt;mover&gt;&lt;mi&gt;V&lt;/mi&gt; &lt;mo&gt;̇&lt;/mo&gt;&lt;/mover&gt; &lt;msub&gt;&lt;mi&gt;O&lt;/mi&gt; &lt;mrow&gt;&lt;mn&gt;2&lt;/mn&gt; &lt;mi&gt;peak&lt;/mi&gt;&lt;/mrow&gt; &lt;/msub&gt; &lt;/msub&gt; &lt;annotation&gt;${{dot{V}}_{{{{mathrm{O}}}_{2{mathrm{peak}}}}}}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; by 17% and attenuated the leg MMR response without altering CPB activation or PC suppression. We conclude that in HFrEF, all three autonomic reflexes are engaged to a varying degree by one-leg cycling. Patient training attenuates the leg MMR without affecting CPB or PC modulation of MSNA during exercise. KEY POINTS: In HFrEF patients, an exaggerated leg MMR is the dominant sympatho-excitatory reflex during one-leg cycling at moderate work rates; with their MSNA response relating inversely to &lt;math&gt; &lt;semantics&gt; &lt;msub&gt;&lt;mover&gt;&lt;mi&gt;V&lt;/mi&gt; &lt;mo&gt;̇&lt;/mo&gt;&lt;/mover&gt; &lt;msub&gt;&lt;mi&gt;O&lt;/mi&gt; &lt;mrow&gt;&lt;mn&gt;2&lt;/mn&gt; &lt;mi&gt;peak&lt;/mi&gt;&lt;/mrow&gt; &lt;/msub&gt; &lt;/msub&gt; &lt;annotation&gt;${{dot{V}}_{{{{mathrm{O}}}_{2{mathrm{peak}}}}}}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; . Activation of the cardiopulmonary baroreflex and peripheral chemoreflex by exercise also contribute, suggesting that exercising supine or while breathing 32% O&lt;sub&gt;2&lt;/sub&gt; may complement conv","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065042","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 silico modelling of multi-electrode arrays for enhancing cardiac drug testing on hiPSC-CM heterogeneous tissues.","authors":"Sofia Botti, Rolf Krause, Luca F Pavarino","doi":"10.1113/JP287276","DOIUrl":"https://doi.org/10.1113/JP287276","url":null,"abstract":"<p><p>Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer a transformative platform for in vitro and in silico testing of patient-specific drugs, enabling detailed study of cardiac electrophysiology. By integrating standard experimental techniques with extracellular potential measurements from multi-electrode arrays (MEAs), researchers can capture key tissue-level electrophysiological properties, such as action potential dynamics and conduction characteristics. This study presents an innovative computational framework that combines an MEA-based electrophysiological model with phenotype-specific hiPSC-CM ionic models, enabling accurate in silico predictions of drug responses. We tested four drug compounds and ion channel blockers using this model and compared these predictions against experimental MEA data, establishing the model's robustness and reliability. Additionally, we examined how tissue heterogeneity in hiPSC-CMs affects conduction velocity, providing insights into how cellular variations can influence drug efficacy and tissue-level electrical behaviour. Our model was further tested through simulations of Brugada syndrome, successfully replicating pathological electrophysiological patterns observed in adult cardiac tissues. These findings highlight the potential of hiPSC-CM MEA-based in silico modelling for advancing drug screening processes, which have the potential to refine disease-specific therapy development, and improve patient outcomes in complex cardiac conditions. KEY POINTS: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer a transformative platform for in vitro and in silico testing of patient-specific drugs, enabling detailed study of cardiac electrophysiology. Development of an innovative computational framework that combines a multi-electrode array (MEA)-based electrophysiological model with phenotype-specific hiPSC-CM ionic models. Drug testing of four compounds and ion channel blockers using this hiPSC-CM MEA model and comparison against experimental MEA data, establishing the model's robustness and reliability. Study of the effect of tissue heterogeneity in hiPSC-CMs on conduction velocity, providing insights into how cellular variations can influence drug efficacy and tissue-level electrical behaviour. Brugada syndrome simulation through the hiPSC-CM MEA model, successfully replicating pathological electrophysiological patterns observed in adult cardiac tissues.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144062961","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":"Endothelial-to-mesenchymal transition in the fetoplacental macrovasculature and microvasculature in pregnancies complicated by gestational diabetes.","authors":"Abigail R Byford, Georgia Fakonti, Ziyu Shao, Sharanam Soni, Sophie L Earle, Muath Bajarwan, Lara C Morley, Beth Holder, Eleanor M Scott, Karen Forbes","doi":"10.1113/JP287931","DOIUrl":"https://doi.org/10.1113/JP287931","url":null,"abstract":"<p><p>Gestational diabetes mellitus (GDM) is linked to altered fetal development and an increased risk of offspring developing cardiometabolic diseases in adulthood. The mechanisms responsible are unclear; however, GDM is associated with altered fetoplacental vascularisation, fibrosis and endothelial dysfunction. In non-pregnant individuals with diabetes, similar vascular changes are attributed to disruptions in endothelial-to-mesenchymal transition (EndMT), a key process where endothelial cells adopt a mesenchymal phenotype. Here, we assess whether alterations in the fetoplacental macro- and microvasculature are attributed to EndMT, using human umbilical vein endothelial cells (HUVECs) and human term placental tissue, respectively. Transforming growth factor (TGF)-β2 and interleukin (IL)-1β induced morphological and molecular changes consistent with EndMT in both GDM and non-GDM HUVECs. The ability of TGF-β2 and IL-1β to alter expression of known EndMT regulators, VWF, TGFBR1, IL1B and IL1R1, was diminished in GDM HUVECs; however, all other hallmarks of EndMT were similar. In placental villous tissue, Slug and Snail, two key transcriptional regulators of EndMT, were detected in the villous stroma, suggesting that EndMT probably occurs in the placental microvasculature. We observed a reduction in endothelial marker genes PECAM1, VWF and CDH5 in GDM placentas, suggesting reduced placental vascularisation. This was accompanied by a reduction in EndMT regulators SNAI2, TGB2, TGFB3 and TGFBR2; however, there was no change in mesenchymal markers or other EndMT regulators. This suggests that there may be some alterations in EndMT in GDM but this probably does not fully explain the endothelial dysfunction and altered vascularisation that occurs in the fetoplacental vasculature in pregnancies complicated by GDM. KEY POINTS: Gestational diabetes mellitus (GDM) has been linked to altered placental vascularisation, fibrosis and endothelial dysfunction. Disruptions in endothelial-to-mesenchymal transition (EndMT), a process where endothelial cells adopt a mesenchymal phenotype, has been linked to vascular complications in diabetes, but EndMT in GDM has not been investigated. Transforming growth factor (TGF)-β2 and interleukin (IL)-1β induced morphological and molecular changes consistent with EndMT in GDM and non-GDM human umbilical vein endothelial cells (HUVECs). Although the expression of EndMT mediators, VWF, TGFBR1, IL1B, and IL1R1, was diminished in GDM HUVECs, other EndMT hallmarks were similar. Transcriptional regulators of EndMT, Slug and Snail, were detected in the human term placenta. Despite a reduction in endothelial markers, PECAM1, VWF and CDH5, as well as SNAI2, TGFB2/3 and TGFBR2 in GDM placenta, there was no change in mesenchymal or other EndMT markers. This suggests that, although there may be some changes to EndMT in GDM, the vascular dysfunction is probably not explained fully by alterations in EndMT.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144030457","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}