Journal of Physiology-London最新文献

{"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}

{"title":"In vivo human gracilis muscle active force-length relationship is explained by the sliding filament theory.","authors":"Zheng Wang, Lomas S Persad, Benjamin I Binder-Markey, Ernest M Hoffman, William J Litchy, Alexander Y Shin, Kenton R Kaufman, Richard L Lieber","doi":"10.1113/JP288322","DOIUrl":"https://doi.org/10.1113/JP288322","url":null,"abstract":"<p><p>The sliding filament theory explains skeletal muscle fibre force change as a function of length based on the overlap of actin and myosin filaments. Although this length-tension (LT) relationship has been well investigated in animal models, it is not known whether this microscopic sarcomere LT property can be scaled up five orders of magnitude to explain the LT behaviour of a long human muscle such as the gracilis. The goal of this study is to validate the sarcomere LT curve in humans based on human filament length combined with in vivo experimental data. Intraoperative measurements of maximal tetanic force and muscle-tendon unit length at four different joint configurations (JC) were obtained from 19 patients undergoing free functioning muscle transfer surgery. With physiologically measured fibre length and estimated sarcomere shortening resulting from tendon compliance, we show that 79.7% variance in isometric force data is explained by a simple human sarcomere LT model. This study demonstrates that the human whole muscle LT relationship can be modelled by the sliding filament theory given patient-specific fibre length, filament length, tendon compliance and sarcomere shortening. KEY POINTS: Whole human gracilis muscle isometric length-tension relationships were measured in the operating room. Grouped whole muscle raw length-tension curves showed no obvious form. The width of each experimental length-tension curve was highly variable across subjects and used to predict fibre length (serial sarcomere number). After whole muscle length-tension curves were normalized to each patient's serial sarcomere number, the whole human muscle length-tension curve was well predicted by the sliding filament theory.</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":"144051894","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":"MicroRNA-138-5p suppresses excitatory synaptic strength at the cerebellar input layer.","authors":"Igor Delvendahl, Reetu Daswani, Jochen Winterer, Pierre-Luc Germain, Nora Maria Uhr, Gerhard Schratt, Martin Müller","doi":"10.1113/JP288019","DOIUrl":"https://doi.org/10.1113/JP288019","url":null,"abstract":"<p><p>MicroRNAs are small, highly conserved non-coding RNAs that negatively regulate mRNA translation and stability. In the brain, miRNAs contribute to neuronal development, synaptogenesis, and synaptic plasticity. MicroRNA 138-5p (miR-138-5p) controls inhibitory synaptic transmission in the hippocampus and is highly expressed in cerebellar excitatory neurons. However, its specific role in cerebellar synaptic transmission remains unknown. Here, we investigated excitatory transmission in the cerebellum of mice expressing a sponge construct that sequesters endogenous miR-138-5p. Mossy fibre stimulation-evoked EPSCs in granule cells were ∼40% larger in miR-138-5p sponge mice compared to controls. Furthermore, we observed larger miniature EPSC amplitudes, suggesting an increased number of functional postsynaptic AMPA receptors. High-frequency train stimulation revealed enhanced short-term depression following miR-138-5p downregulation. Together with computational modelling, this suggests a negative regulation of presynaptic release probability. Overall, our results demonstrate that miR-138-5p suppresses synaptic strength through pre- and postsynaptic mechanisms, providing a potentially powerful mechanism for tuning excitatory synaptic input into the cerebellum. KEY POINTS: MicroRNAs are powerful regulators of mRNA translation and control key cell biological processes including synaptic transmission, but their role in regulating synaptic function in the cerebellum has remained elusive. In this study, we investigated how microRNA-138-5p (miR-138-5p) modulates excitatory transmission at adult murine cerebellar mossy fibre to granule cell synapses. Downregulation of miR-138-5p enhances excitatory synaptic strength at the cerebellar input layer and increases short-term depression. miR-138-5p exerts its regulatory function through both pre- and postsynaptic mechanisms by negatively regulating release probability at mossy fibre boutons, as well as functional AMPA receptor numbers in granule cells. These findings provide insights into the role of miR-138-5p in the cerebellum and expand our understanding of microRNA-dependent control of excitatory synaptic transmission and short-term plasticity.</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":"143992830","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":"Acute ketone monoester ingestion lowers resting cerebral blood flow: a randomized cross-over trial.","authors":"Aedan J Rourke, Claudia M S Yong, Geoff B Coombs, Addriana R Odisho, Jenna A Nash, Jack Bone, Baraa K Al-Khazraji, Jeremy J Walsh","doi":"10.1113/JP287320","DOIUrl":"https://doi.org/10.1113/JP287320","url":null,"abstract":"<p><p>Exogenous ketone monoester (KME) supplements rapidly increase plasma beta-hydroxybutyrate (β-OHB) and may impact cerebral blood flow (CBF). However, it is currently unknown how acute KME ingestion impacts resting CBF and whether differences in KME dose have differential effects on CBF regulation. The purpose of this study was to investigate the effect of two separate KME doses on resting CBF in young adults. On separate days and in a double-blind, placebo-controlled, cross-over design, 20 participants (10 females; aged 23 ± 3 years) ingested either: (1) High-KME (0.6 g kg^-1 β-OHB); (2) Low-KME (0.3 g kg^-1 β-OHB); or (3) placebo drink, and quietly rested for 120 min. Global CBF (gCBF) was assessed using duplex ultrasound of the internal carotid and vertebral arteries, and transcranial Doppler ultrasound was used to assess middle cerebral artery blood velocity at baseline, 45 min and 120 min post-ingestion. End-tidal CO₂ ( <math> <semantics><msub><mi>P</mi> <mrow><mi>ETC</mi> <msub><mi>O</mi> <mn>2</mn></msub> </mrow> </msub> <annotation>${P_{{mathrm{ETC}}{{mathrm{O}}_2}}}$</annotation></semantics> </math> ) was measured using a gas analyser. β-OHB was measured in venous blood. At 45 min post-ingestion, gCBF was significantly reduced by 10.6% in Low-KME and by 14.6% in High-KME compared to baseline. At 120 min, gCBF returned towards baseline in Low-KME, whereas gCBF was further reduced by 19.1% in High-KME compared to baseline. KME dose-dependent reductions in <math> <semantics><msub><mi>P</mi> <mrow><mi>ETC</mi> <msub><mi>O</mi> <mn>2</mn></msub> </mrow> </msub> <annotation>${P_{{mathrm{ETC}}{{mathrm{O}}_2}}}$</annotation></semantics> </math> may have contributed to these reductions in gCBF following KME ingestion. These novel findings provide a foundational characterization of the impact of KME on resting CBF, which prompts further investigation building on these results to isolate underlying mechanisms and develop dosing protocols to mitigate potential CO₂ disruptions. KEY POINTS: Beta-hydroxybutyrate (β-OHB) is a signalling molecule and β-OHB infusion increases cerebral blood flow (CBF) in humans. Ingestion of higher doses of a ketone monoester (KME) supplement have been shown to lower blood pH and arterial CO₂, which are important regulators of CBF. This double-blind and placebo-controlled cross-over study tested the effects of two separate KME doses (Low-KME and High-KME) on resting CBF, end-tidal CO₂ and systemic haemodynamics over a 2 h period post-ingestion in young adults. Low-KME reduced CBF 45 min post-ingestion and High-KME reduced CBF at both 45 and 120 min post-ingestion, which corresponded with dose-dependent reductions in end-tidal CO₂. The findings from this trial represent a foundational characterization of the effects of KME dose on resting CBF.</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":"144050717","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":"14-3-3 proteins: Regulators of cardiac excitation-contraction coupling and stress responses.","authors":"Heather C Spooner, Rose E Dixon","doi":"10.1113/JP288566","DOIUrl":"https://doi.org/10.1113/JP288566","url":null,"abstract":"<p><p>14-3-3 proteins are highly conserved proteins that regulate numerous cellular processes mostly through phosphorylation-dependent protein-protein interactions. In the heart 14-3-3 proteins play critical roles in cardiac conduction pathways, excitation-contraction (EC) coupling, development and stress responses. This review summarizes the current understanding of cardiac 14-3-3 regulation and function, with particular emphasis on its role in ion channel regulation and β-adrenergic signalling. We discuss how 14-3-3 proteins act through three main mechanisms - masking, clamping, and scaffolding - to regulate target proteins, including Cx43, Ca_V1.2, Na_V1.5, and various potassium channels. The seven mammalian 14-3-3 isoforms display distinct but overlapping functions, with tissue-specific expression patterns and isoform-specific regulation through phosphorylation and dimerization. Recent work has revealed 14-3-3's importance in cardiac development and stress responses, where it generally serves a cardioprotective role. However in some pathological contexts such as ischaemia-reperfusion injury, 14-3-3 can be detrimental. We highlight emerging themes in cardiac 14-3-3 biology, including its role in prolonging β-adrenergic signalling. Understanding the complex regulation of cardiac 14-3-3 and its numerous targets presents both opportunities and challenges for therapeutic development.</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":"144042854","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":"Properties of rhythmogenic currents in spinal Shox2 interneurons across postnatal development.","authors":"Shayna Singh, Natalia A Shevtsova, Lihua Yao, Ilya A Rybak, Kimberly J Dougherty","doi":"10.1113/JP287752","DOIUrl":"https://doi.org/10.1113/JP287752","url":null,"abstract":"<p><p>Locomotor behaviours are performed by organisms throughout life, despite developmental changes in cellular properties, neural connectivity and biomechanics. The basic rhythmic activity in the central nervous system underlying locomotion is considered to be generated via a complex interplay between network and intrinsic cellular properties. Within mature mammalian spinal locomotor circuitry, we have yet to determine which properties of spinal interneurons (INs) are critical to rhythmogenesis and how they change during development. Here, we combined whole cell patch clamp recordings, immunohistochemistry and RNAscope targeting lumbar Shox2 INs in mice, which are known to be involved in locomotor rhythm generation. Our goal was to determine the postnatal developmental expression of voltage-sensitive conductances, in addition to respective ion channels, in Shox2 INs. We show that subsets of Shox2 INs display persistent inward currents, M-type potassium currents, slow afterhyperpolarization and T-type calcium currents, which are enhanced with age. By contrast, the hyperpolarization-activated and A-type potassium currents were either found with low prevalence in subsets of neonatal, juvenile, and adult Shox2 INs or did not developmentally change. We show that Shox2 INs become more electrophysiologically diverse by juvenile and adult ages, when locomotor behaviour becomes weight-bearing. Computational modelling was used to simulate and reproduce electrophysiological experiments for representative Shox2 INs to make predictions regarding the interactions between experimentally recorded conductances and persistent inward currents, and bursting behaviour. Our results suggest a developmental shift in the magnitude of rhythmogenic ionic currents and the expression of corresponding ion channels that may be important for mature locomotor behaviour. KEY POINTS: The intrinsic and voltage-sensitive properties of locomotor-related neurons contribute to shaping and maintaining activity. Shox2 interneurons (INs), similar to many other components of locomotor circuitry, are well-characterized in the neonatal mouse. Electrophysiological recordings reveal that subsets of Shox2 INs express 'rhythmogenic properties', including persistent inward currents, M-type potassium currents and slow afterhyperpolarization, as well as corresponding ion channels/RNA. Hierarchical clustering demonstrates that developmental changes seen are related to the emergence of electrophysiological cell types, largely defined by strong rhythmogenic current expression. Our data suggest that Shox2 INs gain electrophysiological diversity with age, and that Shox2 INs from adult mice may employ enhanced voltage-sensitive conductances during rhythmic locomotor activity.</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":"144045176","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":"Load and muscle-dependent changes in triceps surae motor unit firing properties in individuals with non-insertional Achilles tendinopathy.","authors":"Ignacio Contreras-Hernandez, Deborah Falla, Michail Arvanitidis, Francesco Negro, David Jimenez-Grande, Eduardo Martinez-Valdes","doi":"10.1113/JP287588","DOIUrl":"https://doi.org/10.1113/JP287588","url":null,"abstract":"<p><p>Non-insertional Achilles tendinopathy (NIAT) induces morpho-mechanical changes to the Achilles tendon (AT). Evidence on how triceps surae motor unit firing properties are influenced by altered tendon mechanics in NIAT is limited. This study investigated motor unit firing properties (mean discharge rate (DR), recruitment and de-recruitment thresholds, and discharge rate variability (COVisi)), motor unit firing-torque relationships (cross-correlation coefficient between cumulative spike train (CST) and torque, and neuromechanical delay (NMD)) and neural drive distribution (connectivity strength and functional networks) of the medial gastrocnemius (MG), lateral gastrocnemius (LG), and soleus (SO) muscles during isometric plantarflexion contractions at 10%, 40%, and 70% maximal voluntary contraction (MVC) using high-density surface electromyography (HD-sEMG) on 26 individuals with NIAT and 25 healthy controls. AT's morpho-mechanical properties (thickness, cross-sectional area, length, and stiffness) were assessed via ultrasonography. Motor unit properties changed in a load and muscle-dependent manner. LG DR increased (p = 0.002) and de-recruitment threshold decreased (p = 0.039) at 70% MVC in the NIAT group compared to controls. The CST-torque cross-correlation coefficient of the LG decreased at 10% MVC (p < 0.0001) and increased at 70% MVC (p = 0.013) in the NIAT group. Connectivity strength for the 0-5 Hz and 5-15 Hz frequency bands decreased (p < 0.01) in the NIAT group at 10% MVC. Furthermore, NIAT individuals showed reduced tendon stiffness and increased thickness (p < 0.01). This study shows that individuals with NIAT exhibit load- and muscle-dependent changes in motor unit firing properties, motor unit-torque relationships, and neural drive distribution to the triceps surae. These alterations may be due to muscle-specific compensations for AT's modified mechanical properties. KEY POINTS: Individuals with non-insertional Achilles tendinopathy (NIAT) have changes in the neural drive to the lateral gastrocnemius (LG) muscle and altered contribution of the LG to the net plantarflexion torque. Individuals with NIAT show a more uneven distribution of neural drive to the triceps surae muscle at low force levels, characterised by reduced intermuscular coherence between the medial and lateral gastrocnemius in the 0-5 Hz and 5-15 Hz bands compared to the control group. Our findings support the idea that the LG may have a central role in the pathophysiology of this condition, possibly affecting the load transmission to the Achilles tendon (AT).</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":"144045189","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}