Journal of Physiology-London最新文献

{"title":"Effects of inhibition of Janus kinase signalling during controlled mechanical ventilation on the rate of skeletal muscle protein synthesis.","authors":"William J Evans, Mahalakshmi Shankaran, Lars Larsson, Nicola Cacciani, Yvette Hedström, James L Kirkland, Tamar Tchkonia, Hussein Mohammed, Tyler Field, Marc K Hellerstein","doi":"10.1113/JP288982","DOIUrl":"https://doi.org/10.1113/JP288982","url":null,"abstract":"<p><p>We employed a unique murine intensive care unit (ICU) model allowing long-term studies of the ICU condition (immobilization, paralysis, sedation and mechanical ventilation). This model resulted in a substantial loss of myofibrillar protein and muscle size. We hypothesized that an inhibitor of Janus kinase (JAK) activation of transcription 3 (STAT3 (signal transducer and activator of transcription 3)) phosphorylation would help to preserve muscle mass by stimulating the rate of protein synthesis. Sprague-Dawley rats were divided into a control group (CON, n = 5) and two groups exposed to the ICU condition for 8 days. One group was treated with a JAK/STAT3 inhibitor (JST, n = 5) and one without a JST (immobilized group, n = 3) inhibitor. To measure the fractional synthesis rate (FSR) of proteins across the muscle proteome, ²H₂O was administered as an intraparitoneal (IP) bolus followed by continuous infusion of 8% ²H₂O to maintain body water enrichment. Soleus, extensor digitorum longus (EDL), tibialis anterior (TA), gastrocnemius and diaphragm were obtained from all animals. Liquid chromatography-mass spectrometry (LC/MS-MS) analysis was used to measure protein FSR. Compared to CON myofibrillar protein FSR was decreased 39%-73%, with the decrease in gastrocnemius > soleus > TA > diaphragm > EDL. Sarcoplasmic protein FSR was decreased 38%-69%, with the decrease in gastrocnemius > TA > EDL > soleus > diaphragm. Mitochondrial protein FSR was decreased 34%-52%, with the decrease in TA > soleus > gastrocnemius > EDL > diaphragm. The decreases in protein flux rates by ontology corresponded broadly with function and fibre types. Immobilization resulted in profound and tissue-specific decreases in protein FSR, with JAK/STAT3 showing a significant effect to preserve FSR, muscle mass and body weight. KEY POINTS: Mechanical silencing of skeletal muscle resulted in a large lowering of protein fractional synthesis rate (FSR) in all muscles measured, the extent of which was muscle- and fibre specific. All muscle protein ontologies were affected. A Janus kinase (JAK)/STAT inhibitor had a positive effect on body mass, muscle size and protein FSR.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145226297","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":"Intrinsic mechanisms contributing to the biophysical signature of mouse gamma motoneurons.","authors":"Simon A Sharples, Struan J Nisbet, Matthew J Broadhead, Dennis Bo Jensen, Francesca L Sorrell, Claire F Meehan, Gareth B Miles","doi":"10.1113/JP289631","DOIUrl":"https://doi.org/10.1113/JP289631","url":null,"abstract":"<p><p>Precise motor control relies on continuous sensory feedback from muscles, a process in which gamma motoneurons play a key role. These specialized spinal neurons innervate intrafusal muscle fibres, modulating their sensitivity to stretch and maintaining proprioceptive signalling during movement. Gamma motoneurons are characterized by a distinct biophysical profile, including low recruitment thresholds and high firing rates that enable rapid activation of intrafusal fibres at contraction onset. Despite their importance, the intrinsic mechanisms that underlie these properties remain poorly understood. In the present study, we analysed published and unpublished data to identify a population of low-threshold, high-gain motoneurons with features consistent with gamma motoneurons, emerging during the third postnatal week in mice. Their low recruitment threshold was linked to lower membrane capacitance, higher input resistance, a more hyperpolarized activation of persistent inward currents (PICs) and a narrower axon initial segment. By contrast, higher firing rates were associated not with PIC amplitude but with shorter action potential durations and smaller medium afterhyperpolarizations. Notably, 92% of putative gamma motoneurons exhibited a sodium pump-mediated ultra-slow afterhyperpolarization, which was absent in slow alpha motoneurons. This difference could not be attributed to h-current activity or expression of the alpha 3 subunit of the sodium-potassium ATPase. These findings reveal key intrinsic properties that support the unique excitability of gamma motoneurons, offering new insight into their contribution to motor control. This work provides a foundation for future studies into their development, regulation and involvement in neuromuscular disorders. KEY POINTS: A distinct cluster of motoneurons with low recruitment current and high firing gain, characteristic of gamma motoneurons, emerges in the third week of postnatal development. Gamma motoneurons have a low recruitment current as a result of lower capacitance, higher input resistance and a more hyperpolarized activation voltage for persistent inward currents. Their high firing rates are not driven by differences in persistent inward current amplitude but are instead attributed to shorter duration action potentials and smaller amplitude medium afterhyperpolarizations. A narrower axon initial segment in gamma motoneulrons may contribute to their increased excitability compared to alpha motoneurons. Gamma motoneurons present with a higher prevalence of ultra slow afterhyperpolarization than slow alpha motoneurons that cannot be accounted for by differences in h-current or expression of alpha 3 subunits of the sodium potassium ATPase pump.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145226341","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":"Out of breath and looking for options: Understanding pulmonary contributions to exercise intolerance in heart failure with preserved ejection fraction.","authors":"Michael K Stickland","doi":"10.1113/JP289994","DOIUrl":"https://doi.org/10.1113/JP289994","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145207765","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":"Mechanistic insights into sex differences in atrial electrophysiology and arrhythmia vulnerability through sex-specific computational models.","authors":"Nathaniel T Herrera, Haibo Ni, Charlotte E R Smith, Yixuan Wu, Dobromir Dobrev, Stefano Morotti, Eleonora Grandi","doi":"10.1113/JP289425","DOIUrl":"10.1113/JP289425","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Atrial fibrillation (AF), the most common cardiac arrhythmia, shows marked sex differences in clinical presentation, treatment response and outcomes. Although prevalence is similar, women often experience more severe symptoms, higher rates of adverse drug effects and reduced treatment efficacy. To investigate the underlying sex-specific AF mechanisms, we developed and validated male and female human atrial cardiomyocyte models that integrate sex-based differences in electrophysiology and calcium (Ca&lt;sup&gt;2+&lt;/sup&gt;) handling under normal sinus rhythm (nSR) and chronic AF (cAF) conditions. Although the model parameterizations and assumptions (based on limited human data) may not capture the full spectrum of clinical variability, the models reproduced key reported sex-dependent differences in human atrial cardiomyocyte action potential (AP) and Ca&lt;sup&gt;2+&lt;/sup&gt; transient (CaT) dynamics. Simulations revealed that both sexes exhibited shortened effective refractory periods and wavelengths in cAF vs. nSR. Females were more prone to delayed afterdepolarizations (DADs), whereas males were more susceptible to AP duration (APD) and CaT amplitude (CaT&lt;sub&gt;Amp&lt;/sub&gt;) alternans. Population-based modelling identified distinct parameter associations with arrhythmia mechanisms: DAD vulnerability was associated with enhanced ryanodine receptor Ca&lt;sup&gt;2+&lt;/sup&gt; sensitivity in females, and alternans in males correlated with reduced L-type Ca&lt;sup&gt;2+&lt;/sup&gt; current maximal conductance. Pharmacological simulations revealed sex-specific responses to antiarrhythmic therapies. In males, multiple drug combinations restored APD at 90% repolarization (APD&lt;sub&gt;90&lt;/sub&gt;), CaT&lt;sub&gt;Amp&lt;/sub&gt; and reduced alternans susceptibility, whereas females responded to only one combination improving APD&lt;sub&gt;90&lt;/sub&gt; and CaT&lt;sub&gt;Amp&lt;/sub&gt; but with minimal impact on DAD risk. These findings underscore the need for sex-specific therapeutic strategies and support use of computational modelling in guiding precision medicine against AF. KEY POINTS: Atrial fibrillation (AF) is a common heart rhythm disorder that presents differently in males and females, but how the underlying mechanisms differ in males and females is not fully understood. We developed and validated computer models of male and female human atrial cardiomyocytes that incorporate known sex differences in ion channels and calcium handling under normal sinus rhythm and AF conditions. Under normal rhythm, males and females showed distinct electrical activity, which became less pronounced in AF. In AF, both sexes showed reduced effective refractory period and wavelength and depressed calcium transients. Males were more susceptible to electrical alternans, whereas females showed a greater tendency for calcium-driven delayed afterdepolarizations. Simulated drug treatments showed greater benefit in male models, particularly with combinations targeting multiple potassium channels, whereas female models showed limited response. These resul","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12520146/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145208612","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":"Preferential lactate metabolism in the human brain during exogenous and endogenous hyperlactataemia.","authors":"Jodie L Koep, Jennifer S Duffy, Jay M J R Carr, Madden L Brewster, Jordan D Bird, Justin A Monteleone, Tenasia D R Monaghan, Hashim Islam, Andrew R Steele, Connor A Howe, David B MacLeod, Philip N Ainslie, Travis D Gibbons","doi":"10.1113/JP289216","DOIUrl":"https://doi.org/10.1113/JP289216","url":null,"abstract":"&lt;p&gt;&lt;p&gt;At rest, glucose serves as the brain's primary oxidative substrate; however, when circulating lactate is elevated, lactate oxidation increases. Whether this glucose-sparing effect differs when lactate is elevated via passive infusion versus exercise remains unknown. To address this, 13 healthy adults (six females) completed protocols of: (1) intravenous sodium lactate infusion (exogenous hyperlactataemia); and (2) cycling exercise (endogenous hyperlactataemia) to matched elevations in arterial lactate concentration (∼4 and ∼8 mmol/l). Radial arterial and internal jugular venous sampling and measures of cerebral blood flow (CBF) were used to calculate cerebral metabolic rates of glucose (CMR&lt;sub&gt;Glc&lt;/sub&gt;), lactate (CMR&lt;sub&gt;iLac&lt;/sub&gt;), and oxygen ( &lt;math&gt; &lt;semantics&gt;&lt;mrow&gt;&lt;mi&gt;CM&lt;/mi&gt; &lt;msub&gt;&lt;mi&gt;R&lt;/mi&gt; &lt;msub&gt;&lt;mi&gt;O&lt;/mi&gt; &lt;mn&gt;2&lt;/mn&gt;&lt;/msub&gt; &lt;/msub&gt; &lt;/mrow&gt; &lt;annotation&gt;${mathrm{CM}}{{mathrm{R}}_{{{mathrm{O}}_2}}}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; ). The exogenous infusion protocol resulted in a higher CBF compared to exercise (P &lt; 0.001), despite causing systemic alkalosis (P &lt; 0.001). During both protocols &lt;math&gt; &lt;semantics&gt;&lt;mrow&gt;&lt;mi&gt;CM&lt;/mi&gt; &lt;msub&gt;&lt;mi&gt;R&lt;/mi&gt; &lt;msub&gt;&lt;mi&gt;O&lt;/mi&gt; &lt;mn&gt;2&lt;/mn&gt;&lt;/msub&gt; &lt;/msub&gt; &lt;/mrow&gt; &lt;annotation&gt;${mathrm{CM}}{{mathrm{R}}_{{{mathrm{O}}_2}}}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; remained unchanged across increases in lactate concentrations (P = 0.610), while CMR&lt;sub&gt;Glc&lt;/sub&gt; decreased (lactate, P = 0.009; condition, P = 0.373) and CMR&lt;sub&gt;iLac&lt;/sub&gt; increased in a dose-dependent manner (lactate, P &lt; 0.001; condition, P = 0.972). At an arterial concentration of 8 mmol/l, circulating lactate accounted for 24% of total cerebral oxidative metabolism. Elevated circulating lactate leads to preferential lactate oxidation and reduced glucose utilization, irrespective of whether lactate is delivered exogenously or produced endogenously. KEY POINTS: The human brain relies primarily on oxidative glucose metabolism; however, with age and in many pathologies cerebral glucose metabolism declines; therefore, there is interest in investigating alternative fuel sources that can meet the high energetic needs of the brain. The present study investigates whether increased lactate availability exerts a glucose-sparing effect in the healthy human brain, and whether this effect is consistent across physiologically distinct states of exogenous (sodium lactate infusion) and endogenous (exercise-induced) hyperlactataemia. We assessed cerebral uptake and metabolism of glucose and lactate following exercise and lactate infusion, using simultaneous arterial and jugular venous blood samples, and Duplex ultrasound. Despite stark systemic physiological differences between conditions, cerebral glucose metabolism declined in proportion to increased circulating lactate irrespective of whether it is delivered exogenously or produced endogenously. These data provide clear evidence that lactate is preferentially oxidized by the brain when made available, helping p","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145207982","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":"A deep learning-enabled toolkit for the 3D segmentation of ventricular cardiomyocytes.","authors":"Joachim Greiner, Fabio Frangiamore, Frédéric Sonak, Josef Madl, Thomas Seidel, Peter Kohl, Eva A Rog-Zielinska","doi":"10.1113/JP288557","DOIUrl":"https://doi.org/10.1113/JP288557","url":null,"abstract":"<p><p>Segmentation of cardiomyocytes in microscopic 3D volumes is key to our understanding of cardiac (patho-)physiology; however, it poses substantial experimental and analytical challenges. Therefore, researchers often resort to inferring 3D information from 2D segmentations, which can lead to biased and incorrect conclusions. Deep learning-based methods are showing promise with respect to robustly segmenting objects in volumes acquired using various imaging modalities; yet, they have not been applied to high-resolution 3D cardiomyocyte segmentations, and suitable open-source tools and datasets are lacking. Here, we present a deep learning-enabled toolkit for segmentation of individual cardiomyocytes in 3D confocal microscopy volumes. We include a dataset of 73 volumes with expert annotations, covering seven species, including mouse, human, and elephant, and containing samples generated under different experimental conditions, such as post-myocardial infarction and ex vivo slice cultures. The toolkit additionally contains an image restoration workflow to address imaging-related artefacts, such as spatially varying blur. Our automatic cardiomyocyte segmentation workflow achieved an adapted Rand error of 0.063 ± 0.034 (∼94% voxel-pair agreement) on the test set. Our semi-automatic workflow reached a throughput of 3 cells min^-1 on a challenging, previously unseen dataset. The toolkit and data are open-source and accessible through a dedicated graphical user interface. In summary, we provide an accessible toolkit enabling researchers to extract quantitative data on cardiomyocyte microstructure from 3D confocal image stacks of cardiac tissue. Given the size and diversity of our dataset, we expect our methods to perform well across species and experimental conditions, facilitating high-quality 3D reconstructions of large numbers of individual cardiomyocytes. KEY POINTS: 3D cardiomyocyte microstructure is a key determinant of cardiac function in health and disease. However, reliable extraction and quantification of 3D cardiomyocyte cytoarchitecture pose significant experimental and computational challenges. We present an effective experimental protocol and a deep learning-enabled toolkit for sample preparation and 3D analysis of cardiomyocyte morphology in ventricular myocardium. Our method is validated across seven species (mouse to human) and in samples prepared in diverse experimental conditions from a range of models, including myocardial infarction and ex vivo tissue culture, highlighting the robustness and versatility of our workflow. Our open-source dataset and toolkit enable large-scale analyses and extraction of realistic 3D geometries of ventricular microstructure. These can be used to explore a host of research questions and provide a new resource for modelling cardiac function at the cellular level.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145202046","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":"Soft tissue accumulations of phosphate are not always associated with serum phosphate or with calcifications in mouse models of hyperphosphatemia.","authors":"Abul Fajol, Kylie Heitman, S Madison Thomas, Qing Li, Tanecia Mitchell, Jorge Gamboa, Abolfazl Zarjou, Orlando M Gutierrez, Christian Faul","doi":"10.1113/JP289283","DOIUrl":"https://doi.org/10.1113/JP289283","url":null,"abstract":"<p><p>High serum levels of phosphate (hyperphosphatemia) can target vascular smooth muscle cells (VSMC) and induce calcium-phosphate precipitations and vascular calcification, thereby contributing to high cardiovascular mortality rates in chronic kidney disease (CKD). Calcifications within soft tissues beyond the vasculature are not well described, and the involvement of cell types other than VSMCs is not clear. Here, we studied extravascular calcifications in various soft tissues from mouse models with hyperphosphatemia. We found that klotho-deficient (kl/kl) mice without CKD not only developed calcifications in the aorta, but also in the kidney and stomach, which was accompanied by significant elevations in tissue content of phosphate. Administration of a magnesium-rich diet, which blocks the formation of calcium-phosphate crystals, prevented calcifications in these tissues. Liver, heart, skeletal muscle, spleen, brain and skin showed no signs of calcifications. Similarly, CKD mice with global deletion of Col4a3 (Col4a3^-/-) showed significant increases in phosphate content and calcifications in aorta, kidney and stomach, but only when administered a high phosphate diet, which was not accompanied by further elevations in serum phosphate levels. In Col4a3^-/- mice on normal chow, we could only detect an increase in liver phosphate content that occurred in the absence of hepatic calcifications. Our findings indicate that soft tissue calcifications are not always associated with increases in serum phosphate concentrations. Furthermore, in some tissues, the accumulation of phosphate occurs independently of serum phosphate elevations and is not necessarily accompanied by calcifications. Overall, our findings indicate that soft tissues differ in their response to hyperphosphatemia. KEY POINTS: It is known that high serum phosphate levels (hyperphosphatemia) cause vascular calcifications, which are accompanied by increases in tissue phosphate content. Here, we show in mouse models of hyperphosphatemia that calcifications also occur in soft tissue areas outside of the vasculature (extravascular calcification). We also found that in some soft tissues the accumulation of phosphate is not accompanied by calcifications and occurs independently of serum phosphate elevations. Our findings indicate that soft tissues differ in their response to hyperphosphatemia. Because tissue elevations of phosphate drive the calcification process, CKD studies to determine causalities between hyperphosphatemia, tissue injuries and mortality should not be restricted to measuring phosphate levels in the circulation. Our finding that the administration of a magnesium-rich diet protects hyperphosphatemic mice from phosphate accumulations and calcifications in various soft tissues supports ongoing clinical trials that aim to determine the beneficial effects of magnesium elevations in patients with CKD.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145193713","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":"Enviromimetics: From exercise mimetics to cognitomimetics in the quest for enhanced brain health and cognition.","authors":"Anthony J Hannan","doi":"10.1113/JP287484","DOIUrl":"https://doi.org/10.1113/JP287484","url":null,"abstract":"<p><p>Enviromimetics were first proposed over two decades ago, as novel therapeutics to mimic or enhance the beneficial effects of environmental stimulation. In the intervening period, subclasses of enviromimetics have been proposed, most notably exercise mimetics. Epimimetics constitute an additional subclass of enviromimetics, which act via epigenetic mechanisms. In this article, the concept of enviromimetics is updated, including its subclasses, and explored in the context of the development of novel therapeutic approaches to a wide range of human disorders, with a specific focus on neurological diseases and psychiatric disorders. Furthermore, a new concept is introduced, that of 'cognitomimetics', which specifically mimic or enhance the therapeutic effects of cognitive stimulation. One focus of discussion is the beneficial molecular and cellular mechanisms induced by environmental exposures and lifestyle factors, including increased physical activity and cognitive stimulation. Exercise mimetics represent the largest, and most experimentally tractable, subclass of enviromimetics, due to the biologically pervasive and readily quantifiable therapeutic impacts of physical activity, both within the nervous system, and throughout the body. These mechanisms provide new insights into molecular targets for these novel therapeutic approaches. It is hoped that this will lead to new ways to prevent, ameliorate and eventually cure a wide range of human illnesses, particularly brain disorders, which collectively constitute the largest, and most rapidly growing, global burden of disease.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145193761","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":"The only whey to recover: protein-carbohydrate co-ingestion for endurance exercise recovery.","authors":"Ellika Greaves, Ania Avadanei, Andrea Viloria Medina, Mingyang Fan","doi":"10.1113/JP289896","DOIUrl":"https://doi.org/10.1113/JP289896","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182338","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":"Dual cholinergic and serotonergic excitatory pathways mediate oxygen sensing in the zebrafish gill.","authors":"Maddison Reed, Anthea A Mavridis, Jan A Mennigen, Michael G Jonz","doi":"10.1113/JP289409","DOIUrl":"https://doi.org/10.1113/JP289409","url":null,"abstract":"<p><p>The evolution of oxygen sensing included a transition from a diffuse distribution of respiratory chemoreceptors in the gills of water-breathing vertebrates to chemoreceptor clusters confined to the pulmonary epithelium and carotid body in air-breathers. Since the excitatory neurotransmitters mediating oxygen sensing in anamniotes have never been confirmed, the origins of oxygen sensing in vertebrates have remained controversial. In gills isolated from Tg(elavl3:GCaMP6s) zebrafish expressing a genetically encoded reporter of intracellular Ca²⁺ concentration ([Ca²⁺]_i), we demonstrate that acetylcholine (ACh) and nicotine induced a dose-dependent increase in [Ca²⁺]_i in postsynaptic sensory neurons innervating oxygen-chemoreceptive neuroepithelial cells (NECs). Hypoxic stimulation of NECs evoked a similar rise in neuronal [Ca²⁺]_i that was abolished by the nicotinic antagonist hexamethonium. Using immunohistochemistry and RT-qPCR, we identified a novel population of ACh-containing NECs associated with sensory neurons expressing the α2 subunit of nicotinic ACh receptors. In vivo whole-larva Ca²⁺ imaging showed that cholinergic and hypoxic activation of the gills generated Ca²⁺ activity in neurons of vagal sensory ganglia with time-dependent characteristics of neurotransmission towards the hindbrain. We identified a second source of hypoxic activity in vagal sensory ganglia operating exclusively through 5-HT₃ receptors and dependent upon vesicular monoamine transport (VMAT2) in the gill. We traced expression of 5-HT₃ receptors to nerve terminals surrounding a separate population of serotonergic VMAT2-positive NECs. Our investigation reveals independent cholinergic and serotonergic autonomic pathways of oxygen sensing in zebrafish and provides novel physiological evidence consistent with the idea that gill chemoreceptors are homologues of both pulmonary and carotid body chemoreceptors in mammals. KEY POINTS: The excitatory neurotransmitters mediating oxygen sensing in anamniotes have never been confirmed. Thus, the origins of oxygen sensing in vertebrates have remained controversial. In transgenic zebrafish expressing a genetically encoded reporter of intracellular Ca²⁺ concentration, we identified two independent pathways of oxygen sensing in the gill: one involving acetylcholine and interneurons intrinsic to the gill, and the other via serotonin acting directly upon ganglionic neurons. Both pathways resulted in excitation of vagal sensory ganglia that receive hypoxic inputs from the gills and innervate the hindbrain. We argue that gill chemoreceptors are homologues of both pulmonary and carotid body chemoreceptors in mammals.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182315","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}