Journal of Physiology-London最新文献

{"title":"The role of carotid artery perfusion on sympathetic regulation during exercise: Potential implications for exercise intolerance in heart failure.","authors":"Megan K Costain, Khushi Afzal Patel, Arafa Hossain","doi":"10.1113/JP288737","DOIUrl":"https://doi.org/10.1113/JP288737","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144042675","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":"Complexin gains effective access to the assembling SNAREs via its membrane-binding C-terminal domain.","authors":"Justine A Lottermoser, Haowen Liu, Jihong Bai, Zhitao Hu, Jeremy S Dittman","doi":"10.1113/JP286500","DOIUrl":"https://doi.org/10.1113/JP286500","url":null,"abstract":"<p><p>The conserved presynaptic SNARE-binding protein complexin (Cpx) promotes Ca²⁺-triggered synaptic vesicle (SV) fusion and inhibits spontaneous fusion at some synapses. A membrane-binding motif in the C-terminal domain (CTD) of Cpx plays a critical role in Cpx function, but it remains unclear whether the CTD participates in Cpx regulation of synaptic transmission beyond targeting Cpx to membranes. We examined the impact of the Caenorhabditis elegans CPX-1 CTD in vivo and found that this domain profoundly boosted the efficiency of CPX-1-mediated inhibition of spontaneous SV fusion as a function of protein abundance at the synapse. Removing the C-terminal half of CPX-1 and substituting it with the SV protein RAB-3 was able to fully restore both the fusogenic and inhibitory functions of CPX-1 whereas other SV proteins failed to restore CPX-1 function with the same efficiency regardless of abundance. These results indicate that regulation of spontaneous SV fusion requires a specific interaction of CPX-1 with the SV membrane. We propose that Cpx cannot efficiently access assembling SNAREs from the cytoplasm and that interactions of its CTD with the SV membrane guide Cpx to these sites of SNARE assembly. KEY POINTS: Complexin (Cpx) regulates presynaptic SNARE assembly to control synaptic transmission. A membrane curvature-sensing motif within the Cpx C-terminal domain (CTD) recruits Cpx to vesicles. Replacement of the CTD with the synaptic vesicle protein Rab3 can restore full Cpx function whereas other vesicle proteins fail to substitute regardless of abundance. The efficiency of Cpx-mediated inhibition of synaptic vesicle fusion is profoundly enhanced by the specific localization supplied by its CTD. These results suggest that Cpx reaches the assembling SNARE complexes via its specific CTD-membrane interactions and these SNAREs are inaccessible from the cytoplasmic compartment.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990539","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":"Disrupted circadian rhythms and hormonal suppression mediate skeletal muscle mitochondrial dysfunction in nocturia.","authors":"Yu-Hsiang Lin, Yu-Chen Chen, Hsiang-Ying Lee","doi":"10.1113/JP288972","DOIUrl":"https://doi.org/10.1113/JP288972","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144053481","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":"Integrated single-cell functional-proteomic profiling reveals a shift in myofibre specificity in human nemaline myopathy: A proof-of-principle study.","authors":"Robert A E Seaborne, Roger Moreno-Justicia, Jenni Laitila, Chris T A Lewis, Lola Savoure, Edmar Zanoteli, Michael W Lawlor, Heinz Jungbluth, Atul S Deshmukh, Julien Ochala","doi":"10.1113/JP288363","DOIUrl":"https://doi.org/10.1113/JP288363","url":null,"abstract":"<p><p>Skeletal muscle is a complex syncytial arrangement of an array of cell types and, in the case of muscle-specific cells (myofibres), subtypes. There exists extensive heterogeneity in skeletal muscle functional behaviour and molecular landscape at the cell composition, myofibre subtype and intra-myofibre subtype level. This heterogeneity highlights limitations in currently applied methodological approaches, which has stagnated our understanding of fundamental skeletal muscle biology in both healthy and myopathic contexts. Here we developed a novel approach that combines a fluorescence-based assay for the biophysical examination of the sarcomeric protein, myosin, coupled with same-myofibre high-sensitivity proteome profiling, termed single myofibre protein function-omics (SMPFO). Applying this approach as proof-of-principle we identify the integrated relationship between myofibre functionality and the underlying proteomic landscape that guides divergent, but physiologically important, behaviour in myofibre subtypes in healthy human skeletal muscle. By applying SMPFO to two forms of human nemaline myopathy (ACTA1 and TNNT1 mutations), we reveal significant reduction in the divergence of myofibre subtypes across both biophysical and proteomic behaviour. Collectively we demonstrate preliminary findings of SMPFO to support its use to study skeletal muscle with greater specificity, accuracy and resolution than currently applied methods, facilitating that advancement in understanding of skeletal muscle tissue in both healthy and diseased states. KEY POINTS: Skeletal muscle is a complex tissue made up of an array of cell and sub-cell types, with the resident muscle cell - myofibre - critical for contractile function. Although single myofibre studies have advanced, existing methods lack the precision for simultaneous multidata analysis, hindering developments in our understanding of skeletal muscle. We introduce single myofibre protein function-omics (SMPFO), a method enabling functional analysis of sarcomeric myosin alongside global protein abundance within the same myofibre. In healthy myofibres SMyoMFO reveals extensive biochemical diversity in myosin heads, correlating with the abundance of metabolic and sarcomeric proteins, including subtype-specific patterns in sarcoglycan delta (SGCD). In contrast SMyoMFO uniquely reveals a reduction in diversity of myosin function and the myofibre proteome in two forms of nemaline myopathy, highlighting disease-associated alterations. This innovative approach provides a robust framework for investigating myofibre regulation and dysfunction in skeletal muscle biology.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050724","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":"Pathogenic TNNT1 variants are associated with aberrant thin filament compliance and myofibre hyper-contractility.","authors":"Jenni Laitila, Christopher T A Lewis, Anthony L Hessel, Guido Primiano, Aurelio Hernandez-Lain, Chiara Fiorillo, Michael W Lawlor, Coen A C Ottenheijm, Heinz Jungbluth, Ka Fu Man, Arianna Fornili, Julien Ochala","doi":"10.1113/JP288109","DOIUrl":"https://doi.org/10.1113/JP288109","url":null,"abstract":"<p><p>In skeletal muscle, troponin T (TnT) exists in two isoforms, slow skeletal TnT (ssTnT) and fast skeletal TnT (fsTnT), encoded by the TNNT1 and TNNT3 genes, respectively. Nonsense or missense TNNT1 variants have been associated with skeletal muscle weakness and contractures and a histopathological appearance of nemaline myopathy (NM) on muscle biopsy. Little is known about how TNNT1 mutations ultimately lead to muscle dysfunction, preventing the development of targeted therapeutic interventions. Here, we aimed to identify the underlying molecular biophysical mechanisms, by investigating isolated skeletal myofibres from patients with TNNT1-related NM as well as from controls through a combination of structural and functional assays. Our studies revealed variable and unusual ssTnT and fsTnT expression patterns and post-translational modifications. We also observed that, in the presence of TNNT1 variants, the thin filament was more compliant, and this was associated with a higher myofibre Ca²⁺ sensitivity. Altogether, our findings suggest TnT remodelling as the key mechanism ultimately leading to molecular and cellular hyper-contractility, and then inhibitors of altered contractility as potential therapeutic modalities for TNNT1-associated NM. KEY POINTS: No therapeutic treatment exists for patients with genetic TNNT1 mutations and skeletal muscle weakness/contractures. In these patients, expression and post-translational modifications of troponin T are severely disrupted. These are associated with changes in thin filament compliance where troponin T is located. All these induce muscle fibre hyper-contractility that can be reversed by mavacamten, a myosin ATPase inhibitor.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144062962","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":"Neuromotor changes in postural control following bed rest.","authors":"Ramona Ritzmann, Christoph Centner, Luke Hughes, Janice Waldvogel, Uros Marusic","doi":"10.1113/JP285668","DOIUrl":"https://doi.org/10.1113/JP285668","url":null,"abstract":"<p><p>Chronic bed rest (BR) serves as a model for studying the effects of prolonged immobility on physiological and neuromotor functions, particularly postural control. Prolonged BR leads to significant deconditioning of postural balance control, characterized by increased sway path lengths, sway velocity and fall risk, independent of muscle strength. These changes are linked to neural adaptations at spinal and supraspinal levels, including structural and functional brain changes, such as alterations in grey and white matter, increased cerebellar activation, reduced spinal excitability and increased latencies within reflex circuitries. Additionally, BR disrupts sensory integration from proprioceptive, visual and vestibular systems, impairing postural stability. Visual reliance remains stable during BR, though decreased visual acuity and contrast sensitivity are noted. Moreover, BR-induced shifts in cerebrospinal fluid contribute to altered brain activity, impacting sensorimotor function. Vestibular system adaptations, including changes in vestibulospinal reflexes, further exacerbate balance impairments. Understanding these mechanisms is crucial for developing interventions to mitigate the adverse effects of BR on postural control and prevent prolonged recovery times or increased risk of injury. This review highlights the need for further research into the neural underpinnings of BR-induced postural instability, with a focus on sensory integration and neuroplasticity.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144006206","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":"Intervention points for the role of physical activity in prevention and treatment of Alzheimer's disease.","authors":"Nicklas Brendborg, Mark Anthony Febbraio","doi":"10.1113/JP286747","DOIUrl":"https://doi.org/10.1113/JP286747","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a growing global health challenge with limited pharmacological treatments. Epidemiological studies link regular physical activity with a lower risk of AD and cognitive decline in general, whereas randomized controlled trials show that aerobic exercise slows disease progression and improves cognitive function. However the underlying mechanisms remain incompletely understood. In this review we discuss five likely intervention points through which physical activity may influence AD progression and pathology: (1) reducing neuroinflammation and amyloid beta (Aβ) aggregation, (2) enhancing clearance of Aβ aggregates, (3) increasing neuronal resilience, (4) promoting hippocampal neurogenesis and (5) strengthening cognitive reserve. Understanding which of these mechanistic links are most likely to drive the AD-protective effects of exercise could help refine lifestyle-based interventions to complement pharmacological treatments and inform future prevention strategies.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013582","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":"Heartbeat-related activity in the anterior thalamus differs between phasic and tonic REM sleep","authors":"Péter Simor,&nbsp;Róka Zita Lilla,&nbsp;Orsolya Szalárdy,&nbsp;Zsófia Jordán,&nbsp;László Halász,&nbsp;Loránd Erőss,&nbsp;Dániel Fabó,&nbsp;Róbert Bódizs","doi":"10.1113/JP287802","DOIUrl":"https://doi.org/10.1113/JP287802","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <div>Rapid eye movement (REM) sleep is a fundamental sleep state associated with diverse functions from elemental physiological processes to higher order neurocognitive functions. A growing body of research indicates that REM sleep with eye movements (phasic REM) differs from REM periods without ocular activity (tonic) in terms of spontaneous and evoked neural responses. Studies using auditory stimulation consistently observed enhanced evoked responses in tonic <i>versus</i> phasic REM, indicating that external processing is largely diminished when the eyes move during REM sleep. Whereas exteroceptive processing during sleep is widely studied, investigations on interoception (the processing of bodily signals) during sleep are scarce, and limited to scalp electroencephalographic recordings. Here we studied interoceptive processing in a group of epileptic patients (<i>N</i> = 11) by measuring their heartbeat-related neural activity in the anterior nuclei of the thalamus (ANT) during phasic and tonic REM sleep and resting wakefulness. Evoked potentials and beta–low gamma spectral power locked to the heartbeat were significantly different in phasic REM compared with tonic REM and wakefulness. Heartbeat-related neural signals exhibited pronounced inter-trial phase synchronization at lower (7–20 Hz) oscillatory activity in all vigilance states, but reduced gamma synchronization at later time points in phasic REM only. Tonic REM and wakefulness did not show significant differences in heartbeat-related activity in the ANT. Our findings indicate that heartbeat-related neural activity is detectable at the level of the ANT, showing distinct signatures of interoceptive processing in phasic REM compared with tonic REM and wakefulness.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </div>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>We studied interoceptive processing in the anterior the thalamus (ANT).</li>\u0000 \u0000 <li>The ANT tracks cardiac signals during wakefulness and rapid eye movement (REM) sleep.</li>\u0000 \u0000 <li>Phasic REM shows distinct patterns of heartbeat-related oscillatory activity.</li>\u0000 \u0000 <li>Interoceptive processing might be attenuated during REM periods with eye movements.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 9","pages":"2839-2855"},"PeriodicalIF":4.7,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP287802","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143939233","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":"Directional sensitivity of C-low-threshold mechanoreceptors: insights from in vivo calcium imaging","authors":"Sunny Cui,&nbsp;Stephen Kim,&nbsp;Velika Chen","doi":"10.1113/JP288804","DOIUrl":"https://doi.org/10.1113/JP288804","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 9","pages":"2481-2482"},"PeriodicalIF":4.7,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143938821","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":"To be flexible, or not to be flexible, that is the question","authors":"Tomomichi Oya","doi":"10.1113/JP288662","DOIUrl":"https://doi.org/10.1113/JP288662","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 8","pages":"2177-2178"},"PeriodicalIF":4.7,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143861381","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}