Journal of Physiology-London最新文献

{"title":"Microglial phagocytosis in epilepsy: Mechanisms and impact.","authors":"Abhijeet S Barath, Long-Jun Wu","doi":"10.1113/JP288573","DOIUrl":"https://doi.org/10.1113/JP288573","url":null,"abstract":"<p><p>Microglia are resident immune cells critical in maintaining brain homeostasis via their surveillance and phagocytosis function. Under disease contexts such as seizures and epilepsy, microglial phagocytic signalling is activated in response to both inflammatory and non-inflammatory cell death. This process involves a range of well-characterized 'find me' and 'eat me' signals, phagocytic receptors, and less well-characterized intracellular signalling pathways. In addition, epigenetic and transcriptional regulators orchestrate microglial responses to seizures, including the integration of phagocytic and inflammatory pathways. Interestingly, although inhibiting phagocytosis has been shown to improve neuronal survival and cognitive performance after seizures, it paradoxically increases the risk of developing spontaneous recurrent seizures. Reconciling these dual effects requires a deeper understanding the spatiotemporal dynamics of microglial phagocytosis. The objective of this review is to examine the mechanisms and impact of microglial phagocytosis in the context of epilepsy and to highlight unresolved questions that warrant further investigation in this emerging field.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327554","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 stretch-shortening cycle effect is not associated with cortical or spinal excitability modulations.","authors":"Lea-Fedia Rissmann, Brent James Raiteri, Wolfgang Seiberl, Tobias Siebert, Daniel Hahn","doi":"10.1113/JP287508","DOIUrl":"https://doi.org/10.1113/JP287508","url":null,"abstract":"<p><p>It is unclear whether cortical and spinal excitability modulations contribute to enhanced stretch-shortening cycle (SSC) performance. Therefore, this study investigated cortical and spinal excitability modulations during and following shortening of SSC contractions compared with pure shortening (SHO) contractions. Participants (n = 18) performed submaximal voluntary plantar flexion contractions while prone on the dynamometer bench. The right foot was strapped onto the dynamometer's footplate attachment, and the resultant ankle joint torque and crank arm angle were recorded. Cortical and spinal excitability modulations of the soleus muscle were analysed by eliciting compound muscle actional potentials via electrical nerve stimulation, cervicomedullary motor-evoked potentials (CMEPs) via electrical stimulation of the spinal cord, and motor-evoked potentials (MEPs) via magnetic stimulation of the motor cortex. Mean torque following stretch was significantly increased by 7 ± 3% (P = 0.029) compared with the fixed-end reference (REF) contraction, and mean torque during shortening of SSC compared with SHO was significantly increased by 12 ± 24% (P = 0.046). Mean steady-state torque was significantly lower by 13 ± 3% (P = 0.006) and 9 ± 12% (P = 0.011) following SSC compared with REF and SHO, respectively. Mean steady-state torque was not significantly different following SHO compared with REF (7 ± 8%, P = 0.456). CMEPs and MEPs were also not significantly different during shortening of SSC compared with SHO (P ≥ 0.885) or during the steady state of SSC, SHO and REF (P ≥ 0.727). Therefore, our results indicate that SSC performance was not associated with cortical or spinal excitability modulations during or after shortening, but rather driven by mechanical mechanisms triggered during active stretch. KEY POINTS: A stretch-shortening cycle (SSC) effect of 12% was observed during EMG-matched submaximal voluntary contractions of the human plantar flexors. The SSC effect was neither associated with cortical or spinal excitability modulations nor with stretch-reflex activity. The SSC effect was likely driven by mechanical mechanisms related to active muscle stretch, which have long-lasting effects during shortening. Residual force depression following SSC was not attenuated by the long-lasting mechanical mechanisms triggered during active muscle stretch. Steady-state torques were lower following shortening of SSCs versus pure shortening and fixed-end contractions at the same final ankle joint angle, but the torque differences were not correlated with cortical or spinal excitability modulations.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327558","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":"Running toward brain health: How aerobic capacity and liver metabolism shape Alzheimer's pathology.","authors":"Evelin Melekh, Madeleine King, Julia G Stante, Emma L Cook, Grace Sargeant, Sarah Bellaflor","doi":"10.1113/JP289269","DOIUrl":"https://doi.org/10.1113/JP289269","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327557","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":"Obligatory and accessory respiratory muscle structure, function and control in early and advanced disease in the mdx mouse model of Duchenne muscular dystrophy.","authors":"Aoife D Slyne, David P Burns, Karina Wöller, Amandine May, Roisin Dowd, Sarah E Drummond, Grzegorz Jasionek, Ken D O'Halloran","doi":"10.1113/JP288709","DOIUrl":"https://doi.org/10.1113/JP288709","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Peak inspiratory pressure-generating capacity is preserved in the mdx mouse model of Duchenne muscular dystrophy in early disease, despite profound diaphragm muscle weakness and reduced electrical activation, revealing adequate compensation by extra-diaphragmatic muscles. Respiratory system compensation is lost as disease progresses, with the emergence of reduced peak inspiratory pressure-generating capacity in advanced disease. We hypothesised that extra-diaphragmatic inspiratory muscles compensate for diaphragm dysfunction in early dystrophic disease, supporting the maintenance of peak respiratory performance in mdx mice. We reasoned that extra-diaphragmatic muscle dysfunction would emerge with progressive disease, leading to the loss of peak inspiratory pressure-generating capacity in advanced dystrophic disease. We measured ventilation, inspiratory pressure, and obligatory (diaphragm, intercostal and parasternal) and accessory (sternomastoid, cleidomastoid, scalene and trapezius) respiratory muscle form, function and EMG activity in early (4 months) and advanced (16 months) dystrophic disease. Despite obligatory and accessory muscle dysfunction, including structural remodelling, weakness and reduced EMG activity, peak inspiratory pressure-generating capacity and ventilation are preserved in early disease. Obligatory and accessory muscle dysfunction progressively declines with advanced disease, with the emergence of reduced peak inspiratory pressure-generating capacity. However, although there was evidence of progressive accessory muscle dysfunction, more profound remodelling was seen in the diaphragm muscle comparing early and advanced dystrophic disease. In conclusion, in early dystrophic disease, peak inspiratory performance is compensated. A progressive decline in diaphragm and extra-diaphragmatic muscles contributes to respiratory system compromise in advanced disease. Further loss of compensation afforded by extra-diaphragmatic muscles probably contributes to end-stage respiratory failure. KEY POINTS: We characterised obligatory and accessory respiratory muscle form, function and control in early and advanced disease in the mdx mouse model of Duchenne muscular dystrophy. Profound diaphragm muscle remodelling, immune cell infiltration, elevated cytokine concentrations and dysfunction present in early disease, but peak inspiratory performance is fully compensated. The burden of breathing is shared across many muscles, revealed as remodelling, elevated cytokine concentrations, weakness and impaired control in several obligatory and accessory muscles. Peak inspiratory performance declines in advanced disease with evidence of progressive remodelling in the diaphragm muscle with extensive fibrosis and further decline in the form, function and control of accessory muscles of breathing. Diaphragm remodelling with profound fibrosis, more so than progressive accessory muscle remodelling (although evident), is the striking phenotype at 16 mon","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327555","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":"From reflex to relief: modifying the muscle metaboreflex in heart failure.","authors":"Seth W Holwerda","doi":"10.1113/JP289154","DOIUrl":"https://doi.org/10.1113/JP289154","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144310698","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":"Local and global control on mitochondrial ageing.","authors":"Luigi Ferrucci, Natalia Bobba-Alves, David J Marcinek","doi":"10.1113/JP289058","DOIUrl":"https://doi.org/10.1113/JP289058","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144303449","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":"Shared and distinct adaptations to early-life exercise training based on inborn fitness.","authors":"Daniel G Sadler, Lillie Treas, Mary Barre, Taylor Ross, James D Sikes, Ying Zhong, Steven L Britton, Lauren G Koch, Umesh Wankhade, Elisabet Børsheim, Craig Porter","doi":"10.1113/JP288331","DOIUrl":"https://doi.org/10.1113/JP288331","url":null,"abstract":"<p><p>Low cardiorespiratory fitness increases the risk for cardiometabolic disease. Endurance exercise training promotes cardiorespiratory fitness and improves cardiometabolic risk factors, but with great heterogeneity. Here, we tested the hypothesis that the metabolic phenotype imparted by low parental (inborn) cardiorespiratory fitness would be overcome by early-life exercise training, and that exercise adaptations would be influenced in part by inborn fitness. At 26 days of age, male and female rat low-capacity runners (LCR, n = 20) and high-capacity runners (HCR, n = 20) generated by artificial selection were assigned to either sedentary control (CTRL, n = 10) or voluntary wheel running (VWR, n = 10) for 6 weeks. Post-intervention, whole-body metabolic phenotyping was conducted, and the respiratory function of isolated skeletal muscle and liver mitochondria was assayed. Transcriptomic and proteomic profiling of these tissues was performed using RNA-sequencing and mass spectrometry, respectively. Daily VWR volume was 1.8-fold higher in HCR-VWR compared to LCR-VWR. In LCR, VWR reduced adiposity and enhanced glucose tolerance, coincident with elevated total energy expenditure. Although intrinsic skeletal muscle mitochondrial respiratory function was unchanged, estimated skeletal muscle oxidative capacity increased in VWR groups. In liver mitochondria, VWR increased both maximal oxidative capacity and ATP-linked respiration only in HCR. Transcriptomic and proteomic profiling revealed extensive remodelling of skeletal muscle and liver tissue by VWR, elements of which were both shared and distinct based on inborn fitness. Early-life exercise partly offsets the metabolic effects of low inborn fitness, but molecular adaptations to VWR are dependent on inborn fitness, with potential implications for personalized exercise medicine. KEY POINTS: Low cardiorespiratory fitness is a heritable trait associated with increased risk for cardiometabolic disease. Endurance exercise training promotes cardiorespiratory fitness and metabolic health but how genetic (inborn) fitness influences exercise-induced adaptations is unclear. We used rats selectively bred for low (LCR) or high running capacity (HCR) to test whether: (1) early-life voluntary wheel running (VWR) could offset poor metabolic health in LCR rats and (2) inborn fitness modulates adaptations to VWR. VWR improved body composition and glucose tolerance in LCR rats but did not alter mitochondrial respiratory function. Molecular analyses revealed that VWR induced shared and distinct changes in skeletal muscle and liver depending on inborn fitness, highlighting individualized biological responses. These findings suggest that genetic factors linked to fitness influence how the body adapts to exercise, with implications for personalized exercised medicine.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144303450","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 power of movement: rethinking exercise in severe muscular dystrophy.","authors":"Gustavo Almeida Iasniswski, Guilherme Soderini Erlich, Guilherme Domingos Brisque","doi":"10.1113/JP289057","DOIUrl":"https://doi.org/10.1113/JP289057","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144303451","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":"High-frequency electrical tuning and linear filter properties of Knollenorgan electroreceptors of mormyrid electric fish.","authors":"Indira M Raman, Carl D Hopkins","doi":"10.1113/JP288299","DOIUrl":"https://doi.org/10.1113/JP288299","url":null,"abstract":"<p><p>Electrical tuning allows auditory, vestibular, and electrosensory receptor cells to filter sensory signals and selectively transmit specific stimulus frequencies. In auditory hair cells, electrical tuning results from membrane potential resonance produced by voltage-gated Ca and K(Ca) channels, with variable kinetics that generate different tuning properties. Such resonance has been observed only up to ∼1 kHz, however. Additionally, in most species that employ electrical tuning, hearing is constrained to this relatively low-frequency range, raising the question of whether electrical tuning can extend to higher frequencies. Here we investigated this possibility by studying tuning and transduction properties of Knollenorgans, a class of tuberous electroreceptors of mormyrid electric fish. These organs, which generate spike-like receptor potentials, detect species-specific electric organ discharges (EODs). To test whether fish with brief EODs had correspondingly high-frequency electrical tuning, we recorded tuning curves from Knollenorgans of three species, Brevimyrus niger, Gnathonemus petersii, and Pollimyrus adspersus, which have EODs with spectral components exceeding 5 kHz. All species had receptors tuned to a range of frequencies tiling the species-specific EOD spectrum, with best frequencies extending beyond 10 kHz in P. adspersus. We also computed the impulse response of each Knollenorgan by reverse-correlating spikes elicited by white noise stimuli. After incorporation of a spike threshold non-linearity, convolving the impulse response with arbitrary stimulus waveforms successfully predicted spike patterns experimentally evoked by these inputs. These analyses demonstrate that differential electrical tuning properties of Knollenorgans produce distinct, well-timed spike responses that reliably encode time-varying electrical signals at frequencies up to 20 kHz. KEY POINTS: Knollenorgans, among the tuberous electroreceptors of mormyrid electric fish, are modified hair cells that transduce electrical signals into spike-like receptor potentials. Knollenorgans in three species of mormyrids are tuned to frequencies matched to the frequencies present in the species-typical electric organ discharges, suiting them for electric communication. The frequency of highest sensitivity of Knollenorgans can extend well beyond 10 kHz, far exceeding the limit for electrical tuning mechanisms estimated from mechanosensitive hair cells. The timing and probability of spiking by Knollenorgans are accurately predicted by a model composed of linear filtering followed by non-linear rectification and spike thresholding. Differential filtering by different Knollenorgans produces distinct outputs to the same input, with high-tuned receptors effectively transmitting well-timed spikes, on a microsecond time scale, in response to electrical stimuli up to 20 kHz.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144303448","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":"When the lungs speak to the brain: a new reflex pathway in the neural control of circulation during exercise?","authors":"Lauro C Vianna","doi":"10.1113/JP289196","DOIUrl":"https://doi.org/10.1113/JP289196","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144276490","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}