Journal of Physiology-London最新文献

{"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}

{"title":"Short-term disuse shapes the adaptive response to resistance training.","authors":"Jacob Andresen","doi":"10.1113/JP288530","DOIUrl":"https://doi.org/10.1113/JP288530","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143812807","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":"Adipose stromal cells in the human rotator cuff are resistant to fibrotic microenvironmental cues.","authors":"Dakota R Kamm, Akash Shaji, Kathryn L Bohnert, Jay D Keener, Amit Pathak, Gretchen A Meyer","doi":"10.1113/JP286563","DOIUrl":"https://doi.org/10.1113/JP286563","url":null,"abstract":"<p><p>Rotator cuff tears are the most common upper extremity orthopaedic injury, causing degenerative changes within the bone, tendon, joint capsule, bursa and muscle. These degenerative changes are linked to poor rehabilitative and surgical outcomes, which has launched investigations into co-therapeutic biologics. Specifically, mesenchymal stem cells (MSCs) have shown promise in mitigating degenerative changes in animal models of rotator cuff tears, but reports of their impact on clinical outcomes remain mixed. Here we describe an alternative source of MSCs in the human shoulder, adipose stromal cells (ASCs) from the subacromial fat (SAF) pad. Compared to the gold-standard subcutaneous (SQ) fat, we show that SAF ASCs are less sensitive to chemical and mechanical fibrotic cues, (1) retaining smaller cell area with reduced actin stress fibre alignment across a range of physiological and pathological stiffnesses, (2) having reduced traction forces and extracellular matrix production, and (3) having reduced myofibroblastic conversion in response to cytokine challenge. Furthermore, we show that SAF ASCs enhance fusion of primary human myoblasts via paracrine signalling. Despite a fibrotic signature in SAF from rotator cuffs with tendon tears, SAF ASCs sourced from torn rotator cuffs were equally effective at resisting fibroblastic conversion and promoting myogenesis as those from intact rotator cuffs, further supporting autologous clinical use of these cells. In conclusion, this study describes human SAF ASCs as an alternative, and potentially superior, cell source for rotator cuff therapies. KEY POINTS: Adipose tissue within the rotator cuff is a novel and understudied source of therapeutic adipose stromal cells. Here, we detail the impact rotator cuff tears have on adipose tissue within the shoulder, its resident adipose stromal cells, and make a comparison of shoulder adipose stromal cells to subcutaneous adipose stromal cells. Rotator cuff tears cause fibrosis of rotator cuff adipose tissue; this fibrosis does not impact downstream adipose stromal cell morphology or pro-myogenic signaling. Rotator cuff adipose stromal cells resist fibrotic microenvironmental cues and have enhanced pro-myogenic paracrine signaling compared with traditional subcutaneous adipose stromal cells. Rotator cuff adipose stromal cells represent a new cell type that can be impactful in advancing rotator cuff therapies.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143812806","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":"Cathodal weak direct current decreases epileptic excitability with reduced neuronal activity and enhanced delta oscillations.","authors":"Chia-Chu Chiang, Miao-Er Chien, Yu-Chieh Huang, Jyun-Ting Lin, Sheng-Fu Liang, Kuei-Sen Hsu, Dominique M Durand, Yi-Jen Wu","doi":"10.1113/JP287969","DOIUrl":"https://doi.org/10.1113/JP287969","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Seizures are manifestations of hyperexcitability in the brain. Non-invasive weak current stimulation, delivered through cathodal transcranial direct current stimulation (ctDCS), has emerged to treat refractory epilepsy and seizures, although the cellular-to-populational electrophysiological mechanisms remain unclear. Using the ctDCS in vivo model, we investigate how neural excitability is modulated through weak direct currents by analysing the local field potential (LFP) and extracellular unit spike recordings before, during and after ctDCS versus sham stimulation. In rats with kainic acid (KA)-induced acute hippocampal seizures, ctDCS reduced seizure excitability by decreasing the number and amplitude of epileptic spikes in LFP and enhancing delta (δ) power. We identified unit spikes of putative excitatory neurons in CA1 stratum pyramidale based on waveform sorting and validated via optogenetic inhibitions which increased aberrantly in seizure animals. Notably, cathodal stimulation significantly reduced these unit spikes, whereas anodal stimulation exhibited the opposite effect, showing polarity-specific and current strength-dependent responses. The reduced unit spikes after ctDCS coupled to δ oscillations with an increased coupling strength. These effects occurred during stimulation and lasted 90 min post-stimulation, accompanied by inhibitory short-term synaptic plasticity changes shown in paired-pulse stimulation after ctDCS. Consistently, neuronal activations measured by c-Fos significantly decreased after ctDCS, particularly in CaMKII&lt;sup&gt;+&lt;/sup&gt;-excitatory neurons while increased in GAD&lt;sup&gt;+&lt;/sup&gt;-inhibitory neurons. In conclusion, epileptic excitability was alleviated with cathodal weak direct current stimulation by diminishing excitatory neuronal activity and enhancing endogenous δ oscillations through strengthened coupling between unit spikes and δ waves, along with inhibitory plasticity changes, highlighting the potential implications to treat brain disorders characterized by hyperexcitability. KEY POINTS: Electric fields generated by transcranial weak electric current stimulation were measured at CA1, showing polarity-specific and current strength-dependent modulation of unit spike activity. Polyspike epileptiform discharges were observed in rats with kainic acid (KA)-induced hippocampal seizures. Cathodal transcranial direct current stimulation (ctDCS) reduced the number and amplitude of the epileptic spikes in local field potentials (LFPs) while increased δ oscillations. Neuronal unit spikes aberrantly increased in seizures and coupled with epileptiform discharges. ctDCS reduced excitatory neuronal firings at CA1 and strengthened the coupling between unit spikes and δ waves. Neuronal activations, measured by c-Fos, decreased in CaMKII&lt;sup&gt;+&lt;/sup&gt;-excitatory neurons while increased in GAD&lt;sup&gt;+&lt;/sup&gt;-inhibitory neurons after ctDCS. These effects on LFP and unit spikes lasted up to 90 min post-stimulation. Inhibitory short-term","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804633","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":"Volitional exercise elicits physiological and molecular improvements in the severe D2.mdx mouse model of Duchenne muscular dystrophy.","authors":"Stephanie R Mattina, Sean Y Ng, Andrew I Mikhail, Derek W Stouth, Cora E Jornacion, Irena A Rebalka, Thomas J Hawke, Vladimir Ljubicic","doi":"10.1113/JP286768","DOIUrl":"https://doi.org/10.1113/JP286768","url":null,"abstract":"<p><p>Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting and weakness. Prescribed moderate exercise in patients is beneficial, but concerns remain due to the vulnerability of dystrophic muscle to damage. Voluntary wheel running (VWR) is a self-regulated form of exercise that improves muscle health in the typical C57.mdx mouse model of DMD. The purpose of the current study was to investigate the impact of VWR in more severe and clinically relevant D2.mdx mice. Male D2.mdx animals were assigned to a sedentary (D2.mdx SED) or VWR group for 8-10 weeks, whereas DBA/2J wild-type mice served as healthy, sedentary controls (WT SED). Selective skeletal muscle mass and ex vivo force generation were elevated in D2.mdx animals that ran a relatively high volume (D2.mdx High VWR; 1.84 ± 0.84 km/day) compared to low-volume runners (D2.mdx Low VWR; 0.46 ± 0.31 km/day) and SED counterparts. VWR did not exacerbate the dystrophy, and instead attenuated the fibrotic profile compared to D2.mdx SED mice. A VWR-induced shift towards a more slow, oxidative phenotype was also observed. Mitochondrial respiration was reduced in D2.mdx SED animals versus WT SED mice but was partially restored following both Low and High VWR. Finally, a dose-dependent increase in the expression of mitochondrial proteins was observed following VWR, whereas markers of mitochondrial fusion were particularly elevated in D2.mdx High VWR mice. Our results indicate that VWR enhances muscle and mitochondrial biology in D2.mdx animals and further supports the therapeutic role of exercise for DMD patients. KEY POINTS: Duchenne muscular dystrophy (DMD) is a life-limiting neuromuscular disorder characterized by muscle weakness and wasting. Skeletal and cardiac muscle quality is compromised in the dystrophic condition. Exercise promotes functional and molecular adaptations in healthy individuals and mild dystrophic mouse models. However, the effects of exercise in more severe and clinically relevant models of DMD require investigation. A relatively high volume of voluntary wheel running (VWR) augmented selective muscle mass and muscle function without exacerbating the dystrophic pathology in D2.mdx mice. Volitional exercise normalized dystrophic skeletal muscle mitochondrial respiration and upregulated mitochondrial content compared to sedentary counterparts. A higher dose of VWR increased organelle fusion protein expression compared to both healthy and dystrophic sedentary animals, as well as D2.mdx mice that ran lower volumes. Our results provide evidence from a severe preclinical model that volitional exercise may be a safe and efficacious lifestyle-based intervention for DMD.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143796932","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":"Translating physiology of the arterial chemoreflex into novel therapeutic interventions targeting carotid bodies in cardiometabolic disorders.","authors":"Tymoteusz Żera, Bartłomiej Paleczny, Maciej Siński, Sílvia V Conde, Krzysztof Narkiewicz, Piotr Ponikowski, Julian F R Paton, Piotr Niewiński","doi":"10.1113/JP285081","DOIUrl":"https://doi.org/10.1113/JP285081","url":null,"abstract":"<p><p>This review resulted from a conference on the pathological role of arterial chemoreflex and carotid bodies in cardiometabolic diseases held at the 27th Congress of the Polish Cardiac Society in September 2023 in Poznan, Poland. It reflects the contribution of Polish researchers and their international collaborations, which have been fundamental in the development of the field. Aberrant activity of the carotid bodies leads to both high tonicity and increased sensitivity of the arterial chemoreflex with resultant sympathoexcitation in chronic heart failure, resistant hypertension and obstructive sleep apnoea. This observation has led to several successful attempts of removing or denervating the carotid bodies as a therapeutic option in humans. Regrettably, such interventions are accompanied by serious respiratory and acid-base balance side-effects. Rather than a single stereotyped reaction, arterial chemoreflex comprises an integrative multi-system response to a variety of stimulants and its specific reflex components may be individually conveyed at varying intensities. Recent research has revealed that carotid bodies express diverse receptors, synthesize a cocktail of mediators, and respond to a plethora of metabolic, hormonal and autonomic nervous stimuli. This state-of-the-art summary discusses exciting new discoveries regarding GLP-1 receptors, purinergic receptors, the glutamate-GABA system, efferent innervation and regulation of blood flow in the carotid body and how they open new avenues for novel pharmacological treatments selectively targeting specific receptors, mediators and neural pathways to correct distinct responses of the carotid body-evoked arterial chemoreflex in cardiometabolic diseases. The carotid body offers novel and advantageous therapeutic opportunities for future consideration by trialists.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788913","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":"Human skeletal muscle possesses both reversible proteomic signatures and a retained proteomic memory after repeated resistance training.","authors":"Juha J Hulmi, Eeli J Halonen, Adam P Sharples, Thomas M O'Connell, Lauri Kuikka, Veli-Matti Lappi, Kari Salokas, Salla Keskitalo, Markku Varjosalo, Juha P Ahtiainen","doi":"10.1113/JP288104","DOIUrl":"https://doi.org/10.1113/JP288104","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Investigating repeated resistance training (RT) separated by a training break enables exploration of the potential for a proteomic memory of RT-induced skeletal muscle growth, i.e. retained protein adaptations from the previous RT. Our aim was to examine skeletal muscle proteome response to 10-week RT (RT1) followed by 10-week training cessation (i.e. detraining, DT), and finally, 10-week retraining (RT2). Thirty healthy, untrained participants conducted either periodic RT (RT1-DT-RT2, n = 17) or a 10-week no-training control period (n = 13) followed by 20 weeks of RT (n = 11). RT included twice-weekly supervised whole-body RT sessions, and resting vastus lateralis biopsies were obtained every 10 weeks for proteomics analysis using high-end dia-PASEF's mass spectrometry. The first RT period altered 150 proteins (93% increased) involved in, for example, energy metabolism and protein processing compared to minor changes during the control period. The proteome adaptations were similar after the second RT compared to baseline demonstrating reproducibility in proteome adaptations to RT. Many of the proteins induced by RT1 were reversed towards baseline after detraining and increased again after retraining. These reversible proteins were especially involved in aerobic energy metabolism. Interestingly, several proteins which increased after RT1 remain elevated (i.e. retained) after detraining, including carbonyl reductase 1 (CBR1) and proteins involved in muscle contraction, cytoskeleton and calcium binding. Among the latter, calcium-activated protease calpain-2 (CAPN2) has been recently identified as an epigenetic muscle memory gene. We show that resistance training evokes retained protein levels even after 2.5 months of no training, which demonstrates a potential proteomic memory of resistance training-induced muscle growth in human skeletal muscle. KEY POINTS: Repeated resistance training in humans separated by a training break (i.e. detraining) enables the identification of temporal protein signatures over the training, detraining and retraining periods, as well as studying reproducibility of protein changes to resistance training. Muscle proteome adaptations were similar after a second period of resistance training, demonstrating reproducibility in proteome adaptations to earlier resistance training. Many of the proteins induced by resistance training were reversed towards baseline after detraining and increased again after retraining. These reversible proteins were especially involved in aerobic energy metabolism. Several proteins increased after resistance training remain elevated (i.e. retained) after detraining, including carbonyl reductase 1 (CBR1) and calcium-binding proteins such as calpain-2 (CAPN2), a recently identified epigenetic muscle memory gene. Human skeletal muscle experiences retained protein changes following resistance training persisting over 2 months, demonstrating a potential proteomic memory of resistance training-indu","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781720","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":"Balance control threshold to vestibular stimuli.","authors":"Martin Simoneau, Mujda Nooristani, Jean-Sébastien Blouin","doi":"10.1113/JP288016","DOIUrl":"https://doi.org/10.1113/JP288016","url":null,"abstract":"<p><p>Bipedalism renders our erect posture unstable, requiring the integration and processing of multisensory information to remain upright. To understand how each sense contributes to balance, perceptual thresholds to isolated sensory disturbances while standing are typically quantified. Perception, however, is distinct from balance control. Both processes rely on distinct internal body representations, and participants can misattribute the consequences of self-generated balance-correcting actions as an external perturbation. Here, we used signal detection theory to quantify non-perceptual balance control thresholds to isolated vestibular stimuli given the role of vestibular cues in generating balance-correcting responses. We exposed participants standing on force plates to electrical vestibular stimulation (EVS) at varying amplitudes (0.2, 0.4, 0.6 mA) and frequencies (0.1, 0.2, 0.5, 1 Hz). Stimuli delivered at 0.2 mA (0.1-0.5 Hz) and 0.4 mA (0.1, 0.2 Hz) remained unperceived but evoked whole-body responses above the sensorimotor noise underlying balance control. Balance control thresholds ranged from 0.09 to 0.57 mA; they increased with EVS amplitude and decreased with frequency. The physiological mechanisms underlying these EVS amplitude and frequency effects involved a decrease in response gain with increased stimulus amplitude and a reduction in response variability with increased stimulus frequency. Our findings demonstrate that balance responses to isolated vestibular stimuli can be quantified below perceptual thresholds and highlight the dynamic regulation of response gain and the influence of whole-body motion variability in the vestibular control of balance. Our results also open the door to assessing the isolated vestibular contributions to postural control in people with balance impairments. KEY POINTS: Upright balance control relies on sensory information from multiple sensory systems, but balance control thresholds to isolated sensory stimuli remain largely unknown because these stimuli, or their associated responses, can be perceived. We applied isolated electrical vestibular perturbations and used signal detection theory to quantify balance control thresholds to unperceived sensory stimuli. Vestibular stimuli delivered at 0.2 mA (0.1-0.5 Hz) and 0.4 mA (0.1 and 0.2 Hz) remained unperceived but evoked balance-correcting responses above the sensorimotor noise underlying the control of standing. Balance thresholds increased with current amplitude (0.2-0.6 mA) and decreased with stimulus frequency (0.1-1 Hz) and were linked to decreased gain of lateral force and reduced lateral force variability as current amplitude and frequency increased, respectively. These results pave the way for uncovering the sensory contributions to the non-perceptual mechanisms regulating balance-correcting motor commands essential for bipedalism and their potential role in balance impairments.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781662","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":"AstroWars: the return of the astrocytic metabotropic glutamate receptor 5.","authors":"José Duarte Dias, João Filipe Viana, Luís Samuel Alves, Alexandra Veiga, Bruna Matos, João Luís Machado, João Filipe Oliveira","doi":"10.1113/JP288403","DOIUrl":"https://doi.org/10.1113/JP288403","url":null,"abstract":"<p><p>In the brain, astrocytes express glutamate receptors to detect glutamatergic signalling at synapses. Numerous studies have been conducted to characterize the types and levels of receptor expression, their physiological properties and functional roles. The metabotropic glutamate receptor 5 (mGluR5) is particularly noteworthy. Although it is described as the only classical excitatory metabotropic receptor expressed by astrocytes, recent studies indicate that its expression levels are lower in adulthood compared to the postnatal period. Nevertheless, mGluR5 activation in adulthood remains sufficient to induce robust astrocytic activity. To resolve these seemingly contradictory findings, we review the current understanding of the physiology of astrocytic mGluR5, its expression level variations throughout life, activation consequences and functional roles. In summary, astrocytes maintain sufficient functional levels of mGluR5 throughout life, activation of which triggers Ca²⁺ activity. This activation triggers intracellular processes to modulate synaptic and circuit function, which is relevant due to the extensive glutamatergic signalling in the brain. Moreover, most studies on mGluR5 activation in astrocytes have been conducted using cultured astrocytes or acute brain slices from young rodents. Therefore, further research is needed to investigate the roles of mGluR5 in adulthood, not only in synaptic function but also in behavioural processing. Understanding the regulation of mGluR5 expression levels, physiological properties and functional consequences during adulthood is crucial for fully understanding glutamatergic signalling in brain circuits and its role in the pathophysiology of various neurobiological diseases.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781658","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 effect of M-current activation on controller gain and obstructive sleep apnoea severity: a randomised controlled trial using flupirtine.","authors":"Luke D J Thomson, Shane A Landry, Andre Arellano, Jinny Collet, Stuart Huddle, Denise M O'Driscoll, Dwayne L Mann, Caroline Beatty, Simon A Joosten, Garun S Hamilton, Phillip J Berger, Ian Cooke, Bradley A Edwards","doi":"10.1113/JP288337","DOIUrl":"https://doi.org/10.1113/JP288337","url":null,"abstract":"<p><p>Ventilatory control instability, or high loop gain (LG), contributes towards upper airway collapse in approximately one-third of people with obstructive sleep apnoea (OSA). A high LG can be the product of elevated chemosensitivity (controller gain) and/or an excessive ventilatory output (plant gain). Therapies such as carbonic anhydrase inhibitors (targeting plant gain) have been shown to reduce OSA severity; however, there is a lack of viable pharmacological options targeting controller gain. This study investigated the effect of flupirtine (400 mg), a KCNQ potassium channel opener, on LG and OSA severity in fifteen moderate-to-severe OSA patients through a randomised, double-blind, placebo-controlled trial. Despite the hypothesised potential of flupirtine to reduce LG by attenuating chemosensory activity, our findings revealed no significant effect on LG and OSA severity. The lack of overall efficacy of flupirtine is most likely due to multifactorial nature of OSA and the challenges of its management. Our findings suggest a need for a nuanced understanding of OSA pathogenesis and caution against the use of flupirtine in managing OSA. While, pharmacological modulation of ionic channels within the ventilatory control system presents a promising strategy, given the plethora of robust targets available, it remains to be determined whether an effective treatment can capitalise on a single predominant ionic current ubiquitous throughout the ventilatory system, or if a more successful approach necessitates the simultaneous modulation of multiple targets. This research enhances our understanding of the ventilatory control system's contribution to OSA and the complexity of finding a one-size-fits-all treatment. KEY POINTS: Around one-third of obstructive sleep apnoea (OSA) cases involve an unstable control of breathing, leading to airway collapse. This research examined whether the drug flupirtine could stabilise breathing control and reduce OSA severity in 15 patients. Flupirtine, which was expected to improve breathing control by reducing chemosensitivity, showed no significant benefit for OSA. While targeting ionic channels in the breathing system is promising, the search for an effective OSA treatment may require addressing multiple targets simultaneously.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781726","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}