Journal of Physiology-London最新文献

{"title":"The apicobasal dispersion of ventricular repolarization in humans is associated with age and affects arrhythmia vulnerability.","authors":"Vladimír Sobota, Job Stoks, Kiran Haresh Kumar Patel, Roshni Shetty, Haibo Ni, Eleonora Grandi, Fu Siong Ng, Paul G A Volders, Matthijs J M Cluitmans, Jason D Bayer","doi":"10.1113/JP288356","DOIUrl":"https://doi.org/10.1113/JP288356","url":null,"abstract":"<p><p>The apicobasal repolarization gradient (ABRG) plays an important role in determining the sequence of ventricular repolarization, but the effects of sex and age on ABRG are unknown. In this study, we investigate the age- and sex-related differences in ABRG and evaluate their possible role in vulnerability to arrhythmia. Electrocardiographic imaging was performed in 22 healthy subjects (16 females and 6 males) during sinus rhythm, and the average recovery time (RT) at the ventricular apex and base was determined. Fifty-six different ABRGs were simulated in a male and female model of human ventricular epicardium with sex-specific electrophysiology by simultaneously adjusting the apicobasal gradients of the slow and rapid delayed rectifier potassium currents. The models were burst paced from the ventricular apex and right ventricular outflow tract to assess the effect of ABRGs on arrhythmia vulnerability. Apicobasal differences in RT (human subjects) and repolarization time (simulation data) were calculated to quantify the ABRGs. In human subjects, ABRGs diminished and eventually inverted (longer RT at the apex than at the base) with increasing age (r = -0.7265, P = 0.0001). In both male and female models, apical pacing resulted in arrhythmia in 20/ 56 simulations, whereas right ventricular outflow tract pacing resulted in arrhythmia in 15/56 simulations. Arrhythmias were attributable to re-entry from unidirectional block and generally lasted longer in the models with shorter RT at the apex than at the base. Our findings demonstrate that the ABRG diminishes or inverts with ageing in both male and female human ventricles, which can reduce vulnerability to re-entrant ventricular arrhythmia. KEY POINTS: The apicobasal repolarization gradient (ABRG) determines the sequence of ventricular repolarization. Little is known about ABRG variability in humans and the effects of sex and age on the ABRG. Using electrocardiographic imaging data from healthy human subjects, we found that ABRG diminishes or inverts with ageing, in both males and females. Our simulations in computational models of human ventricular epicardium show that diminishing and inverting the ABRG is associated with a low vulnerability to arrhythmia. By linking together electrocardiographic imaging data and computer simulations, we demonstrate that vulnerability to ventricular arrhythmia might depend on age-related differences in ABRG.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144163578","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":"Evidence for control of cerebral neurovascular function by circulating platelets in healthy older adults","authors":"Gabriella M. K. Rossetti,&nbsp;Joanne L. Dunster,&nbsp;Aamir Sohail,&nbsp;Brendan Williams,&nbsp;Kiera M. Cox,&nbsp;Suzannah Rawlings,&nbsp;Elysia Jewett,&nbsp;Eleanor Benford,&nbsp;Julie A. Lovegrove,&nbsp;Jonathan M. Gibbins,&nbsp;Anastasia Christakou","doi":"10.1113/JP288405","DOIUrl":"10.1113/JP288405","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;Platelets play a vital role in preventing haemorrhage through haemostasis, but complications arise when platelets become overly reactive, leading to pathophysiology such as atherothrombosis. Elevated haemostatic markers are linked to dementia and predict its onset in long-term studies. Despite epidemiological evidence, the mechanism linking haemostasis with early brain pathophysiology remains unclear. Here, we aimed to determine whether a mechanistic association exists between platelet function and cerebral neurovascular function in 52 healthy mid- to older-age adults. To do this, we combined, for the first time, magnetic resonance imaging of cerebral neurovascular function, peripheral vascular physiology and &lt;i&gt;in vitro&lt;/i&gt; platelet assaying. We show an association between platelet reactivity and cerebral neurovascular function that is both independent of vascular reactivity and mechanistically specific: Distinct platelet signalling mechanisms (ADP, collagen-related peptide, thrombin receptor activator peptide 6) were associated with different physiological components of the haemodynamic response to neuronal (visual) stimulation (full-width half-maximum, time to peak, area under the curve), an association that was not mediated by peripheral vascular effects. This finding challenges the previous belief that systemic vascular health determines the vascular component of cerebral neurovascular function, highlighting a specific link between circulating platelets and the neurovascular unit. Because altered cerebral neurovascular function marks the initial stages of neurodegenerative pathophysiology, understanding this novel association is now imperative, with the potential to lead to a significant advancement in our comprehension of early dementia pathophysiology.\u0000\u0000 &lt;figure&gt;\u0000 &lt;div&gt;&lt;picture&gt;\u0000 &lt;source&gt;&lt;/source&gt;&lt;/picture&gt;&lt;p&gt;&lt;/p&gt;\u0000 &lt;/div&gt;\u0000 &lt;/figure&gt;\u0000 &lt;/div&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Haemostasis (platelet function) has been linked to the early stages of dementia, but the precise mechanisms are not well understood.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;This study considers whether a causal mechanism exists through atherothrombotic effects on the vasculature which can in turn affect brain health, or through platelet-specific interactions with brain physiology.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Here, we show that elevated platelet reactivity is associated with blunted (delayed, shorter and smaller) cerebral blood flow responses to neuronal activation in healthy middle-aged and older adults.&lt;/li&gt;\u0000 \u0000 ","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 11","pages":"3379-3404"},"PeriodicalIF":4.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP288405","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144163574","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":"Plasticity reloaded: motor skill learning plus stimulation boosts adaptations in the ageing nervous system.","authors":"Wolfgang Taube","doi":"10.1113/JP288884","DOIUrl":"https://doi.org/10.1113/JP288884","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144163575","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":"Muscle regeneration is improved by hot water immersion but unchanged by cold following a simulated musculoskeletal injury in humans.","authors":"Valentin Dablainville, Adèle Mornas, Tom Normand-Gravier, Maha Al-Mulla, Emmanouil Papakostas, Bruno Olory, Theodorakys Marin Fermin, Frantzeska Zampeli, Nelda Nader, Marine Alhammoud, Freya Bayne, Anthony M J Sanchez, Marco Cardinale, Robin Candau, Henri Bernardi, Sébastien Racinais","doi":"10.1113/JP287777","DOIUrl":"https://doi.org/10.1113/JP287777","url":null,"abstract":"<p><p>Cryotherapy is a popular strategy for the treatment of skeletal muscle injuries. However, its effect on post-injury human muscle regeneration remains unclear. In contrast, promising results recently emerged using heat therapy to facilitate recovery from muscle injury. This study aimed to examine the effect of three different thermal treatments on muscle recovery and regeneration following a simulated injury in humans. Thirty-four participants underwent a muscle damage protocol induced by electrically stimulated eccentric contractions triggering regenerative processes following myofibre necrosis. Thereafter, participants were exposed to daily lower body water immersion for 10 days in cold (CWI, 15 min at 12°C), thermoneutral (TWI, 30 min at 32°C) or hot water immersion (HWI, 60 min at 42°C). Muscle biopsies were sampled before and at +5 (D5) and +11 (D11) days post-damage. None of the water immersions differed in recovery of force-generating capacity (P = 0.108). HWI induced a lower perceived muscle pain than TWI (P = 0.035) and lower levels of circulating creatine kinase (P ≤ 0.012) and myoglobin (P < 0.001) than TWI and CWI. Contrary to our hypothesis, CWI did not improve perceived muscle pain or reduce circulating markers of muscle damage (P ≥ 0.207). Expression of heat shock proteins 27 and 70 was significantly increased in HWI (P < 0.038) at D11 and appeared blunted using CWI. Furthermore, nuclear factor-κB expression significantly increased in all conditions except HWI, while interleukin-10 was upregulated only in HWI at D11 (P = 0.014). In conclusion, our results support the use of HWI but not cold, to improve muscle regeneration following an injury. KEY POINTS: Cryotherapy and heat therapy are popular strategies in the treatment of skeletal muscle injury; however, existing literature is equivocal, and their effects on human muscle regeneration remain unknown. We investigated the effect of three thermal treatments (cold water immersion (CWI): 15 min at 12°C; thermoneutral water immersion (TWI): 30 min at 32°C; or hot water immersion (HWI): 60 min at 42°C) performed daily for 10 days following electrically stimulated eccentric muscle damage inducing regenerative mechanisms. CWI did not improve chronic perceived muscle pain nor reduce circulating markers of muscle damage. HWI limited chronic perceived pain and circulating markers of muscle damage, potentially influenced inflammatory mechanisms, and increased the expression of heat shock proteins. HWI appears more beneficial than CWI in improving muscle regeneration after a muscle injury.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144175426","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":"Computational analysis to assess hemodynamic forces in descending thoracic aortic aneurysms.","authors":"Francesca Duca, Daniele Bissacco, Luca Crugnola, Chiara Faitini, Maurizio Domanin, Francesco Migliavacca, Santi Trimarchi, Christian Vergara","doi":"10.1113/JP287278","DOIUrl":"https://doi.org/10.1113/JP287278","url":null,"abstract":"<p><p>Descending thoracic aortic aneurysm (DTAA) is a life-threatening disorder, defined as a localized enlargement of the descending portion of the thoracic aorta. In this context, we develop a fluid-structure interaction (FSI) computational framework, with the inclusion of a turbulence model and different material properties for the healthy and the aneurysmatic portions of the vessel, to study the hemodynamics and its relationship with DTAA. We first provide an analysis on nine ideal scenarios, accounting for different aortic arch types and DTAA ubications, to study changes in blood pressure, flow patterns, turbulence, wall shear stress, drag forces and internal wall stresses. Our findings demonstrate that the hemodynamics in DTAA is profoundly disturbed, with the presence of flow re-circulation, formation of vortices and transition to turbulence. In particular, configurations with a steeper aortic arch exhibit a more chaotic hemodynamics. We notice also an increase in pressure values for configurations with less steep aortic arch and in drag forces for configurations with distal DTAA. Second, we replicate our analysis for three patient-specific cases (one for type of arch) obtaining comforting results in terms of accordance with the ideal scenarios. Finally, in a very preliminary way, we try to relate our findings to possible stent-graft migrations after TEVAR procedure to provide predictions on the postoperative state. KEY POINTS: This study employs computational methods to assess hemodynamic forces in descending thoracic aortic aneurysms. We consider ideal cases by varying aortic arch type and aneurysm location. Our results show: chaotic hemodynamics for steep aortic arches; increase in pressure values for less steep aortic arches; high risk of plaque deposition in the aneurysmal sac for proximal aneurysms and near the neck for distal aneurysms. We also analyse three patient-specific cases, confirming the major outcomes found for the ideal cases. We try to suggest how our preoperative findings may correlate to assess the risk of stent-graft migration of a possible TEVAR procedure.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144163571","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":"Impact of medial calcification on arterial mechanics and haemodynamics","authors":"Pak-Wing Fok,&nbsp;Kun Gou,&nbsp;Brandon Myers,&nbsp;Peter Lanzer","doi":"10.1113/JP288112","DOIUrl":"10.1113/JP288112","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <div>Medial arterial calcification (MAC) often occurs in ageing arteries, promoted by diabetes mellitus and chronic kidney disease. Advanced MAC represents a frequent cause of chronic limb-threatening ischaemia and limb amputation. Through a 1D haemodynamics simulation, we study how the mechanical properties of calcified arterial tissue and hydraulic resistance in the peripheral circulation jointly impact haemodynamics as MAC develops. We find that (i) there is a greater drop in systolic pressure across calcified arteries compared to healthy arteries, but this drop can be offset by greater peripheral resistance, provided left ventricular function is intact, (ii) both calcification and enhanced peripheral resistance lead to reduced flow rates, reduced peripheral perfusion and peripheral tissue hypoxaemia, and (iii) pressurized calcified arteries present lumen areas that are smaller than healthy arteries, even though they are larger when unpressurized. We also explore the effects of positive remodelling and elevated blood pressure. We find that a global luminal enlargement reduces the systolic and mean pressure drop across a calcified artery while increasing the mean outflow rate, thereby making a calcified artery behave more like a healthy one, hydrodynamically. Increasing the global pressure in a calcified artery further enhances the drop in systolic and mean pressure while increasing the mean outflow rate. Our simulations suggest that the increased impedance in calcified arteries results from smaller <i>in vivo</i> lumen areas. This can reduce the outflow rate, but the effect is complicated by arteriole closures, vessel geometry and global pressure. These findings confirm previously reported observations of flow reduction in calcified arteries.\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>Medial arterial calcification (MAC) often occurs in ageing arteries, promoted by diabetes mellitus and chronic kidney disease. Patients with advanced calcification may develop limb-threatening ischaemia due to malperfusion.</li>\u0000 \u0000 <li>Through theoretical modelling and simulation, we find that calcified arteries experience a reduced flow rate because they present smaller lumen areas compared to healthy arteries.</li>\u0000 \u0000 <li>Systolic pressure decreases across calcified arteries, whereas in healthy arteries it usually increases. These findings have broad implications for localized detection of MAC.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 11","pages":"3341-3355"},"PeriodicalIF":4.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144152694","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 keto cure? Exploring ketogenic diet in heart failure with preserved ejection fraction.","authors":"Bagus Aditya Ansharullah, Galih Januar Adytia, Alief Waitupu, Henry Sutanto","doi":"10.1113/JP289056","DOIUrl":"https://doi.org/10.1113/JP289056","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144163581","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 skeletal muscle response to high-intensity training assessed by single-nucleus RNA-sequencing is blunted in individuals with type 2 diabetes","authors":"Maria Hansen,&nbsp;Julius E. R. Grothen,&nbsp;Anders Karlsen,&nbsp;Jaime M. Martinez,&nbsp;Nikos Sidiropoulos,&nbsp;Jørn W. Helge,&nbsp;Thomas Å. Pedersen,&nbsp;Flemming Dela","doi":"10.1113/JP288368","DOIUrl":"10.1113/JP288368","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;Training can improve insulin sensitivity in individuals with type 2 diabetes, but a clear understanding of the mechanisms remains elusive. To further our knowledge in this area, we aimed to examine the effect of type 2 diabetes and of high-intensity interval training (HIIT) on the nuclear transcriptional response in skeletal muscle. We performed single-nucleus RNA-sequencing (snRNA-seq) and immunofluorescence analysis on muscle biopsies from the trained and the untrained legs of participants with and without type 2 diabetes, after 2 weeks of one-legged HIIT on a cycle ergometer. Surprisingly, the type 2 diabetes condition only seemed to have a minor effect on transcriptional activity in myonuclei related to major metabolic pathways when comparing the untrained legs. However, while in particular the type IIA myonuclei in the control group displayed a considerable metabolic response to HIIT, with increases in genes related to glycogen breakdown and glycolysis primarily in the type IIA myonuclei of the trained leg, this response was blunted in the diabetes group, despite a marked increase in glucose clearance in both groups. Additionally, we observed that fibre type distribution assessed by immunofluorescence significantly correlated with the proportion of myonuclei in the snRNA-seq analysis. In conclusion, the type 2 diabetes condition blunts the metabolic transcriptional response to HIIT in the type IIA myonuclei without affecting the improvement in insulin sensitivity. Additionally, our results indicate that snRNA-seq can be used as a surrogate marker for fibre type distribution in sedentary middle-aged adults.\u0000\u0000 &lt;figure&gt;\u0000 &lt;div&gt;&lt;picture&gt;\u0000 &lt;source&gt;&lt;/source&gt;&lt;/picture&gt;&lt;p&gt;&lt;/p&gt;\u0000 &lt;/div&gt;\u0000 &lt;/figure&gt;\u0000 &lt;/div&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;The study utilized single-nucleus RNA sequencing (snRNA-seq) to analyse 38 skeletal muscle biopsies, revealing distinct transcriptional profiles in myonuclei from individuals with and without type 2 diabetes (T2D) after 2 weeks of HIIT.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;snRNA-seq identified significant differences in gene expression, with 14 differentially expressed genes (DEGs) in type IIA myonuclei of the control group, specifically related to glycogen breakdown and glycolysis, which were blunted in the T2D group.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;In the control group, HIIT induced a substantial transcriptional response in type IIA myonuclei, enhancing metabolic pathways associated with insulin sensitivity, while the T2D group showed minimal transcriptional changes despite improved insulin se","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 11","pages":"3357-3377"},"PeriodicalIF":4.7,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP288368","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144144101","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":"A novel medication approach to treating obstructive sleep apnoea","authors":"Keith Burgess","doi":"10.1113/JP288922","DOIUrl":"10.1113/JP288922","url":null,"abstract":"&lt;p&gt;The paper by Thomson et al. (&lt;span&gt;2025&lt;/span&gt;) in this issue of &lt;i&gt;The Journal of Physiology&lt;/i&gt; is a novel and very interesting attempt to translate recent knowledge from the bench to the bedside. It reports the results of a placebo controlled double-blind cross-over trial of a novel drug, flupirtine, on 15 volunteers with known obstructive sleep apnoea (OSA). OSA is a common clinical entity affecting ∼20% of the adult population of most western countries. It is defined as the absence of breathing lasting for more than 10 s, occurring more than five times per hour during sleep. OSA syndrome includes a requirement for excessive sleepiness. OSA pathogenesis is considered to be a result of the complex interaction of respiratory control (controller gain), sleep state and airway collapsibility (Deacon &amp; Catcheside, &lt;span&gt;2015&lt;/span&gt;; White, &lt;span&gt;2005&lt;/span&gt;).&lt;/p&gt;&lt;p&gt;Current main stream therapies for OSA include continuous positive airway pressure, mandibular advance devices, weight loss and upper airway surgery. In previous centuries some ‘tonics’ included small doses of strychnine, which raised muscle tone by blocking inhibitory spinal neurons. Over the years, many drugs have been tried as therapies for OSA (Hedner &amp; Zou, &lt;span&gt;2018&lt;/span&gt;), including antidepressants such as mirtazapine to increase muscle tone, hypnotics such as benzodiazepines to reduce arousal threshold, progesterone to increase respiratory drive, and carbonic anhydrase inhibitors to reduce controller and plant gain.&lt;/p&gt;&lt;p&gt;Flupirtine is a KCNQ potassium channel opener (Costi et al., &lt;span&gt;2022&lt;/span&gt;) that was considered to potentially attenuate respiratory drive during sleep, thereby reduce the severity of OSA. The paper by Thomson et al. (&lt;span&gt;2025&lt;/span&gt;) could be thought of as three experiments with flupirtine simultaneously. These comprise (i) the main study looking at overall effects on AHI and, in addition, two subsidiary ones trying to understand potential mechanisms of the expected (but absent) effect on apnoea-hypopnea index (AHI): (ii) a study on controller gain (Burgess, &lt;span&gt;2012&lt;/span&gt;) and (iii) a study aiming to assess airway collapsibility (Thomson et al., &lt;span&gt;2025&lt;/span&gt;).&lt;/p&gt;&lt;p&gt;Although there was no effect of the flupirtine on the severity of OSA in the group as a whole there did appear to be different effects in ‘good responders’ and ‘bad responders’. This dichotomy is well illustrated in their figure 4. In a subset of subjects, the AHI rose with drug (‘bad responders’ in red) and, in another subset, it fell (‘good responders’ in blue). There was no apparent correlation between those outcomes and the subject characteristics, nor during carotid body challenge testing to assess the degree of ventilatory responsiveness. One could interpret the results as confirming that the pathogenesis of OSA is indeed complex, but probably different in different patients. So, a drug that reduced controller gain might improve OSA in those patients with abnormally ","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 10","pages":"2899-2900"},"PeriodicalIF":4.7,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP288922","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144121372","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":"Shaping the waves: Mitochondrial regulation of calcium oscillations in smooth muscle","authors":"Harold A. Coleman,&nbsp;Helena C. Parkington","doi":"10.1113/JP288974","DOIUrl":"10.1113/JP288974","url":null,"abstract":"&lt;p&gt;That cytoplasmic free calcium is a critical player in many cellular processes has been known for decades. The major enduring question is how this one ion is able to activate diverse processes within the same cell with some degree of specificity.&lt;/p&gt;&lt;p&gt;Microdomains could provide a good explanation, of which membrane invaginations, caveolae, in association with the endoplasmic reticulum (ER, a major calcium store), provide a conceptually understandable basis, particularly since a gap of only ∼20 nm separates the plasmalemmal caveolae and the ER. Compelling imaging and functional studies indicate that calcium movement pathways cluster together in these microdomains resulting in expeditious signalling (Akin et al., &lt;span&gt;2023&lt;/span&gt;). Also, physical tethering between caveolar and ER proteins stabilized this niche. Another microdomain occurs between the ER and mitochondria, which also includes physical tethering, enabling complex interactions (Cartes-Saavedra et al., &lt;span&gt;2025&lt;/span&gt;).&lt;/p&gt;&lt;p&gt;An intriguing question is the different roles played by the various sources of calcium. In smooth muscle, waves of intracellular calcium can propagate between cells. The function(s) of these waves and their relationship to the electrical and contractile activity of smooth muscle are not clear. Action potentials occur in near synchrony throughout the cell resulting in a global increase in calcium as a result of influx through voltage-gated calcium channels (VGCCs). In many smooth muscles, it is this calcium that is responsible for contractions (Gravina et al., &lt;span&gt;2010&lt;/span&gt;) while in some others, VGCC-mediated calcium influx evokes the release of calcium from intracellular stores which then activates contraction or provides calcium for refilling the store (Akin et al., &lt;span&gt;2023&lt;/span&gt;).&lt;/p&gt;&lt;p&gt;The ER and mitochondria come into close contact. In this microdomain, the calcium-conducting IP&lt;sub&gt;3&lt;/sub&gt; receptors in the ER membrane are tethered to the abundant mitochondrial VDAC-1 ion channels via the GrP75 linker protein. VDAC conducts ions, including calcium. Mitochondrial calcium-activated dehydrogenase increases NADH and ATP production (Cartes-Saavedra et al., &lt;span&gt;2025&lt;/span&gt;). This system plays a major role in heart function. In some smooth muscles, mitochondria may exert a modulatory role in both pace making and contractile activity (Gravina et al., &lt;span&gt;2010&lt;/span&gt;).&lt;/p&gt;&lt;p&gt;To better understand mitochondrial function in smooth muscle, an elegant study by Yamamura et al (&lt;span&gt;2018&lt;/span&gt;) used isolated cells to use sophisticated imaging techniques coupled with patch clamp electrophysiology. The results provide valuable insights into the voltage dependence and time course of stimulus-evoked changes in cytoplasmic and mitochondrial calcium levels and provide evidence that mitochondria are functionally coupled to the ER. In smooth muscle tissue, the cells are normally coupled to each other and, in some cases, also to other cell types such as endothelial ","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 10","pages":"2897-2898"},"PeriodicalIF":4.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP288974","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144112601","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}