Journal of Physiology-London最新文献

{"title":"Optogenetic cardioversion: To depolarize or to hyperpolarize?","authors":"Emilia Entcheva, Matthew W Kay","doi":"10.1113/JP292377","DOIUrl":"https://doi.org/10.1113/JP292377","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221018","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":"Harnessing the ion transportome to treat cancer.","authors":"Alina L Capatina, Jodie R Malcolm, Aamir Ahmed, Jason Bruce, Paul J Buchanan, Thomas R Eykyn, Elizabeth M Fitzgerald, Amanda J Foust, Tim G Hales, Yoshikatsu Hayashi, Stuart G Higgins, Alson Huang, Antony P Jackson, Andrew D James, Frederick Jones, Sarah J Lilley, Karen McCloskey, Sara Moodad, Hugh Robinson, Samantha C Salvage, Orkun S Soyer, Serife Yerlikaya, Jonathan Ashmore, Ruth Murrell-Lagnado, William J Brackenbury","doi":"10.1113/JP290738","DOIUrl":"https://doi.org/10.1113/JP290738","url":null,"abstract":"<p><p>Despite significant advances in early detection and therapeutic opportunities, cancer remains a critical global health challenge. The greatest barrier to reducing cancer-associated mortality is the persistent problem of therapeutic resistance and metastasis. Standard treatment approaches, including surgery combined with chemotherapy and radiation, are effective for many patients with localised disease. However, a substantial proportion of patients will experience recurrence and therapy resistance, leading to treatment failure and poor outcomes. This adverse prognosis for patients highlights the critical need to identify new therapeutic targets capable of improving long-term survival. The ion transportome comprises ion channels, solute transporters and pumps that regulate controlled movement of sodium (Na⁺), potassium (K⁺), calcium (Ca²⁺), chloride (Cl^-) and hydrogen (H⁺) across cell membranes. Ion transport is central to many cellular processes, including cell growth, volume regulation, proliferation and migration. In many solid tumours, the finely tuned ionic balance becomes dysregulated, with aberrant expression or activity of membrane transport proteins being closely linked to many of the hallmarks of cancer. Ion channel modulation using pharmacological agents designed to treat channelopathies has demonstrated promise in suppressing cancer progression in preclinical models. Thus, targeting ion-driven vulnerabilities within solid tumours may complement existing therapies to overcome resistance and improve patient outcomes. The dynamic nature of ion transport mechanisms means that addressing critical research questions regarding their suitability as pharmacological targets is challenging, highlighting the need to develop innovative approaches to study these processes in oncology.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149217303","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":"Channelrhodopsin ion selectivity determines mechanisms and efficacy of optogenetic defibrillation in human atria and ventricles.","authors":"Sophia Ohnemus, Albert Dasí, Ahmed F Ramadan, Joachim Greiner, Eike M Wülfers, Matthew R Stoyek, Linda Tillert, Johannes Vierock, T Alexander Quinn, Peter Kohl, Patrick M Boyle, Viviane Timmermann, Franziska Schneider-Warme","doi":"10.1113/JP291707","DOIUrl":"https://doi.org/10.1113/JP291707","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Cardiac re-entrant arrhythmias are a major cause of sudden cardiac death. Optogenetic defibrillation has emerged as a promising anti-arrhythmic strategy based on photoactivation of channelrhodopsins, yet the efficacy and potential adverse consequences of activating different classes of light-gated ion channels have not been systematically evaluated. Previous studies assessed either cation (e.g. ChR2) or anion (e.g. GtACR1) non-selective channels, both of which depolarize resting cardiomyocytes. Recently identified light-gated K&lt;sup&gt;+&lt;/sup&gt; channels (e.g. WiChR) suppress cardiomyocyte activity while maintaining the membrane potential near its resting state, but their defibrillation potential remains unexplored. We used computational simulations to compare ChR2, GtACR1 and WiChR. Single-cell simulations showed that ChR2 and GtACR1 markedly increased diastolic intracellular Ca&lt;sup&gt;2+&lt;/sup&gt; (by 42.6% and 52.6%, respectively), whereas WiChR induced only minimal changes (by 4.0%), suggesting lower pro-arrhythmogenic risk. WiChR, however, slightly increased intracellular Na&lt;sup&gt;+&lt;/sup&gt; (by 15.1% vs. 0.1% and 3.4% for ChR2 and GtACR1), consistent with the residual Na&lt;sup&gt;+&lt;/sup&gt; permeability of currently available K&lt;sup&gt;+&lt;/sup&gt;-conducting channelrhodopsins. Simulations in human ventricles and atria showed that GtACR1 most effectively terminated re-entrant arrhythmias at low light intensities, whereas WiChR achieved comparable efficacy at ≥5 mW/mm&lt;sup&gt;2&lt;/sup&gt;. Complementary tissue-scale simulations revealed that defibrillation occurs through depolarization within the excitable gap followed by fast Na&lt;sup&gt;+&lt;/sup&gt; channel inactivation (ChR2 and partly GtACR1), or through reduced membrane resistance at sufficiently high light intensities (large-conductance channels GtACR1 and WiChR). Overall, we demonstrate that channelrhodopsin ion selectivity is a key determinant of both optogenetic defibrillation efficacy and its underlying mechanisms. TRANSLATIONAL PERSPECTIVE: Re-entrant arrhythmias are a leading cause of sudden cardiac death. Standard therapies, including the activation of implantable cardioverter-defibrillators, carry burdens such as pain and myocardial injury. Optogenetic defibrillation has been suggested as a potentially gentler alternative, replacing high-voltage electrical shocks by photoactivation of light-gated ion channels expressed in cardiac cells. Determining which light-gated ion channel optimally balances efficacy and adverse effects on cardiac electrophysiology is critical for clinical translation. We addressed this question using computational simulations and validation experiments in zebrafish hearts. We identify ion selectivity as a key determinant of both the success rate for arrhythmia termination and the underlying mechanisms: non-selective cation- and anion-conducting channels terminate re-entry efficiently while promoting intracellular Ca&lt;sup&gt;2+&lt;/sup&gt; accumulation, a plausible substrate for pro-arrhythmic side effects that c","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149217321","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":"Strength in numbers: How intramolecular interactions help shape sodium channel biophysics","authors":"Elizabeth J. Akin,&nbsp;Przemysław B. Radwański","doi":"10.1113/JP292546","DOIUrl":"10.1113/JP292546","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"604 20","pages":"8301-8302"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149138975","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":"Slow calcium removal contributes to impaired lusitropic response to β-adrenergic stimulation in HFpEF mice","authors":"Tamzin Zawadzki,&nbsp;Diana S. Usai,&nbsp;Sif G. Kaad,&nbsp;Katrine H. Rasmussen,&nbsp;Mie S. Larsen,&nbsp;Jens C. B. Jacobsen,&nbsp;Morten B. Thomsen","doi":"10.1113/JP291587","DOIUrl":"10.1113/JP291587","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;Heart failure with preserved ejection fraction (HFpEF) accounts for over half of heart failure cases, yet its underlying mechanisms remain incompletely understood and effective therapies are lacking. Diastolic dysfunction, a hallmark of HFpEF, may arise from impaired active myocardial relaxation, but the contribution of intracellular calcium (Ca&lt;sup&gt;2+&lt;/sup&gt;) handling remains unclear. This study aimed to document impaired lusitropy and diastolic dysfunction in HFpEF, and to determine the contribution of altered ventricular Ca&lt;sup&gt;2+&lt;/sup&gt; handling to slowed myocardial relaxation. HFpEF was induced by diet-driven obesity and hypertension. Cardiac function was assessed &lt;i&gt;in vivo&lt;/i&gt; by echocardiography, &lt;i&gt;ex vivo&lt;/i&gt; in preload-controlled isolated hearts and at the cellular level by Ca&lt;sup&gt;2+&lt;/sup&gt; imaging of isolated ventricular myocytes. HFpEF mice developed diastolic dysfunction, hypertrophy, reduced cardiac output and exercise intolerance, yet ejection fraction was preserved. Impaired lusitropy was evident &lt;i&gt;in vivo&lt;/i&gt;, &lt;i&gt;ex vivo&lt;/i&gt; and at the cellular level, where basal cytosolic Ca&lt;sup&gt;2+&lt;/sup&gt; handling was preserved, but the β-adrenergic-recruitable acceleration of Ca&lt;sup&gt;2+&lt;/sup&gt; clearance was impaired. This attenuated lusitropic response to β-adrenergic stimulation in HFpEF myocytes was mirrored &lt;i&gt;in vivo&lt;/i&gt; during echocardiography. Slowed myocardial relaxation is a consistent feature of HFpEF, evident at the organ, tissue and cellular levels. β-Adrenergic stimulation normally enhances lusitropy, but this response is blunted in HFpEF hearts both &lt;i&gt;in vivo&lt;/i&gt; and in isolated cardiomyocytes. Impaired β-adrenergic amplification of Ca&lt;sup&gt;2+&lt;/sup&gt; removal is associated with slowed ventricular relaxation, reduced cardiac output and exercise intolerance in HFpEF, identifying defective lusitropic reserve as a potential therapeutic target.\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;Heart failure with preserved ejection fraction (HFpEF) lacks effective therapies, in part because the disease mechanisms remain incompletely defined.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Using a mouse model combining obesity and hypertension, we demonstrate diastolic dysfunction, reduced cardiac output and exercise intolerance despite preserved ejection fraction. Ventricular relaxation was impaired in HFpEF mice &lt;i&gt;in vivo&lt;/i&gt; and &lt;i&gt;ex vivo&lt;/i&gt;.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;β-Adrenergic lusitropic reserve was reduced in HFpEF mice during ultrasound echoc","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"604 20","pages":"8345-8359"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP291587","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149117787","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":"Can diet determine glucocorticoid efficacy? Metabolic control of mitochondrial homeostasis in dystrophic muscle","authors":"Anusha Liaqat,&nbsp;Salman Ahmad","doi":"10.1113/JP292108","DOIUrl":"10.1113/JP292108","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"604 20","pages":"8317-8319"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148963904","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 first brain at the centre: An enteric reframing of the nervous system","authors":"Tim Hibberd,&nbsp;Hayley Rhodes,&nbsp;Nick J. Spencer","doi":"10.1113/JP292328","DOIUrl":"10.1113/JP292328","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"604 20","pages":"8303-8306"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149065576","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":"Effects of exercise followed by a low-carbohydrate diet on peak fat oxidation and mitochondrial coupling control and efficiency in healthy trained men","authors":"K. K. Lange,&nbsp;L. Becker,&nbsp;T. Rømer,&nbsp;M. Hassing,&nbsp;S. T. Høybye,&nbsp;N. Smailes,&nbsp;P. Pardo,&nbsp;B. Danisman,&nbsp;P. F. Andersen,&nbsp;S. Larsen,&nbsp;J. W. Helge","doi":"10.1113/JP291697","DOIUrl":"10.1113/JP291697","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;Whole-body fat oxidation correlates with mitochondrial oxidative capacity, emphasizing the role of mitochondrial function in systemic and skeletal muscle substrate utilization during exercise – a relationship that may be modulated by the prevailing fuel availability. Muscle glycogen is an important fuel during exercise due to its effects on substrate metabolism, but its influence on peak fat oxidation (PFO) and mitochondrial coupling control and efficiency (MCCE) remains unclear. The aim of the study was to investigate the influence of muscle glycogen content on PFO, the intensity eliciting PFO (Fat&lt;sub&gt;max&lt;/sub&gt;) and MCCE. Ten trained men participated in a randomized crossover study comprising two interventions conducted over two consecutive days. Day 1 included anthropometric assessments, blood sampling, a muscle biopsy and a graded exercise test followed by a glycogen depletion protocol. The following day blood sampling, muscle biopsy and the graded exercise test were repeated. A diet high or low in carbohydrate was consumed between the days to manipulate glycogen levels. The experiment was repeated after 7–14 days. Muscle samples were analysed for glycogen and triacylglycerol content and MCCE. PFO increased after both interventions and was further enhanced by the combined exercise and low-carbohydrate intervention, where muscle glycogen was low. Fat&lt;sub&gt;max&lt;/sub&gt; increased only following the combined exercise and low-carbohydrate intervention. MCCE was unaffected by the interventions. The study concludes that exercise-induced glycogen depletion together with a low-carbohydrate diet increases PFO and Fat&lt;sub&gt;max&lt;/sub&gt; but does not influence MCCE. These findings have implications towards understanding and optimizing fat oxidation and as a potential read out of metabolic flexibility.\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;Whole-body fat oxidation is linked to mitochondrial capacity, yet the role of endogenous fuel availability in this relationship has not been studied.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Muscle glycogen is a primary exercise fuel, but its specific influence on peak fat oxidation (PFO), the exercise intensity that elicits PFO (Fat&lt;sub&gt;max&lt;/sub&gt;) and mitochondrial coupling control and efficiency (MCCE) is unclear.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Ten trained men completed a randomized crossover study using glycogen depletion and dietary intervention to alter glycogen levels, with exercise tests and muscle biopsies performed ","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"604 20","pages":"8467-8483"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP291697","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149065662","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 century of Chinese physiology: The Chinese Association for Physiological Sciences as scientific infrastructure and a bridge to the world","authors":"Yun Wang,&nbsp;Xiao-Min Wang,&nbsp;Ming Fan,&nbsp;Tai Yao,&nbsp;Xiong-Li Yang","doi":"10.1113/JP292670","DOIUrl":"10.1113/JP292670","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"604 20","pages":"8290-8294"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP292670","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149117771","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":"Interplay between store-operated calcium entry and mitochondrial phosphate handling modulates force and fatigue during exercise","authors":"Emmet A. Francis,&nbsp;Juliette Hamid,&nbsp;Anusha Kumar,&nbsp;Padmini Rangamani","doi":"10.1113/JP289463","DOIUrl":"10.1113/JP289463","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;The dynamics of calcium ions (&lt;span&gt;&lt;/span&gt;&lt;math&gt;\u0000 &lt;semantics&gt;\u0000 &lt;msup&gt;\u0000 &lt;mtext&gt;Ca&lt;/mtext&gt;\u0000 &lt;mrow&gt;\u0000 &lt;mn&gt;2&lt;/mn&gt;\u0000 &lt;mo&gt;+&lt;/mo&gt;\u0000 &lt;/mrow&gt;\u0000 &lt;/msup&gt;\u0000 &lt;annotation&gt;$text{Ca}^{2+}$&lt;/annotation&gt;\u0000 &lt;/semantics&gt;&lt;/math&gt;) in skeletal muscles link electrochemical activation and contractile force generation. Recent experimental data suggest that store-operated &lt;span&gt;&lt;/span&gt;&lt;math&gt;\u0000 &lt;semantics&gt;\u0000 &lt;msup&gt;\u0000 &lt;mtext&gt;Ca&lt;/mtext&gt;\u0000 &lt;mrow&gt;\u0000 &lt;mn&gt;2&lt;/mn&gt;\u0000 &lt;mo&gt;+&lt;/mo&gt;\u0000 &lt;/mrow&gt;\u0000 &lt;/msup&gt;\u0000 &lt;annotation&gt;$text{Ca}^{2+}$&lt;/annotation&gt;\u0000 &lt;/semantics&gt;&lt;/math&gt; entry (SOCE), the process of extracellular &lt;span&gt;&lt;/span&gt;&lt;math&gt;\u0000 &lt;semantics&gt;\u0000 &lt;msup&gt;\u0000 &lt;mtext&gt;Ca&lt;/mtext&gt;\u0000 &lt;mrow&gt;\u0000 &lt;mn&gt;2&lt;/mn&gt;\u0000 &lt;mo&gt;+&lt;/mo&gt;\u0000 &lt;/mrow&gt;\u0000 &lt;/msup&gt;\u0000 &lt;annotation&gt;$text{Ca}^{2+}$&lt;/annotation&gt;\u0000 &lt;/semantics&gt;&lt;/math&gt; influx upon the depletion of &lt;span&gt;&lt;/span&gt;&lt;math&gt;\u0000 &lt;semantics&gt;\u0000 &lt;msup&gt;\u0000 &lt;mtext&gt;Ca&lt;/mtext&gt;\u0000 &lt;mrow&gt;\u0000 &lt;mn&gt;2&lt;/mn&gt;\u0000 &lt;mo&gt;+&lt;/mo&gt;\u0000 &lt;/mrow&gt;\u0000 &lt;/msup&gt;\u0000 &lt;annotation&gt;$text{Ca}^{2+}$&lt;/annotation&gt;\u0000 &lt;/semantics&gt;&lt;/math&gt; from the sarcoplasmic reticulum (SR), helps delay the onset of muscle fatigue during exercise. We hypothesize that SOCE regulates force generation during prolonged muscle activity by allowing for sustained &lt;span&gt;&lt;/span&gt;&lt;math&gt;\u0000 &lt;semantics&gt;\u0000 &lt;msup&gt;\u0000 &lt;mtext&gt;Ca&lt;/mtext&gt;\u0000 &lt;mrow&gt;\u0000 &lt;mn&gt;2&lt;/mn&gt;\u0000 &lt;mo&gt;+&lt;/mo&gt;\u0000 &lt;/mrow&gt;\u0000 &lt;/msup&gt;\u0000 &lt;annotation&gt;$text{Ca}^{2+}$&lt;/annotation&gt;\u0000 &lt;/semantics&gt;&lt;/math&gt; release from the SR. We test this hypothesis with a quantitative biophysical model that simulates the biochemical events of muscle contraction, from depolarization at the T-tubules to &lt;span&gt;&lt;/span&gt;&lt;math&gt;\u0000 &lt;semantics&gt;\u0000 &lt;msup&gt;\u0000 &lt;mtext&gt;Ca&lt;/mtext&gt;\u0000 &lt;mrow&gt;\u0000 ","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"604 20","pages":"8379-8427"},"PeriodicalIF":4.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP289463","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149138954","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}