Journal of Physiology-London最新文献

{"title":"Atypical delayed paired-pulse depression at an identified synapse","authors":"Michelle Sanchez-Rivera, Montserrat G. Cercós, Citlali Trueta","doi":"10.1113/JP287156","DOIUrl":"10.1113/JP287156","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <div>At chemical synapses, the interplay between the stimulation pattern, the dynamics of presynaptic calcium concentration and the use and replenishment of the vesicle pool causes plasticity phenomena such as synaptic facilitation and depression. These phenomena may coexist, with their relative contribution depending mostly on the initial release probability. Synaptic facilitation is caused by an increased probability of release as a result of presynaptic calcium accumulation, whereas synaptic depression is attributed to depletion of the releasable vesicle pool. Here, we show an unusual form of paired-pulse delayed depression at the synapse between pressure-sensitive and anterior pagoda neurons of the leech. Two presynaptic impulses with short (<700 ms) interstimulus intervals produced facilitation, which extinguished gradually, consistent with the residual calcium hypothesis and showing that a single impulse does not deplete the vesicle pool. However, long (>700 ms) interstimulus intervals produced delayed depression, that increased with the interval up to 1000 ms, but was reduced by pre-incubation with EGTA-AM. Depression emerged with an abrupt deviation from the facilitation decrease curve, and not with the continuous transition expected from a gradual decrease in release probability and a slow recovery of the vesicle pool. In addition, strong facilitation could be elicited after delayed depression, even when depression was increased by increasing previous release. Classical models of plasticity, solely considering vesicular depletion-replenishment and calcium-dependent changes in release probability, are unable to explain our data. We propose a new model that includes a slow calcium-dependent mechanism removing vesicles from the readily releasable pool with a delay after each presynaptic impulse.\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>Synaptic plasticity produces dynamic changes in the efficiency of transmission at chemical synapses.</li>\u0000 \u0000 <li>Synaptic depression is usually attributed to depletion of the presynaptic pool of releasable vesicles.</li>\u0000 \u0000 <li>Here, we show an unusual form of synaptic depression, which occurs with a delay after previous release, depends on calcium and is not caused by depletion of the vesicle pool by its previous use.</li>\u0000 \u0000 <li>We propose a mechanism where vesicles are removed from the releasable pool after activation of a second messenger cascade.</li>\u0000 </ul>\u0000 </div>\u0000 ","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 19","pages":"5655-5680"},"PeriodicalIF":4.4,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145034484","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":"Prediabetic cardiomyopathy is attenuated by hypothalamic PVN oxytocin neuron activation.","authors":"Anna Nilsson, Joan Escobar, Kira Kuraoka, Ian Venter, Cielo A Carnate, Matthew W Kay, David Mendelowitz, Kathryn J Schunke","doi":"10.1113/JP287928","DOIUrl":"https://doi.org/10.1113/JP287928","url":null,"abstract":"<p><p>Diagnoses of prediabetes and metabolic syndromes, such as metabolic-associated steatotic liver disease (MASLD), are increasing at an alarming rate worldwide, often simultaneously. A significant consequence of these is high risk of cardiovascular disease, highlighting the need for cardiac-specific therapeutics for intervention during the prediabetic stage. Recent studies have demonstrated that chemogenetic activation of the cardiac parasympathetic system through hypothalamic oxytocin (OXT) neurons provides cardioprotective effects in heart disease models by targeting excitatory neurotransmission to brainstem cardiac vagal neurons. In a prediabetic rat model, we hypothesized that stimulating this neural network would offer cardioprotection. To test this, we induced prediabetes through prolonged high-fat, high-fructose feeding. We stereotactically injected viral vectors into the paraventricular nucleus (PVN) of the hypothalamus in neonatal rats to express designer receptors exclusively activated by designer drugs (i.e. Designer Receptors Exclusively Activated by Designer Drugs; DREADDs) in a subset of PVN OXT neurons, chronically activated using the designer drug clozapine N-oxide (CNO). Treated animals exhibited improved cardiac diastolic function and reduced left ventricular fibrosis compared to non-treated diseased animals after 4 weeks of CNO, with no change to systemic insulin resistance, hyperinsulinaemia, and elevated triglycerides. Transcriptional analysis of left ventricular tissue indicates the preservation of pathways involved in metabolism (Pdk4, Pdp1 and Hk2) and ion handling (Sln, Atp1a2 and Atp1a4) in treated compared to diseased animals. These findings underscore the benefits of stimulating the OXT network to counteract prediabetic cardiomyopathy, independent of systemic prediabetes. OXT neurons and their downstream networks appear to be a promising therapeutic target for activating protective parasympathetic-mediated cellular pathways within the heart during prediabetic cardiomyopathy. KEY POINTS: Male rats fed a long-term high-fat, high-fructose diet develop prediabetes, marked by systemic insulin resistance and hyperinsulinaemia, along with characteristics of metabolic-associated steatotic liver disease. Animals exhibit prediabetic cardiomyopathy marked by diastolic dysfunction, interstitial fibrosis, a thickened left ventricular wall and tachycardia with reduced heart rate variability. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)-mediated chemogenetic activation of oxytocin-expressing neurons in the paraventricular nucleus of the hypothalamus improves cardiac diastolic dysfunction, reduces fibrosis and restores autonomic balance without impacting systemic insulin resistance or hyperinsulinaemia. Transcriptomic analysis of the left ventricle suggests that activation of hypothalamic oxytocin neurons influences cardiac metabolism and ion handling, potentially serving as mechanisms of protection. Our dat","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145034460","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":"Revisiting brown adipose tissue whitening: Physiological mechanisms and pathophysiological consequences","authors":"Le Zhao,&nbsp;Qing-jun Zhu,&nbsp;Min-hao Li,&nbsp;Hai-li Yang,&nbsp;Yong-ju Zhao","doi":"10.1113/JP289263","DOIUrl":"10.1113/JP289263","url":null,"abstract":"<p>This review aims to explore the various factors that contribute to the whitening of brown adipose tissue (BAT) and to summarize the key regulatory mechanisms involved. The goal is to uncover novel therapeutic strategies for obesity that delay or inhibit BAT whitening. The development of obesity is often linked to changes in adipose tissue (AT) and metabolic disorders, with BAT whitening emerging as a chronic obesity-related complication. Current research shows that BAT whitening is strongly influenced by various factors such as age, diet and thermoneutrality through distinct mechanisms. The key regulatory factors have been investigated, with a particular focus on their involvement in mitochondrial dysfunction, vascular damage and inflammation within BAT. Certain BAT-promoting or -activating interventions such as cold exposure, β-adrenergic receptor stimulation and targeted exercise regimens have been proposed for obesity management; however, the exact pathogenic mechanisms involved in preventing BAT whitening and its impact on metabolic health remain unclear. Further research and recommendations in this domain are required to enhance obesity treatment strategies.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 19","pages":"5299-5326"},"PeriodicalIF":4.4,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://physoc.onlinelibrary.wiley.com/doi/epdf/10.1113/JP289263","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145034424","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":"Blood flow stasis improvements after simulated occlusion of the left atrial appendage in paroxysmal atrial fibrillation using 4-D computed tomography.","authors":"Omar Hassan, Hadi Hassan, Shuvam Prasai","doi":"10.1113/JP289846","DOIUrl":"https://doi.org/10.1113/JP289846","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145016563","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":"Integrative physiology of skeletal muscle for maintaining cognitive health.","authors":"Matthew H Brisendine, Joshua C Drake","doi":"10.1113/JP286748","DOIUrl":"https://doi.org/10.1113/JP286748","url":null,"abstract":"<p><p>Cognitive decline and physical impairment are often linked with ageing, contributing to declines in health span and loss of independence in older adults. Pathological cognitive decline with age is largely considered to be a brain-centric challenge. However, recent findings have begun to challenge this paradigm as the health of peripheral systems, namely skeletal muscle, predict cognitive decline associated with Alzheimer's disease (AD). Loss of muscle strength (dynapenia), loss of muscle mass (sarcopenia) and associated impairment in peripheral motor nerves and neuromuscular junctions have all been shown to either precede or coincide with AD pathology in the brain. The importance for skeletal muscle is also demonstrated in its role as an endocrine organ, secreting factors like brain-derived neurotrophic factor that promote neurogenesis in the brain. In this review we summarize the importance of skeletal muscle for cognition and discuss how the health of skeletal muscle and peripheral motor nerves may be novel sentinels for AD risk.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145016590","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":"Exercise-induced arterial hypoxaemia in patients with heart failure with preserved ejection fraction.","authors":"Michael G Leahy, James P MacNamara, Andrew R Tomlinson, Denis J Wakeham, Tiffany L Brazile, Abidan Abulimiti, Kevin C Lutz, Benjamin D Levine, Satyam Sarma, Tony G Babb, Bryce N Balmain","doi":"10.1113/JP289362","DOIUrl":"https://doi.org/10.1113/JP289362","url":null,"abstract":"<p><p>Some patients with heart failure with preserved ejection fraction (HFpEF) have demonstrated evidence of exercise-induced arterial hypoxaemia (EIAH). However, EIAH was not quantified using <math> <semantics><msub><mi>S</mi> <mrow><mi>a</mi> <msub><mi>O</mi> <mn>2</mn></msub> </mrow> </msub> <annotation>${{S}_{{mathrm{a}}{{{mathrm{O}}}_2}}}$</annotation></semantics> </math> , <math> <semantics><msub><mi>P</mi> <mrow><mi>a</mi> <msub><mi>O</mi> <mn>2</mn></msub> </mrow> </msub> <annotation>${{P}_{{mathrm{a}}{{{mathrm{O}}}_2}}}$</annotation></semantics> </math> , and <math> <semantics><msub><mi>P</mi> <mrow><mrow><mi>A</mi> <mo>-</mo> <mi>a</mi></mrow> <msub><mi>O</mi> <mn>2</mn></msub> </mrow> </msub> <annotation>${{P}_{{mathrm{A - a}}{{{mathrm{O}}}_{mathrm{2}}}}}$</annotation></semantics> </math> measurements as previously conducted in healthy adults nor was EIAH quantified alongside simultaneous measurements of pulmonary vascular pressures, cardiorespiratory responses, or dyspnoea on exertion (DOE) in these patients. Given the effects of hypoxaemia on pulmonary vasoconstriction, cardiorespiratory responses, and DOE, we tested the hypothesis that patients with HFpEF and EIAH (EIAH⁺) would demonstrate higher pulmonary vascular pressures, worse oxygen uptake, and greater DOE compared with patients without EIAH (EIAH^-). Sixty patients with HFpEF underwent invasive (pulmonary and radial artery catheters) constant-load (20 W) and maximal incremental cycle testing. Pulmonary vascular measures (pulmonary artery catheter), arterial blood (radial artery catheter) and expired gases, and ratings of breathlessness (RPB, Borg 0-10) were assessed. EIAH was characterized by one or more of the following criteria: (1) <math> <semantics><msub><mi>S</mi> <mrow><mi>a</mi> <msub><mi>O</mi> <mn>2</mn></msub> </mrow> </msub> <annotation>${{S}_{{mathrm{a}}{{{mathrm{O}}}_2}}}$</annotation></semantics> </math>  < 93% during exercise, (2) <math> <semantics><msub><mi>P</mi> <mrow><mrow><mi>A</mi> <mo>-</mo> <mi>a</mi></mrow> <msub><mi>O</mi> <mn>2</mn></msub> </mrow> </msub> <annotation>${{P}_{{mathrm{A - a}}{{{mathrm{O}}}_{mathrm{2}}}}}$</annotation></semantics> </math>  ≥ 25 mmHg from rest to exercise or (3) <math> <semantics><msub><mi>P</mi> <mrow><mi>a</mi> <msub><mi>O</mi> <mn>2</mn></msub> </mrow> </msub> <annotation>${{P}_{{mathrm{a}}{{{mathrm{O}}}_2}}}$</annotation></semantics> </math>  ≥ 10 mmHg from rest to exercise. About 25 patients had EIAH (EIAH⁺) and 35 did not have EIAH (EIAH^-). mPAP, PCWP, and pulmonary vascular resistance were similar between groups at rest, 20 W, and peak exercise. Although all cardiorespiratory responses were similar between groups at rest, 20 W, and peak exercise, RPB was greater in EIAH⁺ throughout rest and peak exercise. Our findings suggest that EIAH has no effect on central haemodynamics and is likely to be a consequence of pulmonary gas exchange abnormalities including vent","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145016603","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":"Endurance training increases a ubiquitylated form of histone H3 in the skeletal muscle, supporting Notch1 upregulation in an MDM2-dependent manner","authors":"Brian Lam,&nbsp;Manpreet Gulri,&nbsp;Sokaina Akhtar,&nbsp;Pierre Lemieux,&nbsp;Monica Tawadrous,&nbsp;Mayoorey Murugathasan,&nbsp;Ali A. Abdul-Sater,&nbsp;Emilie Roudier","doi":"10.1113/JP288947","DOIUrl":"10.1113/JP288947","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;At the onset of training, each exercise session transiently shifts the distribution of histone post-transcriptional modifications (HPTMs) to activate genes that drive muscle adaptations. The resulting cyclic changes in gene expression promote the acquisition of high oxidative capacities and gains in capillaries. If training stops or remains at the same intensity, adaptation ceases. Whether silencing HPTMs helps to halt adaptation remains understudied. The E3 ubiquitin ligase murine double minute (MDM2) and enhancer of zester homolog 2 (EZH2) interact and tri-methylate histone H3 on lysine 27 (H3K27&lt;sup&gt;me3&lt;/sup&gt;), silencing genes. C57Bl6 mice ran for 9 weeks (5 days a week) maintaining a constant running speed for the last 5 weeks of training. Muscles were collected 72 h after the last run. Training increased MDM2 and EZH2 proteins and led to an H3K27&lt;sup&gt;me3&lt;/sup&gt; enrichment in &lt;i&gt;Kdr&lt;/i&gt; and &lt;i&gt;Notch1&lt;/i&gt; regulatory sequences&lt;i&gt;. Kdr&lt;/i&gt; mRNA levels decreased, following the canonical model that H3K27&lt;sup&gt;me3&lt;/sup&gt; silences genes. &lt;i&gt;Notch1&lt;/i&gt; mRNA increased. Trained muscles had greater levels of H3K27&lt;sup&gt;me3&lt;/sup&gt; detected at 25 kDa and no change at the expected molecular weight of 17 kDa. The 25 kDa band was identified as a ubiquitylated form of H3 (H3&lt;sup&gt;Ub&lt;/sup&gt;). C2C12 myotubes exposed to four consecutive days of 90 min electrostimulation had higher levels of H3&lt;sup&gt;Ub&lt;/sup&gt;. EZH2 inhibition counteracted the electrostimulation-driven accumulation of H3&lt;sup&gt;Ub&lt;/sup&gt; and increased &lt;i&gt;Notch1&lt;/i&gt; mRNA. Serdemetan, an MDM2 ring domain inhibitor, reduced &lt;i&gt;Notch1&lt;/i&gt; mRNA and H3&lt;sup&gt;Ub&lt;/sup&gt; level in myotubes. MDM2-dependent ubiquitylation of H3 might upregulate &lt;i&gt;Notch1&lt;/i&gt; when endurance training ceases. The role H3&lt;sup&gt;Ub&lt;/sup&gt; plays in establishing a new muscle homeostasis remains unclear.\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;Whether epigenetic silencing histone marks play a role once skeletal muscle adaptations have occurred following endurance training remains unclear.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;The E3 ubiquitin ligase MDM2 and the epigenetic writer EZH2 interact to establish H3K27&lt;sup&gt;me3&lt;/sup&gt; marks that silence genes, and endurance training increased the expression of both proteins.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;After weeks of training new capillaries were established, and lower levels of &lt;i&gt;Kdr&lt;/i&gt; mRNA and increased H3K27&lt;sup&gt;me3&lt;/sup&gt; marking on &lt;i&gt;Kdr&lt;/i&gt; regulatory sequences question whether silencing of thi","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 19","pages":"5477-5508"},"PeriodicalIF":4.4,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://physoc.onlinelibrary.wiley.com/doi/epdf/10.1113/JP288947","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006797","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":"Haemodynamic-energetic mechanism of sudden cardiac death in severe aortic stenosis: A modelling study.","authors":"Martin Dvoulety, Michal Sitina","doi":"10.1113/JP288423","DOIUrl":"https://doi.org/10.1113/JP288423","url":null,"abstract":"<p><p>Severe aortic stenosis (AS) is a recognized risk factor for sudden cardiac death (SCD). Although ventricular tachyarrhythmias are the most common immediate cause of SCD, the majority of cases of SCD in patients with severe AS exhibited bradyarrhythmia as the primary rhythm. Enhanced activation of left ventricular baroreceptors (Bezold-Jarisch reflex) has been implicated in the pathogenesis of syncope in patients with AS. However, the precise mechanism by which an otherwise benign circulatory syncope can progress to cardiac arrest in severe AS remains unclear. This study proposes a haemodynamic-energetic mechanism to explain this progression, and demonstrates its plausibility using a mathematical model of cardiac haemodynamics and energetics. The model identifies states of cardiac energy imbalance, in which the energy expenditure of the heart exceeds the energy delivered to it. In individuals with a normal aortic valve, compensatory mechanisms can restore energy balance following syncope. By contrast, in severe AS, all conditions involving low peripheral vascular resistance are energetically unstable, regardless of compensatory response. Because energy imbalance is incompatible with sustained cardiac function, such states inevitably result in cardiac arrest. Importantly, the proposed mechanism does not require an exaggerated Bezold-Jarisch reflex, although the reflex probably acts as a trigger of syncope by initiating peripheral vasodilatation. Additionally, the limited coronary vasodilatory reserve commonly observed in severe AS significantly contributes to the development of myocardial energy imbalance. KEY POINTS: The precise mechanism of sudden cardiac death in patients with severe aortic stenosis remains uncertain. In the present study, we propose a novel haemodynamic-energetic mechanism of sudden cardiac death explaining how otherwise benign circulatory syncope can progress to cardiac arrest in patients with severe aortic stenosis. The plausibility of the mechanism is verified using a mathematical model. The model identifies states of cardiac energy imbalance in patients with severe aortic stenosis, where the energy expenditure of the heart exceeds the energy delivered to it, which inevitably leads to cardiac arrest. Mathematical simulation of a circulatory syncope reveals significant differences in the effects of compensatory response in patients with and without severe aortic stenosis. The results provide a comprehensive understanding of the mechanism of sudden cardiac death in patients with severe aortic stenosis.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006710","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 cardiac pacemakers: A paradigm of robustness in evolutionary biology.","authors":"Denis Noble","doi":"10.1113/JP287139","DOIUrl":"https://doi.org/10.1113/JP287139","url":null,"abstract":"<p><p>The cardiac pacemaker activity is formed from multiple interlocking physiological networks, any one of which can generate rhythm. The interlocking is reciprocal so that they automatically replace each other. In such interlocking control systems, the association scores for individual components are necessarily low, even though causation, measured by the electric current carried by the relevant ion channels, is large. This kind of reciprocally based robustness is widespread in living organisms, which explains why most association scores in genome-wide association studies are low, or even zero. It also explains why the polygenic scores do not reliably predict disease states. Genomics alone is therefore a poor method for the discovery of treatments for polygenic diseases. Reliance on genomics has led to a gene-centric impasse in healthcare, which requires a shift in favour of physiological studies that can reveal genuine causation rather than just association. The case for such a shift includes understanding that DNA is not a good self-replicator in very large genomes. Self-replication of DNA and RNA in purely chemical environments confirms that fact. The error rate would amount to hundreds of thousands in a genome of three billion base pairs. Living cells can orchestrate the enzymes necessary for nearly perfect replication before cell division by correcting those errors. These cellular proof-reading processes also open the way to control processes that are used to generate new DNA sequences when the immune and other systems need to do so.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006723","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":"Danicamtiv increases cardiac mechanical efficiency","authors":"Trent Meehan,&nbsp;Toan Pham,&nbsp;Kenneth Tran,&nbsp;Andrew J. Taberner,&nbsp;June-Chiew Han","doi":"10.1113/JP288913","DOIUrl":"10.1113/JP288913","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;Danicamtiv is a recently developed cardiac-specific myosin activator that directly increases actomyosin interaction and, thereby, increases force. It is currently studied pre-clinically and has entered clinical trials. In this study, we provide the first assessment of its effects on cardiac energetics. Ventricular trabeculae from rats were isolated and studied &lt;i&gt;in vitro&lt;/i&gt;. Each trabecula was stimulated to produce twitch force over ranges of muscle lengths and afterloads, with muscle heat output simultaneously measured. Each trabecula was superfused with and without danicamtiv (5 µM). In both interventions, muscles were required to undergo both isometric and work-loop contraction protocols to quantify the components of heat output – that from muscle contraction, that from intracellular Ca&lt;sup&gt;2+&lt;/sup&gt; cycling and that from actomyosin cross-bridge cycling. Danicamtiv was found to increase twitch force, muscle heat and cross-bridge heat, with no effect on the energy expenditure associated with intracellular Ca&lt;sup&gt;2+&lt;/sup&gt; cycling. Danicamtiv slowed isometric twitch force kinetics and slowed shortening kinetics. Danicamtiv increased the extent of muscle shortening, increased muscle work output and increased mechanical efficiency, while preserving cross-bridge efficiency. In conclusion, danicamtiv increases mechanical efficiency, the mechanism of which arises from the greater increase of force and muscle shortening that increase mechanical work than the increase of heat. The relative smaller increase of heat is due to a null effect of danicamtiv on the energy for intracellular Ca&lt;sup&gt;2+&lt;/sup&gt; cycling. Our results provide perspective for the utility of danicamtiv as an inotropic agent not only for mechanical enhancement but also for energetic enhancement in increasing mechanical efficiency.\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;Clinical trials are presently exploring the potential of a new myotrope, danicamtiv, to improve cardiac mechanics by increasing muscle force output.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;A range of active pre-clinical research is likewise uncovering the biophysical mechanism of how danicamtiv affects cardiac mechanics, increases cardiac force and slows contractile kinetics.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;This study provides the first energetic assessment of danicamtiv by measuring muscle heat output, and shows that danicamtiv increases cardiac energy efficiency.\u0000&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Th","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 19","pages":"5509-5528"},"PeriodicalIF":4.4,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://physoc.onlinelibrary.wiley.com/doi/epdf/10.1113/JP288913","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006728","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}