Journal of Physiology-London最新文献

{"title":"Impact of medial calcification on arterial mechanics and haemodynamics.","authors":"Pak-Wing Fok, Kun Gou, Brandon Myers, Peter Lanzer","doi":"10.1113/JP288112","DOIUrl":"https://doi.org/10.1113/JP288112","url":null,"abstract":"<p><p>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 in vivo 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. KEY POINTS: 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. 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. Systolic pressure decreases across calcified arteries, whereas in healthy arteries it usually increases. These findings have broad implications for localized detection of MAC.</p>","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":"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 skeletal muscle response to high-intensity training assessed by single-nucleus RNA-sequencing is blunted in individuals with type 2 diabetes.","authors":"Maria Hansen, Julius E R Grothen, Anders Karlsen, Jaime M Martinez, Nikos Sidiropoulos, Jørn W Helge, Thomas Å Pedersen, Flemming Dela","doi":"10.1113/JP288368","DOIUrl":"https://doi.org/10.1113/JP288368","url":null,"abstract":"<p><p>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. KEY POINTS: 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. 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. 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 sensitivity. The T2D group exhibited a blunted response in metabolic gene expression, indicating that the training effect on muscle adaptation was significantly impaired compared to healthy controls. Overall, the findings highlight the differential impact of HIIT on muscle metabolism, emphasizing the need for tailored exercise interventions for individuals with T2D.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/10.1113/JP288922","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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, Helena C Parkington","doi":"10.1113/JP288974","DOIUrl":"https://doi.org/10.1113/JP288974","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potassium homeostasis during disease progression of Alzheimer's disease.","authors":"Evgeniia Samokhina, Armaan Mangat, Chandra S Malladi, Erika Gyengesi, John W Morley, Yossi Buskila","doi":"10.1113/JP287903","DOIUrl":"https://doi.org/10.1113/JP287903","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder characterized by neuronal loss leading to dementia and ultimately death. Whilst the loss of neurons is central to this disease, it is becoming clear that glia, specifically astrocytes, contribute to the onset and progression of neurodegeneration. The role of astrocytes in maintaining ion homeostasis in the extracellular milieu is fundamental for multiple brain functions, including synaptic plasticity and neuronal excitability, which are compromised during AD and affect neuronal signalling. In this study, we measured the astrocytic K⁺ clearance rate in the hippocampus and somatosensory cortex of a mouse model for AD during disease progression. Our results establish that astrocytic [K⁺]_o (extracellular K⁺ concentration) clearance in the hippocampus is reduced in symptomatic 5xFAD mice, and this decrease is region-specific, as no significant alterations were detected in the superficial layers of the somatosensory cortex. The decrease in the [K⁺]_o clearance rate correlated with a significant reduction in the expression and conductivity of Kir4.1 channels and a decline in the number of primary connected astrocytes. Moreover, astrocytes in the hippocampus of symptomatic 5xFAD mice demonstrated increased reactivity which was accompanied by an increased excitability and altered spiking profile of nearby neurons. These findings indicate that the supportive function astrocytes typically provide to nearby neurons is diminished during disease progression, which affects the neuronal circuit signalling in this area and provides a potential explanation for the increased vulnerability of neurons in AD. KEY POINTS: Astrocytic potassium clearance from the extracellular milleu is fundamental for multiple brain functions. Alterations in the clearance rate can affect the excitability and overall viability of neurons. A symptomatic mouse model for Alzheimer's disease (5xFAD) exhibits a significant decline in astrocytic K⁺ clearance at the hippocampus, but not the somatosensory cortex. The decrease in the clearance rate correlated with a reduction in the expression and conductivity of astrocytic Kir4.1 channels and a decrease in the number of primary connected astrocytes, specifically at the stratum lacunosum moleculare layer of the CA1 region. Astrocytes in the hippocampus of symptomatic 5xFAD mice displayed increased reactivity. The excitability profile and firing patterns of neurons at the hippocampus were affected by alterations in K⁺ homeostasis, indicating that the supportive function astrocytes typically provide to nearby neurons is diminished during progression of Alzheimer's disease.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144006281","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":"Varied ionic currents underlie functional diversity of hypoglossal motoneurons innervating the superior longitudinalis and genioglossus tongue muscles.","authors":"Michael Frazure, Emily Flanigan, Lila B Wollman, Ralph Fregosi","doi":"10.1113/JP288599","DOIUrl":"https://doi.org/10.1113/JP288599","url":null,"abstract":"<p><p>Hypoglossal motoneurons (XIIMNs) control tongue movement, which must be precisely coordinated for communication, swallowing and respiration. We previously found that XIIMNs innervating intrinsic and extrinsic tongue muscles exhibit diverse firing properties. Here we investigate the mechanisms behind functional differences of XIIMNs that control the superior longitudinalis (SL) and genioglossus (GG) muscles, which retract and protrude the tongue, respectively. We hypothesized that varied ionic currents drive muscle-specific firing properties in XIIMNs. We obtained whole-cell patch-clamp recordings from retrogradely labelled SL and GG XIIMNs obtained from male and female neonatal rats. SL and GG XIIMNs exhibited distinct firing patterns, and SL XIIMNs had higher intrinsic excitability than GG XIIMNs. Next, voltage-clamp studies aimed to determine the ionic mechanisms responsible for functional differences between SL and GG XIIMNs. While whole-cell K⁺ conductance was similar in both populations, SL XIIMNs exhibited a large, sustained Ca²⁺-sensitive K⁺ current that was not observed in GG XIIMNs. Subsequent current-clamp studies evaluated the influence of Ca²⁺-sensitive K⁺ currents on firing behaviour. Bath application of the Ca²⁺ channel antagonist CdCl₂ produced opposite effects on firing behaviour in SL and GG XIIMNs. Ca²⁺ blockade impaired repetitive firing in SL XIIMNs and increased firing frequency in GG XIIMNs. These data indicate that distinct ionic currents contribute to the functional specialization of XIIMNs that control different tongue muscles. KEY POINTS: Using retrograde labelling and electrophysiology, we found that hypoglossal motoneurons innervating the superior longitudinalis (SL) and genioglossus (GG) muscles exhibit distinct biophysical properties. Until recently, hypoglossal motoneurons have been considered functionally homogeneous. Motoneurons innervating the SL had depolarized resting membrane potentials, lower firing thresholds and steeper frequency-current curves than GG motoneurons. SL motoneurons exhibited a prominent calcium-sensitive potassium current that was not observed in GG motoneurons. Calcium channel blockade differentially affected firing behaviour in SL and GG motoneurons. While SL motoneurons exhibited impaired repetitive discharge, GG motoneurons displayed increased firing frequency. Our findings suggest that hypoglossal motoneurons exhibit functional specialization, with distinct intrinsic membrane properties tailored to the specific motor demands of the tongue muscles they innervate.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024501","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":"Elucidating the cellular determinants of the end-systolic pressure-volume relationship of the heart via computational modelling.","authors":"Francesco Regazzoni, Corrado Poggesi, Cecilia Ferrantini","doi":"10.1113/JP287282","DOIUrl":"https://doi.org/10.1113/JP287282","url":null,"abstract":"<p><p>The left ventricular end-systolic pressure-volume relationship (ESPVr) is a key indicator of cardiac contractility. Despite its established importance, several studies suggested that the mechanical mode of contraction, such as isovolumetric or ejecting contractions, may affect the ESPVr, challenging the traditional notion of a single, consistent relationship. Furthermore, it remains unclear whether the observed effects of ejection on force generation are inherent to the ventricular chamber itself or are a fundamental property of the myocardial tissue, with the underlying mechanisms remaining poorly understood. We investigated these aspects using a multiscale in silico model that allowed us to elucidate the links between subcellular mechanisms and organ-level function. Simulations of ejecting and isovolumetric beats with different preload and afterload resistance were performed by modulating calcium and cross-bridge kinetics. The results suggest that the ESPVr is not a fixed curve but depends on the mechanical history of the contraction, with potentially both positive and negative effects of ejection. Cell scale simulations suggest that these phenomena are intrinsic to the myocardial tissue, rather than properties of the ventricular chamber. Our results suggest that the ESPVr results from the balance between positive and negative effects of ejection, related to a memory effect of the increased apparent calcium sensitivity at high sarcomere length, and to the inverse relationship between force and velocity. Numerical simulations allowed us to reconcile conflicting results in the literature and suggest translational implications for clinical conditions such as hypertrophic cardiomyopathy, where altered calcium dynamics and cross-bridge kinetics may impact the ESPVr. KEY POINTS: The left ventricular end-systolic pressure-volume relationship (ESPVr) is a fundamental indicator of cardiac contractility, but the traditional notion of a single, consistent curve across different mechanical modes of contraction (isovolumetric vs. ejecting) has been challenged. Using multiscale computational simulations, our findings suggest that the ESPVr is not a fixed curve but depends on the mechanical history of the contraction, with both positive and negative inotropic effects during muscle shortening (ejection). Our results suggest that these phenomena are intrinsic to myocardial tissue properties, specifically involving calcium kinetics and cross-bridge cycling, rather than being due to ventricular chamber mechanics. Our study reconciles conflicting findings in the literature by providing a mechanistic explanation of how length-dependent activation and the force-velocity relationship influence ESPVr. This work has potential translational implications for clinical conditions such as hypertrophic cardiomyopathy, where altered calcium dynamics and enhanced cross-bridge kinetics may significantly affect cardiac contractility and the ESPVr.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144057128","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":"Tumour necrosis factor-alpha at the intersection of renal epithelial and immune cell function.","authors":"Sara Hubbi, Shoujin Hao, Jarred Epps, Nicholas R Ferreri","doi":"10.1113/JP286756","DOIUrl":"https://doi.org/10.1113/JP286756","url":null,"abstract":"<p><p>This review explores the roles of tumour necrosis factor-alpha (TNF) in kidney physiology and pathology. TNF, produced by renal epithelial cells, regulates glucose, electrolyte, water and urea transport by modulating key transporters such as sodium-glucose co-transporter-2 (SGLT2), sodium-potassium-chloride cotransporter 2 (NKCC2), sodium chloride cotransporter (NCC), epithelial sodium channel (ENaC), aquaporin-2 (AQP2) and urea transporters. Under non-inflammatory conditions, TNF functions as a regulatory 'brake' on water and solute transport, particularly by attenuating NKCC2 and AQP2 activity. Disruption of these actions, coupled with increased salt intake, shifts mice from being salt-resistant to salt-sensitive, thereby altering their blood pressure. In autoimmune diseases, chronic kidney disease (CKD), hypertension with renal inflammation, and sepsis, TNF drives immune responses and disease progression. Although mechanisms underlying tubular epithelial cell (TEC)-immune cell interactions remain unclear, emerging evidence indicates that the spatial organization of immune responses in the kidney is associated with distinct TEC signature phenotypes. Hypertonicity- and NFAT5 (i.e. nuclear factor of activated T cells 5)-driven TNF production in TECs and T lymphocytes may influence immune cell communication by affecting co-stimulatory molecule expression and ENaC activity on macrophages and dendritic cells. Although TNF is generally pathogenic in renal diseases, its inhibition does not always confer protection because its effects on endoplasmic reticulum stress, ion transport, vascular smooth muscle and immune cells are influenced by distinct cellular sources and signalling mechanisms through TNF receptors 1 and 2. Anti-TNF therapies are crucial for treating chronic inflammatory diseases and may also aid in preventing the progression of acute kidney injury to CKD. A more complete understanding of the role of TNF in immunophysiological responses may enable the development of more targeted therapeutic strategies.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144025222","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":"Hyperglycaemia-induced reactive oxygen species production in cardiac ventricular myocytes differs among mammals.","authors":"Shan Lu, Maria J Baier, Risto-Pekka Polonen, Zhandi Liao, Jody L Martin, Kenneth S Ginsburg, Julian Mustroph, Donald M Bers","doi":"10.1113/JP287886","DOIUrl":"https://doi.org/10.1113/JP287886","url":null,"abstract":"<p><strong>Background: </strong>Diabetic cardiomyopathy (DbCM) preclinical studies have used animal models from different species and implicated altered redox regulation and reactive oxygen species (ROS) in this disease. However hyperglycaemia-induced ROS signalling may differ in ventricular myocytes from different species, and here we compare mice, rats, rabbits and humans with respect to hyperglycaemia-induced ROS production.</p><p><strong>Methods: </strong>Using the chemical sensor H₂DCFDA and genetically encoded redox sensors, we measured time-dependent ROS signals in response to high glucose (HiGlu). Live cell confocal imaging was used to determine redox and glucose levels, contractility and Ca²⁺ transients in isolated cardiomyocytes. Western blotting and activity assays were used to evaluate superoxide dismutase (SOD) expression and activity.</p><p><strong>Results: </strong>Consistent with our prior mouse studies, HiGlu exposure in rat and human ventricular myocytes increased cytosolic (not mitochondrial) ROS production via a mechanism involving Ca-calmodulin-dependent protein kinase (CaMKII) O-GlcNAcylation (at Ser280) and NADPH oxidase 2 (NOX2) activation. However in rabbit ventricular myocytes HiGlu alone did not induce significant ROS production, unless complemented by low levels of angiotensin II and inhibition of the enzyme that reverses O-GlcNAcylation using 100 nM Thiamet G, where both cytosolic and mitochondrial ROS accumulation were involved by more complex signalling networks.</p><p><strong>Conclusion: </strong>Acute hyperglycaemia readily induces robust ROS production in mouse, rat and human ventricular myocytes, but rabbit myocytes are intrinsically better protected from this HiGlu-induced ROS responses. In most regards rabbit are much more human-like than rodents for many aspects of myocyte function, but this surprisingly is not the case for HiGlu-induced ROS production.</p><p><strong>Key points: </strong>In mouse ventricular myocytes we previously showed that acute hyperglycaemia (HiGlu) induced increase in reactive oxygen species (ROS) mediated by O-GlcNAcylation of Ca-calmodulin-dependent protein kinase at Ser280 and consequent NADPH oxidase 2 (NOX2) activation. Here we demonstrate that this same pathway is functional in human and rat ventricular myocytes but not in rabbit ventricular myocytes. In rat and human myocytes HiGlu induced an increase in cytosolic, but not mitochondrial, ROS production. In rabbit myocytes HiGlu only produced increased ROS (cytosolic and mitochondrial) only when it was accompanied by both low concentration angiotensin II and an O-GlcNAcylase inhibitor (that individually did not promote ROS production). This direct HiGlu-induced ROS production in cardiac myocytes may contribute to pathological signalling in diabetes.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143993934","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":"Adverse effects of high-fat diet consumption on contractile mechanics of isolated mouse skeletal muscle are reduced when supplemented with resveratrol","authors":"Sharn P. Shelley,&nbsp;Rob S. James,&nbsp;Steven J. Eustace,&nbsp;Mark C. Turner,&nbsp;Ryan Brett,&nbsp;Emma L. J. Eyre,&nbsp;Jason Tallis","doi":"10.1113/JP287056","DOIUrl":"https://doi.org/10.1113/JP287056","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;Increasing evidence indicates resveratrol (RES) supplementation evokes anti-obesogenic responses that could mitigate obesity-induced reductions in skeletal muscle (SkM) contractility. Contractile function is a key facet of SkM health that underpins whole body health. For the first time, the present study examines the effects of a high-fat diet and RES supplementation on isolated soleus (SOL) and extensor digitorum longus (EDL) contractile function. Female CD-1 mice, ∼6 weeks old (&lt;i&gt;n&lt;/i&gt; = 38), consumed a standard laboratory diet (SLD) or a high-fat diet (HFD), with or without RES (4 g kg&lt;sup&gt;−1&lt;/sup&gt; diet) for 12 weeks. SOL and EDL (&lt;i&gt;n&lt;/i&gt; = 8–10 per muscle, per group) were isolated and then absolute and normalised (to muscle size and body mass) isometric force and work loop power output (PO) were measured, and fatigue resistance was determined. Furthermore, sirtuin-1 expression was determined to provide mechanistic insight into any potential contractile changes. For SOL absolute force was higher in HFDRES compared to HFD (&lt;i&gt;P&lt;/i&gt; = 0.033), and PO normalised to body mass and cumulative work during fatigue were reduced in HFD groups (&lt;i&gt;P &lt;/i&gt;&lt; 0.014). EDL absolute and normalised PO and cumulative work during fatigue were lower in HFD compared to other groups (&lt;i&gt;P &lt;/i&gt;&lt; 0.019). RES negated most adverse effects of HFD consumption on EDL contractility, with HFDRES producing PO and cumulative work comparable to the SLD groups. Sirtuin-1 expression was not influenced by diet in either muscle (&lt;i&gt;P &lt;/i&gt;&gt; 0.165). This study uniquely demonstrates that RES attenuates HFD-induced reductions in contractile performance of EDL, but this response is not explained by altered sirtuin-1 expression. These results suggest RES may be an appropriate strategy to alleviate obesity-induced declines in SkM function.\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;Skeletal muscle health, a precursor for disease prevention, whole body health and quality of life, is substantially reduced because of obesity.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Growing evidence suggests that the anti-obesogenic effects of nutritional supplement resveratrol may mitigate against obesity-induced muscle pathology. However, the effect of resveratrol on skeletal muscle contractile performance, a primary marker of skeletal muscle health, is yet to be examined.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Our findings indicate that resveratrol reduces the adverse effects of high-fat diet consumption ","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 9","pages":"2675-2698"},"PeriodicalIF":4.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP287056","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143938916","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}