Journal of Physiology-London最新文献

{"title":"Determinants of maximal oxygen uptake in highly trained females and males: a mechanistic study of sex differences using advanced invasive methods.","authors":"Øyvind Skattebo, Marcos Martin-Rincon, Bjarne Rud, Joachim Nielsen, Lars Henrik N Hegg, Andreas V Kleive, Niels Ørtenblad, Øyvind Sandbakk, Robert Boushel, Hans-Christer Holmberg, Jose A L Calbet, Jostein Hallén","doi":"10.1113/JP289218","DOIUrl":"https://doi.org/10.1113/JP289218","url":null,"abstract":"<p><p>Females typically have lower body mass-normalised maximal oxygen uptake ( <math> <semantics> <msub><mover><mi>V</mi> <mo>̇</mo></mover> <mrow><msub><mi>O</mi> <mn>2</mn></msub> <mspace></mspace> <mi>max</mi></mrow> </msub> <annotation>${dot V_{{{mathrm{O}}_2}!max }}$</annotation></semantics> </math> ) than males. However, whether this difference is solely due to body composition or also reflects sex-based differences in cardiovascular and muscular capacities for O<sub>2</sub> delivery and O<sub>2</sub> extraction remains unclear. This study examined sex differences in the O<sub>2</sub> transport chain when normalised to lean body mass (LBM). Twenty-three highly trained cyclists and triathletes (10 females; 29 ± 6 years) performed incremental cycling to exhaustion on an ergometer with simultaneous assessment of cardiac output, leg blood flow (thermodilution), O<sub>2</sub> delivery, and leg O<sub>2</sub> extraction (arterial and femoral venous catheters). Mitochondrial (TEM) and capillary (immunohistochemistry) densities were assessed in the vastus lateralis. Maximal cardiac output was 26% lower in females than males (22 ± 3 vs. 30 ± 3 l min<sup>-1</sup>; P < 0.001). However, this difference disappeared when normalised to LBM (P = 0.375). Two-leg blood flow was similar after normalisation to leg lean mass (LLM; P = 0.327). However, females had 10% lower haemoglobin concentration and arterial O<sub>2</sub> content (177 ± 10 vs. 194 ± 15 ml l<sup>-1</sup>; P = 0.004), resulting in 11%-14% lower lean mass-normalised systemic and leg O<sub>2</sub> delivery. Leg O<sub>2</sub> extraction (91 ± 3 vs. 92 ± 3%; P = 0.204) and mitochondria, cristae, and capillary densities were similar between sexes. Therefore, proportional to sex differences in O<sub>2</sub> delivery, females had lower lean mass-normalised pulmonary (63 ± 8 vs. 73 ± 4 ml min<sup>-1</sup> kg<sub>LBM</sub> <sup>-1</sup>; P = 0.003) and leg (135 ± 14 vs. 160 ± 14 ml min<sup>-1</sup> kg<sub>LLM</sub> <sup>-1</sup>; P = 0.002) <math> <semantics> <msub><mover><mi>V</mi> <mo>̇</mo></mover> <mrow><msub><mi>O</mi> <mn>2</mn></msub> <mspace></mspace> <mi>max</mi></mrow> </msub> <annotation>${dot V_{{{mathrm{O}}_2}!max }}$</annotation></semantics> </math> . These findings demonstrate that highly trained females and males have similar muscle O<sub>2</sub> extraction and perfusion per kg LBM. However, females' 10% lower haemoglobin concentration results in lower LBM-normalised O<sub>2</sub> delivery and <math> <semantics> <msub><mover><mi>V</mi> <mo>̇</mo></mover> <mrow><msub><mi>O</mi> <mn>2</mn></msub> <mspace></mspace> <mi>max</mi></mrow> </msub> <annotation>${dot V_{{{mathrm{O}}_2}!max }}$</annotation></semantics> </math> . KEY POINTS: Females and males differ substantially in body size and composition, with males having greater skeletal muscle mass and females a higher body fat percentage. During maximal exercise, the active skeletal muscles consume most of the body's oxygen uptake. Conseque","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103193","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 Christianson syndrome protein, sodium hydrogen exchanger isoform 6, is required for fat accumulation.","authors":"Ruby Gupta, Allatah X Mekile, Rachana L Patnayak, Monish Ram Makena, Ray Wesley Bowman, Cory J White, Damaris N Lorenzo, Rajini Rao","doi":"10.1113/JP289613","DOIUrl":"https://doi.org/10.1113/JP289613","url":null,"abstract":"<p><p>Mutations in NHE6 (human gene name SLC9A6) lead to the rare X-linked disorder Christianson syndrome (CS) characterized by intellectual disability, autism and ataxia. NHE6 is a Na⁺/H⁺ exchanger that regulates pH and ionic equilibria across endosomal membranes in a variety of tissues, although its non-neuronal role is understudied. A common co-morbidity in CS is low body weight, with body mass index in the 3-5th percentile range. In the present study, we use a Nhe6^KO mouse model of CS to demonstrate a role for NHE6 in fat accumulation and glucose homeostasis. On both chow and a high-fat diet, Nhe6^KO mice displayed lower body weight and decreased fat accumulation in adipose tissue. By contrast, glycogen accumulation was strongly increased in liver of Nhe6^KO mice on a high-fat diet. Knockdown of NHE6 (NHE6 KD) in 3T3L1 adipocytes resulted in smaller lipid droplets, pointing to a cell autonomous role in fat accumulation. NHE6 KD adipocytes also exhibit dysregulation of insulin-responsive uptake of fatty acids, glucose and Fe/transferrin, as well as the cell surface translocation of the corresponding transporters. Furthermore, we observed selective downregulation of key components of the insulin signalling pathway that could be restored using the Na⁺/H⁺ exchanger mimetic monensin or the V-ATPase inhibitor bafilomycin, pointing to pH dysregulation as the underlying defect. These findings establish NHE6 as a novel contributor to energy metabolism with implications for CS patients. KEY POINTS: NHE6 is an endosomal Na⁺/H⁺ exchanger mutated in Christianson syndrome. Nhe6 null mice accumulate less fat and weigh less than control animals. In adipocytes, NHE6 knockdown reduces insulin-stimulated fatty acid and glucose uptake. NHE6 exerts proteostatic control over multiple components of the insulin signalling pathway.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092734","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":"Cardiac stalling: Modelling energy balance in aortic stenosis and its role in syncope.","authors":"DeWayne Townsend","doi":"10.1113/JP289772","DOIUrl":"https://doi.org/10.1113/JP289772","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092711","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":"Sarcomere lego to understand myofilament dysfunction underlying hypertrophic cardiomyopathy due to gene mutations","authors":"James T. Pearson","doi":"10.1113/JP289966","DOIUrl":"10.1113/JP289966","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 19","pages":"5249-5250"},"PeriodicalIF":4.4,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092750","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":"Ensemble learning of the atrial fibre orientation with physics-informed neural networks.","authors":"Efraín Magaña, Simone Pezzuto, Francisco Sahli Costabal","doi":"10.1113/JP288001","DOIUrl":"https://doi.org/10.1113/JP288001","url":null,"abstract":"<p><p>The anisotropic structure of the myocardium is a key determinant of the cardiac function. To date there is no imaging modality to assess in vivo the cardiac fibre structure. We recently proposed Fibernet, a method for the automatic identification of the anisotropic conduction - and thus fibres - in the atria from local electrical recordings. Fibernet uses cardiac activation as recorded during electroanatomical mappings to infer local conduction properties using physics-informed neural networks. In this work we extend Fibernet to cope with the uncertainty in the estimated fibre field. Specifically we use an ensemble of neural networks to produce multiple samples, all fitting the observed data, and compute posterior statistics. We also introduce a methodology to select the best fibre orientation members and define the input of the neural networks directly on the atrial surface. With these improvements we outperform the previous methodology in terms of fibre orientation error in eight different atrial anatomies. Currently our approach can estimate the fibre orientation and conduction velocities in under 7 min with quantified uncertainty, which opens the door to its application in clinical practice. We hope the proposed methodology will enable further personalisation of cardiac digital twins for precision medicine. KEY POINTS: The direction of heart muscle fibres strongly affects how electrical signals travel, but current imaging methods cannot measure these fibres inside the living atria. We improved our previous method (Fibernet) by introducing <math><semantics><mi>Δ</mi> <annotation>$Delta$</annotation></semantics> </math> -Fibernet, which is more accurate and can estimate uncertainty in the results. <math><semantics><mi>Δ</mi> <annotation>$Delta$</annotation></semantics> </math> -Fibernet works directly on the surface of the heart and includes a new approach to select the most reliable fibre direction. The method produces results in under 7 min and could support personalised treatment planning for heart rhythm disorders.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092741","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":"High-elevation adaptation and gestational hypoxia jointly shape vascular development in a rodent placenta.","authors":"Kathryn Wilsterman, Zachary A Cheviron, Jeffrey M Good, Kai Gurnoe-Brantley, Kylie E Jewett, Katherine Kiel, Ashley M Larson","doi":"10.1113/JP289376","DOIUrl":"https://doi.org/10.1113/JP289376","url":null,"abstract":"<p><p>Gestational hypoxia reduces fetal growth and birth weight across mammals, including humans. Evolutionary adaptation to high-elevation hypoxia mitigates these negative effects, and identifying these protective mechanisms may offer insight into how environmental factors interact with gestational physiology to influence health outcomes. We know that gestational hypoxia modifies development of the placenta, which mediates maternal-fetal exchange, but little is known about how high-altitude adaptation interacts with this developmental plasticity to influence placental exchange capacity. We tested the hypothesis that hypoxia-dependent remodelling of the placental exchange surface is protective for fetal growth and thus will be exaggerated in highland-adapted individuals by using a model rodent system, the North American deer mouse. We acclimated lowland- and highland-ancestry deer mice to normoxia or hypoxia (12.3% O₂) during gestation and found that lowland-ancestry deer mice expand their placenta and maternal blood spaces in the placenta in response to environmental hypoxia. Highland-ancestry deer mice produce even larger placentas and maternal blood spaces, suggesting that these hypoxia-driven responses may benefit fetal growth by increasing total exchange capacity. Notably, we also found that the fetal blood spaces in highland-ancestry placentas have increased perimeter (a proxy for surface area) per unit area occupied by blood. Similar changes to fetal vasculature have been observed in high-elevation-adapted human populations, which is suggestive of convergent adaptation. Our results demonstrate that the hypoxia-sensitive development of placental vasculature is remodelled by adaptation to environmental hypoxia and that some of these processes may be points for convergent adaptation across species despite distinct placental architectures. KEY POINTS: Evolutionary adaptation to high elevations provides protection against hypoxia-dependent fetal growth restriction. The placenta is a key determinant of fetal growth because it defines the total surface area available for nutrient and gas exchange between the gestational parent and offspring. We tested the hypothesis that evolutionary adaptation to high elevations protects fetal growth by increasing placental surface area for exchange using acclimation experiments in a model rodent system, the North American deer mouse. As we predicted, high-elevation ancestry increased the size of maternal blood spaces in the placenta, especially under gestational hypoxia; however, highland ancestry was also associated with narrower fetal blood spaces, which could increase exchange efficiency. The patterns observed in deer mice resemble developmental plasticity observed in placentas from humans with high-elevation ancestry, pointing to potential for convergent adaptation across species with distinct placental architectures.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145082188","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 influence of biological sex on the metabolic basis of skeletal muscle fatigue in vivo.","authors":"Fabio G Laginestra, Ryan M Broxterman, Danilo Iannetta, Matthew T Lewis, Jason S Kofoed, Jesse C Craig, Gregory Stoddard, Gwenael Layec, Eun-Kee Jeong, Markus Amann","doi":"10.1113/JP289709","DOIUrl":"https://doi.org/10.1113/JP289709","url":null,"abstract":"<p><p>This study in humans was designed to evaluate: (1) the overall relationships between muscle fatigue and inorganic phosphate (Pi) and hydrogen ions (H⁺) in women and men, and (2) whether the decline in contractile function for a given change in these intramuscular metabolites differs between sexes (i.e. muscle fatigue sensitivity). Sixteen healthy, young individuals (eight women) performed two consecutive (interspersed by 5 min of rest) intermittent isometric single-leg knee-extensor trials (60 maximal voluntary contractions; 3 s contraction, 2 s relaxation). Throughout both trials, intramuscular quadriceps [Pi] and [H⁺] were quantified using phosphorus magnetic resonance spectroscopy, and quadriceps twitch force (Q_tw) was measured using electrical femoral nerve stimulation. The exercise-induced reduction in Q_tw was greater in men than in women in both trials (both P < 0.048). In both sexes, the Q_tw-[Pi] relationship was unchanged across trials, while the Q_tw-[H⁺] relationship shifted downwards. The decline in Q_tw for a given increase in [Pi] or [H⁺] was not different between men and women. The exercise-induced reduction in Q_tw was strongly associated only with Pi accumulation (r = 0.761, P < 0.001). These results show that, in both sexes, Q_tw is more consistently related to Pi than to H⁺, and that the decrease in Q_tw for a given increase in [Pi] and [H⁺] does not differ between women and men. This supports that the in vivo metabolic basis of muscle fatigue is similar across sexes, and that differences in the exercise-induced reduction in contractile function relate to the extent of metabolic disturbance, rather than to an inherent fatigue resistance. KEY POINTS: The decline in muscle contractile function during high-intensity exercise (i.e. muscle fatigue) is generally less in women than in men. Sex-related differences in the intrinsic resistance to intramuscular metabolites may explain this divergence. We evaluated (1) the overall relationships between muscle fatigue and inorganic phosphate (Pi) and hydrogen ions (H⁺) in women and men, and (2) whether the decline in contractile function for a given change in intramuscular metabolites differs between sexes. In both sexes, intramuscular Pi was more consistently related to muscle fatigue compared with H⁺. For each metabolite (Pi or H⁺), the decrease in contractile function for a given intramuscular accumulation was similar in women and men. In conclusion, in vivo the metabolic basis of muscle fatigue is similar between sexes. Sex differences in the magnitude of fatigue are therefore probably not due to an intrinsic resistance to intramuscular metabolites.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145082326","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":"Digesting the influence of diet and exercise on the microbiome.","authors":"Simon Keely, Kerith Duncanson","doi":"10.1113/JP289733","DOIUrl":"https://doi.org/10.1113/JP289733","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145082252","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 autonomic nervous system: Time for a conceptual reframing?","authors":"Alexandru C Barboi, Vaughan G Macefield","doi":"10.1113/JP288973","DOIUrl":"https://doi.org/10.1113/JP288973","url":null,"abstract":"<p><p>After having reviewed the history of the autonomic nervous system (ANS), and how Langley's concept of the ANS was born, we suggest that the terms 'cranial visceral' and 'spinal visceral' nerves are more appropriate. We discuss the limitations of the terms 'sympathetic' and 'parasympathetic' nerves and functions and suggest a way forward that avoids these terms altogether. We propose that the term 'autonomic' should not refer to a separate nervous system, because somatic components of the nervous system can also operate automatically, i.e. in a manner that is not under voluntary control.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145076401","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":"<ArticleTitle xmlns:ns0=\"http://www.w3.org/1998/Math/MathML\">You can't extract what has not been delivered: Sex differences and <ns0:math> <ns0:semantics> <ns0:msub><ns0:mover><ns0:mi>V</ns0:mi> <ns0:mo>̇</ns0:mo></ns0:mover> <ns0:mrow><ns0:msub><ns0:mi>O</ns0:mi> <ns0:mn>2</ns0:mn></ns0:msub> <ns0:mi>max</ns0:mi></ns0:mrow> </ns0:msub> <ns0:annotation>${dot V_{{{mathrm{O}}_2}{mathrm{max}}}}$</ns0:annotation></ns0:semantics></ns0:math>.","authors":"Michael J Joyner, Shalaya Kipp","doi":"10.1113/JP289841","DOIUrl":"https://doi.org/10.1113/JP289841","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071045","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}