Journal of Physiology

Wiley
Wiley
ISSN: 00223751, 14697793
SCImago
Q1
WOS
Q1
Impact factor
4.7
SJR
1.708
CiteScore
9.7
Categories
Physiology
Sports Science
Areas
Biochemistry, Genetics and Molecular Biology
Years of issue
1878-2025
journal names
Journal of Physiology
J PHYSIOL-LONDON
Publications
39 717
Citations
1 929 294
h-index
389
Top-3 citing journals
Journal of Physiology
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Journal of Neurophysiology
Journal of Neurophysiology (37318 citations)
Top-3 organizations
University College London
University College London (524 publications)
University of Copenhagen
University of Copenhagen (493 publications)
University of Cambridge
University of Cambridge (391 publications)
Top-3 countries
USA (7431 publications)
United Kingdom (4145 publications)
Canada (1946 publications)

Most cited in 5 years

Kierans S.J., Taylor C.T.
Journal of Physiology Q1 Q1
2020-10-15 citations by CoLab: 531 Abstract
Under conditions of hypoxia, most eukaryotic cells can shift their primary metabolic strategy from predominantly mitochondrial respiration towards increased glycolysis to maintain ATP levels. This hypoxia-induced reprogramming of metabolism is key to satisfying cellular energetic requirements during acute hypoxic stress. At a transcriptional level, this metabolic switch can be regulated by several pathways including the hypoxia inducible factor-1α (HIF-1α) which induces an increased expression of glycolytic enzymes. While this increase in glycolytic flux is beneficial for maintaining bioenergetic homeostasis during hypoxia, the pathways mediating this increase can also be exploited by cancer cells to promote tumour survival and growth, an area which has been extensively studied. It has recently become appreciated that increased glycolytic metabolism in hypoxia may also have profound effects on cellular physiology in hypoxic immune and endothelial cells. Therefore, understanding the mechanisms central to mediating this reprogramming are of importance from both physiological and pathophysiological standpoints. In this review, we highlight the role of HIF-1α in the regulation of hypoxic glycolysis and its implications for physiological processes such as angiogenesis and immune cell effector function.
Vaupel P., Multhoff G.
Journal of Physiology Q1 Q1
2021-01-04 citations by CoLab: 488 Abstract
Contrary to Warburg's original thesis, accelerated aerobic glycolysis is not a primary, permanent and universal consequence of dysfunctional or impaired mitochondria compensating for poor ATP yield per mole of glucose. Instead, in most tumours the Warburg effect is an essential part of a ‘selfish’ metabolic reprogramming, which results from the interplay between (normoxic/hypoxic) hypoxia-inducible factor-1 (HIF-1) overexpression, oncogene activation (cMyc, Ras), loss of function of tumour suppressors (mutant p53, mutant phosphatase and tensin homologue (PTEN), microRNAs and sirtuins with suppressor functions), activated (PI3K–Akt–mTORC1, Ras–Raf–MEK–ERK–cMyc, Jak–Stat3) or deactivated (LKB1–AMPK) signalling pathways, components of the tumour microenvironment, and HIF-1 cooperation with epigenetic mechanisms. Molecular and functional processes of the Warburg effect include: (a) considerable acceleration of glycolytic fluxes; (b) adequate ATP generation per unit time to maintain energy homeostasis and electrochemical gradients; (c) backup and diversion of glycolytic intermediates facilitating the biosynthesis of nucleotides, non-essential amino acids, lipids and hexosamines; (d) inhibition of pyruvate entry into mitochondria; (e) excessive formation and accumulation of lactate, which stimulates tumour growth and suppression of anti-tumour immunity – in addition, lactate can serve as an energy source for normoxic cancer cells and drives malignant progression and resistances to conventional therapies; (f) cytosolic lactate being mainly exported through upregulated lactate–proton symporters (MCT4), working together with other H+ transporters, and carbonic anhydrases (CAII, CAIX), which hydrate CO2 from oxidative metabolism to form H+ and bicarbonate; (g) these proton export mechanisms, in concert with poor vascular drainage, being responsible for extracellular acidification, driving malignant progression and resistance to conventional therapies; (h) maintenance of the cellular redox homeostasis and low reactive oxygen species (ROS) formation; and (i) HIF-1 overexpression, mutant p53 and mutant PTEN, which inhibit mitochondrial biogenesis and functions, negatively impacting cellular respiration rate. The glycolytic switch is an early event in oncogenesis and primarily supports cell survival. All in all, the Warburg effect, i.e. aerobic glycolysis in the presence of oxygen and – in principle – functioning mitochondria, constitutes a major driver of the cancer progression machinery, resistance to conventional therapies, and poor patient outcome. However, as evidenced during the last two decades, in a minority of tumours primary mitochondrial defects can play a key role promoting the Warburg effect and tumour progression due to mutations in some Krebs cycle enzymes and mitochondrial ROS overproduction.
Percie du Sert N., Hurst V., Ahluwalia A., Alam S., Avey M.T., Baker M., Browne W.J., Clark A., Cuthill I.C., Dirnagl U., Emerson M., Garner P., Holgate S.T., Howells D.W., Karp N.A., et. al.
Journal of Physiology Q1 Q1
2020-07-14 citations by CoLab: 356 Abstract
Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into 2 sets, the ‘ARRIVE Essential 10,’ which constitutes the minimum requirement, and the ‘Recommended Set,’ which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts, and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers, and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.
Poole D.C., Rossiter H.B., Brooks G.A., Gladden L.B.
Journal of Physiology Q1 Q1
2020-11-19 citations by CoLab: 190 Abstract
The anaerobic threshold (AT) remains a widely recognized, and contentious, concept in exercise physiology and medicine. As conceived by Karlman Wasserman, the AT coalesced the increase of blood lactate concentration ([La−]), during a progressive exercise test, with an excess pulmonary carbon dioxide output (). Its principal tenets were: limiting oxygen (O2) delivery to exercising muscle→increased glycolysis, La− and H+ production→decreased muscle and blood pH→with increased H+ buffered by blood [HCO3−]→increased CO2 release from blood→increased and pulmonary ventilation. This schema stimulated scientific scrutiny which challenged the fundamental premise that muscle anoxia was requisite for increased muscle and blood [La−]. It is now recognized that insufficient O2 is not the primary basis for lactataemia. Increased production and utilization of La− represent the response to increased glycolytic flux elicited by increasing work rate, and determine the oxygen uptake () at which La− accumulates in the arterial blood (the lactate threshold; LT). However, the threshold for a sustained non-oxidative contribution to exercise energetics is the critical power, which occurs at a metabolic rate often far above the LT and separates heavy from very heavy/severe-intensity exercise. Lactate is now appreciated as a crucial energy source, major gluconeogenic precursor and signalling molecule but there is no ipso facto evidence for muscle dysoxia or anoxia. Non-invasive estimation of LT using the gas exchange threshold (non-linear increase of versus ) remains important in exercise training and in the clinic, but its conceptual basis should now be understood in light of lactate shuttle biology.
Glancy B., Kane D.A., Kavazis A.N., Goodwin M.L., Willis W.T., Gladden L.B.
Journal of Physiology Q1 Q1
2020-05-27 citations by CoLab: 127 Abstract
Mitochondrial structures were probably observed microscopically in the 1840s, but the idea of oxidative phosphorylation (OXPHOS) within mitochondria did not appear until the 1930s. The foundation for research into energetics arose from Meyerhof's experiments on oxidation of lactate in isolated muscles recovering from electrical contractions in an O2 atmosphere. Today, we know that mitochondria are actually reticula and that the energy released from electron pairs being passed along the electron transport chain from NADH to O2 generates a membrane potential and pH gradient of protons that can enter the molecular machine of ATP synthase to resynthesize ATP. Lactate stands at the crossroads of glycolytic and oxidative energy metabolism. Based on reported research and our own modelling in silico, we contend that lactate is not directly oxidized in the mitochondrial matrix. Instead, the interim glycolytic products (pyruvate and NADH) are held in cytosolic equilibrium with the products of the lactate dehydrogenase (LDH) reaction and the intermediates of the malate-aspartate and glycerol 3-phosphate shuttles. This equilibrium supplies the glycolytic products to the mitochondrial matrix for OXPHOS. LDH in the mitochondrial matrix is not compatible with the cytoplasmic/matrix redox gradient; its presence would drain matrix reducing power and substantially dissipate the proton motive force. OXPHOS requires O2 as the final electron acceptor, but O2 supply is sufficient in most situations, including exercise and often acute illness. Recent studies suggest that atmospheric normoxia may constitute a cellular hyperoxia in mitochondrial disease. As research proceeds appropriate oxygenation levels should be carefully considered.
Kamm D.R., McCommis K.S.
Journal of Physiology Q1 Q1
2022-03-30 citations by CoLab: 123 Abstract
Hepatic stellate cells (HSCs) comprise a minor cell population in the liver but serve numerous critical functions in the normal liver and in response to injury. HSCs are primarily known for their activation upon liver injury and for producing the collagen-rich extracellular matrix in liver fibrosis. In the absence of liver injury, HSCs reside in a quiescent state, in which their main function appears to be the storage of retinoids or vitamin A-containing metabolites. Less appreciated functions of HSCs include amplifying the hepatic inflammatory response and expressing growth factors that are critical for liver development and both the initiation and termination of liver regeneration. Recent single-cell RNA sequencing studies have corroborated earlier studies indictaing that HSC activation involves a diverse array of phenotypic alterations and identified unique HSC populations. This review serves to highlight these many functions of HSCs, and to briefly describe the recent genetic tools that will help to thoroughly investigate the role of HSCs in hepatic physiology and pathology.
Brooks G.A., Arevalo J.A., Osmond A.D., Leija R.G., Curl C.C., Tovar A.P.
Journal of Physiology Q1 Q1
2021-02-25 citations by CoLab: 123 Abstract
After a century, it's time to turn the page on understanding of lactate metabolism and appreciate that lactate shuttling is an important component of intermediary metabolism in vivo. Cell-cell and intracellular lactate shuttles fulfil purposes of energy substrate production and distribution, as well as cell signalling under fully aerobic conditions. Recognition of lactate shuttling came first in studies of physical exercise where the roles of driver (producer) and recipient (consumer) cells and tissues were obvious. Moreover, the presence of lactate shuttling as part of postprandial glucose disposal and satiety signalling has been recognized. Mitochondrial respiration creates the physiological sink for lactate disposal in vivo. Repeated lactate exposure from regular exercise results in adaptive processes such as mitochondrial biogenesis and other healthful circulatory and neurological characteristics such as improved physical work capacity, metabolic flexibility, learning, and memory. The importance of lactate and lactate shuttling in healthful living is further emphasized when lactate signalling and shuttling are dysregulated as occurs in particular illnesses and injuries. Like a phoenix, lactate has risen to major importance in 21st century biology.
Biltz N.K., Collins K.H., Shen K.C., Schwartz K., Harris C.A., Meyer G.A.
Journal of Physiology Q1 Q1
2020-06-03 citations by CoLab: 121 Abstract
Muscle infiltration with adipose tissue (IMAT) is common and associated with loss of skeletal muscle strength and physical function across a diverse set of pathologies. Whether the association between IMAT and muscle weakness is causative or simply correlative remains an open question that needs to be addressed to effectively guide muscle strengthening interventions in people with increased IMAT. In the present studies, we demonstrate that IMAT deposition causes decreased muscle strength using mouse models. These findings indicate IMAT is a novel therapeutic target for muscle dysfunction.Intramuscular adipose tissue (IMAT) is associated with deficits in strength and physical function across a wide array of conditions, from injury to ageing to metabolic disease. Due to the diverse aetiologies of the primary disorders involving IMAT and the strength of the associations, it has long been proposed that IMAT directly contributes to this muscle dysfunction. However, infiltration of IMAT and reduced strength could both be driven by muscle disuse, injury and systemic disease, making IMAT simply an 'innocent bystander.' Here, we utilize novel mouse models to evaluate the direct effect of IMAT on muscle contraction. First, we utilize intramuscular glycerol injection in wild-type mice to evaluate IMAT in the absence of systemic disease. In this model we find that, in isolation from the neuromuscular and circulatory systems, there remains a muscle-intrinsic association between increased IMAT volume and decreased contractile tension (r2 > 0.5, P < 0.01) that cannot be explained by reduction in contractile material. Second, we utilize a lipodystrophic mouse model which cannot generate adipocytes to 'rescue' the deficits. We demonstrate that without IMAT infiltration, glycerol treatment does not reduce contractile force (P > 0.8). Taken together, this indicates that IMAT is not an inert feature of muscle pathology but rather has a direct impact on muscle contraction. This finding suggests that novel strategies targeting IMAT may improve muscle strength and function in a number of populations.
Calverley T.A., Ogoh S., Marley C.J., Steggall M., Marchi N., Brassard P., Lucas S.J., Cotter J.D., Roig M., Ainslie P.N., Wisløff U., Bailey D.M.
Journal of Physiology Q1 Q1
2020-06-01 citations by CoLab: 102 Abstract
The increasing number of older adults has seen a corresponding growth in those affected by neurovascular diseases, including stroke and dementia. Since cures are currently unavailable, major efforts in improving brain health need to focus on prevention, with emphasis on modifiable risk factors such as promoting physical activity. Moderate-intensity continuous training (MICT) paradigms have been shown to confer vascular benefits translating into improved musculoskeletal, cardiopulmonary and cerebrovascular function. However, the time commitment associated with MICT is a potential barrier to participation, and high-intensity interval training (HIIT) has since emerged as a more time-efficient mode of exercise that can promote similar if not indeed superior improvements in cardiorespiratory fitness for a given training volume and further promote vascular adaptation. However, randomised controlled trials (RCTs) investigating the impact of HIIT on the brain are surprisingly limited. The present review outlines how the HIIT paradigm has evolved from a historical perspective and describes the established physiological changes including its mechanistic bases. Given the dearth of RCTs, the vascular benefits of MICT are discussed with a focus on the translational neuroprotective benefits including their mechanistic bases that could be further potentiated through HIIT. Safety implications are highlighted and components of an optimal HIIT intervention are discussed including practical recommendations. Finally, statistical effect sizes have been calculated to allow prospective research to be appropriately powered and optimise the potential for detecting treatment effects. Future RCTs that focus on the potential clinical benefits of HIIT are encouraged given the prevalence of cognitive decline in an ever-ageing population.
Tsai M., Byun M.K., Shin J., Crotty Alexander L.E.
Journal of Physiology Q1 Q1
2020-10-12 citations by CoLab: 92 Abstract
E-cigarette aerosols are exceedingly different from conventional tobacco smoke, containing dozens of chemicals not found in cigarette smoke. It is highly likely that chronic use of e-cigarettes will induce pathological changes in both the heart and lungs. Here we review human and animal studies published to date and summarize the cardiopulmonary physiological changes caused by vaping. In terms of cardiac physiology, acute exposure to e-cigarette aerosols in human subjects led to increased blood pressure and heart rate, similar to traditional cigarettes. Chronic exposure to e-cigarette aerosols using animal models caused increased arterial stiffness, vascular endothelial changes, increased angiogenesis, cardiorenal fibrosis and increased atherosclerotic plaque formation. Pulmonary physiology is also affected by e-cigarette aerosol inhalation, with increased airway reactivity, airway obstruction, inflammation and emphysema. Research thus far demonstrates that the heart and lung undergo numerous changes in response to e-cigarette use, and disease development will depend on how those changes combine with both environmental and genetic factors. E-cigarettes have been advertised as a healthy alternative to cigarette smoking, and users are under the impression that vaping of e-cigarettes is harmless, but these claims that e-cigarettes are safer and healthier are not based on evidence. Data from both humans and animal models are consistent in demonstrating that vaping of e-cigarettes causes health effects both similar to and disparate from those of cigarette smoking. Further work is needed to define the long-term cardiopulmonary effects of e-cigarette use in humans.
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Publications found: 39730
Fork in the road: therapeutic and pathological actions for fibro‐adipogenic progenitors following musculoskeletal injury
Owen A.M., Gonzalez‐Velez S., Keeble A.R., Thomas N.T., Fry C.S.
Q1
Wiley
Journal of Physiology 2025 citations by CoLab: 0  |  Abstract
AbstractMusculoskeletal injuries are a substantial source of global disability through weakness and loss of function, which can be attributable, in part, to deficits in skeletal muscle quality. Poor muscle quality, resulting from fibrotic pathology or fatty infiltration, strongly predicts lower rates of patient recovery following injury and higher rates of re‐injury. The cellular sources of fibrosis and fatty infiltration within skeletal muscle are mesenchymal fibro‐adipogenic progenitors (FAPs), which are central effectors to support muscle homeostasis, regeneration and growth. However, following acute or chronic musculoskeletal injury, FAPs can promote fibro/fatty pathology within muscle that is likely to limit recovery and repair. Given their indispensable role within skeletal muscle, FAPs have emerged as a compelling cellular target to promote tissue recovery following acute and chronic injury. This review provides insight into the aetiology of FAP activity following various musculoskeletal injuries, in addition to signalling components that effect FAP differentiation. Contrasting pathology with therapeutic potential, insight into disease‐ and injury‐specific FAP activation further cements their role as crucial effectors to improve muscle function and enhance patient outcomes. image
Vascular remodelling in a mouse model of heart failure with preserved ejection fraction
Sanhueza‐Olivares F., Valenzuela‐Arce F., Calle‐Chalco X., Silva D., Muñoz‐Córdova F., Mella‐Torres A., Ortega‐Muñoz A., Troncoso M.F., Muñoz‐Rodriguez C., Pino de la Fuente F., Guerrero‐Moncayo A., Hernández A., Hill J.A., Castro P.F., Gabrielli L., et. al.
Q1
Wiley
Journal of Physiology 2025 citations by CoLab: 0  |  Abstract
AbstractHeart failure (HF) with preserved ejection fraction (HFpEF) is a complex syndrome characterized by symptoms of HF despite normal left ventricular function. It now accounts for &gt;50% of all HF cases, with the only effective treatment (morbidity benefit) so far being sodium‐glucose co‐transporter‐2 inhibitors, finerenone and tirzepatide. Recently, vascular dysfunction has been highlighted as one of the main pathophysiological mechanisms of HFpEF. Recently, a ‘two‐hit’ experimental model of HFpEF was described in which mice fed a high‐fat diet (HFD) and l‐NAME developed a phenotype that mimics human HFpEF. We further characterize this model by assessing vascular remodelling in the aorta, carotid and femoral arteries. C57BL/6N mice aged 11–12 weeks were fed a HFD and water supplemented with l‐NAME 1.5 g/L for 15 weeks. These mice manifested increased body weight and blood pressure, glucose and exercise intolerance, and cardiac structural and functional alterations consistent with HFpEF. Morphometric analyses were performed in the aorta, carotid and femoral arteries, revealing increased media thickness and media‐to‐lumen ratios. Moreover, we detected evidence of fibrosis in the middle layer of the aorta. A correlation between increased aortic remodelling and fibrosis with diastolic dysfunction was observed. Vascular reactivity studies using wire myography uncovered impaired vasoconstriction and vasodilatation responses, suggesting aortic stiffness. We also detected the presence of a senescence‐like phenotype in the aortic wall. Together, these data offer valuable contributions to understanding the vascular mechanisms underlying HFpEF. imageKey points Heart failure with preserved ejection fraction (HFpEF) represents &gt;50% of heart failure patients. Despite its growing prevalence, the aetiology of HFpEF continues to be incompletely understood, mainly due to the lack of reliable animal models. An HFpEF mouse model, obtained by feeding mice a high‐fat diet and exposing them to l‐NAME, reproduces the majority of the clinical features observed in HFpEF patients. Possible vascular alterations elicited by this model remain unknown. Here, we report that HFpEF mice manifest aortic, carotid and femoral artery remodelling. The aorta also harboured fibrosis plus impaired vasodilatation and vasoconstriction responses. Aortic remodelling and fibrosis correlated with diastolic dysfunction. The aorta from HFpEF mice harboured increased p53, IL‐6 and VCAM‐1 protein levels, suggesting a senescence‐like phenotype. These data reveal that this HFpEF mouse model displays vascular alterations similar to those reported in HFpEF patients. These findings unveil novel insights into the vascular remodelling of HFpEF and, furthermore, validate a reliable animal model that can be used to study HFpEF aetiology and potentially develop future therapeutic approaches.
Critical closing pressure and resistance‐area product as markers of cerebral autoregulation dynamics (S.J. Payne)
Panerai R.B., Minhas J.S., Llwyd O., Salinet A.S., Robinson T.G.
Q1
Wiley
Journal of Physiology 2025 citations by CoLab: 0
Pregnancy does not affect progression of mild experimental asthma in sheepx
Roff A.J., Davies A.N., Clifton V.L., Stark M.J., Tai A., Robinson J.L., Hammond S.J., Darby J.R., Meakin A.S., Lock M.C., Wiese M.D., Sharkey D.J., Bischof R.J., Morrison J.L., Gatford K.L.
Q1
Wiley
Journal of Physiology 2025 citations by CoLab: 0  |  Abstract
AbstractAsthma is the most common respiratory condition during pregnancy and increases the risks of adverse pregnancy and perinatal outcomes. Asthma symptoms change in ∼60% of pregnancies, but whether this is due to pregnancy itself is unclear. We tested the hypothesis that physiological changes during pregnancy worsen asthma severity in an ovine experimental model of allergic asthma. Three‐year‐old Merino ewes were randomly allocated to either control or allergic asthma groups. Asthma was induced through sensitisation and repeated airway challenge with house dust mite allergen. We compared airway function, circulating cytokine profile and airway immune response to allergen challenge throughout the study and airway structure between groups, in non‐pregnant (control n = 8, asthma n = 9), singleton‐pregnant (control n = 5, asthma n = 8) and twin‐pregnant ewes (control n = 6, asthma n = 9). Within non‐pregnant animals, transpulmonary pressure at Day 132 of the study was 37% higher in asthmatic than control ewes (P = 0.031), but not different between treatments in singleton‐pregnant (P = 0.594) or twin‐pregnant (P = 0.074) ewes. Between premating and Day 132, dynamic compliance decreased more in asthmatic than control ewes (P = 0.040), and this change did not differ between litter sizes (P = 0.096). Neither asthma nor pregnancy affected eosinophils in bronchoalveolar lavage or lung tissue. There was no evidence of lung airway remodelling in the cohort. The results of this study suggest that pregnancy does not increase asthma symptoms or severity of mild asthma. imageKey points Asthma severity changes in ∼60% of pregnancies, but whether this is due to pregnancy itself is unclear. Using a sheep model of allergic asthma, we tested the hypothesis that physiological changes during pregnancy worsen asthma severity. Dynamic compliance decreased to a greater extent in asthmatic than control ewes over the course of the study, indicating the development of a mild asthma phenotype, and this decrease was similar in non‐pregnant, singleton‐pregnant and twin‐pregnant ewes. Eosinophil proportions in bronchoalveolar lavage and lung tissue were not affected by either asthma or pregnancy, nor was there evidence of lung airway remodelling in this cohort. Our findings suggest that pregnancy does not increase asthma symptoms or severity of mild asthma
Impact of resistance and endurance exercise training on femoral artery function: sex differences in humans
Green D.J., Thomas H.J., Marsh C.E., Lester L., Naylor L.H., Haynes A.
Q1
Wiley
Journal of Physiology 2025 citations by CoLab: 0  |  Abstract
AbstractExercise has direct and indirect anti‐atherogenic impacts on arterial function and health in humans. Few studies have directly compared the impacts of different commonly adopted exercise approaches on femoral artery function. We hypothesized that, owing to its direct impact via sustained increases in shear stress, endurance (END) training would have larger impacts on arterial diameter and function than resistance (RES) training. Thirty‐nine young, healthy participants (age 26.9 ± 6.2 years, 22♀) completed 12 weeks of both RES and END training in random order, separated by a 12 week washout. Resting femoral artery diameter and flow‐mediated dilatation (FMD) were collected before and after each exercise intervention. END training was associated with an increase in both FMD (Δ1.61 ± 3.09%, P = 0.005) and resting diameter (Δ0.15 ± 0.29 mm, P = 0.004). Neither resting diameter nor FMD increased following RES. However, sex difference analysis revealed that males increased FMD following RES (Δ2.21 ± 3.76%, P = 0.015), whereas no RES change was evident for females. Following END, both males and females increased FMD (♂, Δ1.11 ± 1.65%; ♀, Δ1.88 ± 3.67%; both P = 0.025), with males also showing an increase in resting arterial diameter following END (Δ0.23 ± 0.2 mm, P &lt; 0.001). Group data revealed that END has greater impacts than RES on femoral artery diameter and flow‐mediated functional responses, which are endothelium mediated and nitric oxide dependent. Males exhibit beneficial impacts in response to both END and RES, whereas females respond predominantly to END. Our findings suggest that arterial adaptation to exercise might be influenced by exercise modality and sex. imageKey points Exercise has anti‐atherogenic effects and lowers the risk of cardiovascular diseases. This is mediated, in part, by the direct haemodynamic impacts of exercise on arterial function, structure and health. Different modalities of exercise have distinct effects on arterial haemodynamics, but few studies have directly compared, within subjects and using a cross‐over design of trial, the relative impacts of distinct forms of exercise training on arterial adaptation. In this study, endurance training increased baseline femoral artery diameter and flow‐mediated dilatation, which is endothelium dependent and mediated by nitric oxide. Resistance training had a beneficial but lesser impact. Females and males were responsive to endurance training, but only males responded positively to resistance training in this study. These results show that changing the training mode modifies training‐induced arterial adaptation; this has implications for the optimization of exercise prescription for individual benefit.
Multiple carbamylation events are required for differential modulation of Cx26 hemichannels and gap junctions by CO2
Nijjar S., Brotherton D., Butler J., Dospinescu V., Gannon H.G., Linthwaite V., Cann M., Cameron A., Dale N.
Q1
Wiley
Journal of Physiology 2025 citations by CoLab: 0  |  Abstract
AbstractCO2 directly modifies the gating of connexin26 (Cx26) gap junction channels and hemichannels. This gating depends upon Lys125, and the proposed mechanism involves carbamylation of Lys125 to allow formation of a salt bridge with Arg104 on the neighbouring subunit. We demonstrate via carbamate trapping and tandem mass spectrometry that five Lys residues within the cytoplasmic loop, including Lys125, are indeed carbamylated by CO2. The cytoplasmic loop appears to provide a chemical microenvironment that facilitates carbamylation. Systematic mutation of these Lys residues to Arg shows that only carbamylation of Lys125 is essential for hemichannel opening. By contrast, carbamylation of Lys108 and Lys125 is essential for gap junction closure to CO2. Chicken (Gallus gallus) Cx26 gap junction channels lack Lys108 and do not close to CO2, as shown by both a dye transfer assay and a high‐resolution cryogenic electron microscopy structure. The mutation Lys108Arg prevents CO2‐dependent gap junction channel closure in human Cx26. Our findings directly demonstrate carbamylation in connexins, provide further insight into the differential action of CO2 on Cx26 hemichannels and gap junction channels, and increase support for the role of the N‐terminus in gating the Cx26 channel. imageKey points Direct evidence of carbamylation of multiple lysine residues in the cytoplasmic loop of Cx26. Concentration‐dependent carbamylation at lysines 108, 122 and 125. Only carbamylation of lysine 125 is essential for hemichannel opening to CO2. Carbamylation of lysine 108 along with lysine 125 is essential for CO2‐dependent gap junction channel closure.
Evolutionary poker lacks a full deck when modelling the LTEE Cit+ phenotype
Minnich S.A., Hovde C.J.
Q1
Wiley
Journal of Physiology 2025 citations by CoLab: 0
CaMKII at the crossroads: calcium dysregulation, and post‐translational modifications driving cell death
Mattiazzi A., Jaquenod De Giusti C., Valverde C.A.
Q1
Wiley
Journal of Physiology 2025 citations by CoLab: 0  |  Abstract
AbstractThe multifunctional Ca2+/calmodulin‐dependent protein kinase II (CaMKII) regulates numerous proteins involved in excitation–contraction–relaxation coupling and cardiac excitability. However, its overactivation induces severe Ca2+/handling alterations, playing a significant role in the pathogenesis of diseases such as hypertrophy, arrhythmias and cell death, which can ultimately lead to heart failure. Being a suitable target for various aberrant signals that characterize several diseases, such as Ca2+ overload, oxidative stress or excessive glycosylation, CaMKII shifts under these conditions from a physiological regulator to a pathological molecule. In this review, we explore the evolution of knowledge regarding the role of CaMKII activation on cell death across different pathological contexts, focusing on the converging mechanisms that transform the enzyme from an ally into a villain. image
A physiological pragmatic view of the philosophical debate on freedom to choose1
Marom S.
Q1
Wiley
Journal of Physiology 2025 citations by CoLab: 0
Physiological mechanisms of neuromuscular impairment in diabetes‐related complications: Can physical exercise help prevent it?
Lecce E., Bellini A., Greco G., Martire F., Scotto di Palumbo A., Sacchetti M., Bazzucchi I.
Q1
Wiley
Journal of Physiology 2025 citations by CoLab: 0  |  Abstract
AbstractDiabetes mellitus is a chronic disorder that progressively induces complications, compromising daily independence. Among these, diabetic neuropathy is particularly prevalent and contributes to substantial neuromuscular impairments in both types 1 and 2 diabetes. This condition leads to structural damage affecting both the central and peripheral nervous systems, resulting in a significant decline in sensorimotor functions. Alongside neuropathy, diabetic myopathy also contributes to muscle impairment and reduced motor performance, intensifying the neuromuscular decline. Diabetic neuropathy typically implicates neurogenic muscle atrophy, motoneuron loss and clustering of muscle fibres as a result of aberrant denervation‐reinervation processes. These complications are associated with compromised neuromuscular junctions, where alterations occur in pre‐synaptic vesicles, mitochondrial content and post‐synaptic signalling. Neural damage is intensified by chronic hyperglycaemia and oxidative stress, exacerbating vascular dysfunction and reducing oxygen delivery. These complications imply a severe decline in neuromuscular performance, evidenced by reductions in maximal force and power output, rate of force development and muscle endurance. Furthermore, diabetes‐related complications are compounded by age‐related degenerative changes in long‐term patients. Aerobic and resistance training offer promising approaches for managing blood glucose levels and neuromuscular function. Aerobic exercise promotes mitochondrial biogenesis and angiogenesis, supporting metabolic and cardiovascular health. Resistance training primarily enhances neural plasticity, muscle strength and hypertrophy, which are crucial factors for mitigating sarcopenia and preserving functional independence. This topical review examines current evidence on the physiological mechanisms underlying diabetic neuropathy and the potential impact of physical activity in counteracting this decline. image
The LINC complex in blood vessels: from physiology to pathological implications in arterioles
Ferreira G., Cardozo R., Chavarria L., Santander A., Sobrevia L., Chang W., Gundersen G., Nicolson G.L.
Q1
Wiley
Journal of Physiology 2025 citations by CoLab: 0  |  Abstract
AbstractThe LINC (linker of nucleoskeleton and cytoskeleton) complex is a critical component of the cellular architecture that bridges the nucleoskeleton and cytoskeleton and mediates mechanotransduction to and from the nucleus. Though it plays important roles in all blood vessels, it is in arterioles that this complex plays a pivotal role in maintaining endothelial cell integrity, regulating vascular tone, forming new microvessels and modulating responses to mechanical and biochemical stimuli. It is also important in vascular smooth muscle cells and fibroblasts, where it possibly plays a role in the contractile to secretory phenotypic transformation during atherosclerosis and vascular ageing, and in fibroblasts' migration and inflammatory responses in the adventitia. Physiologically, the LINC complex contributes to the stability of arteriolar structure, adaptations to changes in blood flow and injury repair mechanisms. Pathologically, dysregulation or mutations in LINC complex components can lead to compromised endothelial function, vascular remodelling and exacerbation of cardiovascular diseases such as atherosclerosis (arteriolosclerosis). This review summarizes our current understanding of the roles of the LINC complex in cells from arterioles, highlighting its most important physiological functions, exploring its implications for vascular pathology and emphasizing some of its functional characteristics in endothelial cells. By elucidating the LINC complex's role in health and disease, we aim to provide insights that could improve future therapeutic strategies targeting LINC complex‐related vascular disorders. image
Inhibition of BK channels by GABAb receptors enhances intrinsic excitability of layer 2/3 vasoactive intestinal polypeptide‐expressing interneurons in mouse neocortex
Bogaj K., Urban‐Ciecko J.
Q1
Wiley
Journal of Physiology 2025 citations by CoLab: 0  |  Abstract
AbstractGABAb receptors (GABAbRs) affect many signalling pathways, and hence the net effect of the activity of these receptors depends upon the specific ion channels that they are linked to, leading to different effects on specific neuronal populations. Typically, GABAbRs suppress neuronal activity in the cerebral cortex. Previously, we found that neocortical parvalbumin‐expressing cells are strongly inhibited through GABAbRs, whereas somatostatin interneurons are immune to this modulation. Here, we employed in vitro whole‐cell patch‐clamp recordings to study whether GABAbRs modulate the activity of vasoactive intestinal polypeptide‐expressing interneurons (VIP‐INs) in layer (L) 2/3 of the mouse primary somatosensory cortex. Utilizing machine learning algorithms (hierarchical clustering and principal component analysis), we revealed that one VIP‐IN cluster (about 68% of all VIP‐INs) was sensitive to GABAbR activation. Paradoxically, when recordings were performed in standard conditions with high extracellular Ca2+ level, GABAbRs indirectly inhibited the activity of large conductance voltage‐ and calcium‐activated potassium (BK) channels and reduced GABAaR‐mediated inhibition, leading to an increase in intrinsic excitability of these interneurons. However, a classical inhibitory effect of GABAbRs on L2/3 VIP‐INs was observed in modified artificial cerebrospinal fluid with physiological (low) Ca2+ concentration. Our results are essential for a deeper understanding of mechanisms underlying the modulation of cortical networks. imageKey points Layer 2/3 vasoactive intestinal polypeptide‐expressing interneurons (VIP‐INs) in the mouse somatosensory cortex cluster into three electrophysiological types differentially sensitive to GABAb receptors (GABAbRs). The majority of VIP‐INs (type 1, about 68% of all VIP‐INs) are regulated through pre‐ and postsynaptic GABAbRs, while a subset of these interneurons (types 2 and 3) is controlled only presynaptically. The net effect of GABAbR activation on VIP‐IN excitability depends on [Ca2+] in artificial cerebrospinal fluid. When [Ca2+] is high (2.5 mM), GABAbRs indirectly inhibit BK channels and reduce GABAaR inhibition leading to increased intrinsic excitability of type 1 VIP‐INs. When [Ca2+] is low (1 mM), which is more physiological, BK channels do not regulate the intrinsic excitability of VIP‐INs and thus postsynaptic GABAbRs canonically decrease the intrinsic excitability of type 1 VIP‐INs.
Increased muscle satellite cell content and preserved telomere length in response to combined exercise training in patients with FSHD
Horwath O., Montiel‐Rojas D., Ponsot E., Féasson L., Kadi F.
Q1
Wiley
Journal of Physiology 2025 citations by CoLab: 0  |  Abstract
AbstractFacioscapulohumeral muscular dystrophy (FSHD) is an inherited muscle disease characterized by weakness and muscle wasting. In the absence of available treatments, exercise training has emerged as a potential strategy to attenuate muscle tissue deterioration. However, little is known about the impact of chronic exercise on degenerative events and regenerative capacity in FSHD muscle. Muscle biopsies were obtained from 16 FSHD patients before and after a 24 week training program combining aerobic‐, strength‐ and high‐intensity exercise (Control; n = 8, Training; n = 8). Histochemical and immunohistochemical approaches were applied to assess histopathological signs, markers of regeneration, inflammatory infiltrates and satellite cell content. Muscle telomere length was measured as an indicator of the remaining regenerative capacity. The proportion of muscle fibres expressing developmental myosins and centralized myonuclei was not exacerbated after the intervention. Similarly, no alterations were observed in the number of inflammatory infiltrates (CD68+ cells). Alongside muscle hypertrophy in slow (P = 0.022) and fast fibres (P = 0.022 and P = 0.008), satellite cell content increased specifically in fast fibres (+75 %, P = 0.015), indicating a functional satellite cell pool in FSHD muscle. Importantly, exercise training was not associated with a shortening of muscle telomere length, suggesting that muscle cell turnover was not accelerated despite an expansion of the satellite cell pool. Our findings suggest that combined exercise training elicits beneficial muscular adaptations without impairing important indicators of skeletal muscle regenerative capacity in patients with FSHD. imageKey points A 24 week combined exercise training program is a safe and well‐tolerated strategy to attenuate skeletal muscle deterioration in facioscapulohumeral muscular dystrophy (FSHD) patients. Markers of histopathology, muscle fibre regeneration and inflammatory infiltrates were not exacerbated following exercise training in FSHD muscle. Here, we show novel data that exercise training in FSHD patients induced muscle fibre hypertrophy and triggered an expansion of the satellite cell pool specifically in fast fibres. Exercise training in these patients is not associated with a shortening of muscle telomere length thereby indicating a preserved capacity for muscle regeneration.
Heart‐derived factors and organ cross‐talk in settings of health and disease: new knowledge and clinical opportunities for multimorbidity
Sen M.G., Chooi R., McMullen J.R.
Q1
Wiley
Journal of Physiology 2025 citations by CoLab: 0  |  Abstract
AbstractCardiovascular disease affects millions of people worldwide and often presents with other conditions including metabolic, renal and neurological disorders. A variety of secreted factors from multiple organs/tissues (proteins, nucleic acids and lipids) have been implicated in facilitating organ cross‐talk that may contribute to the development of multimorbidity. Secreted proteins have received the most attention, with the greatest body of research related to factors released from adipose tissue (adipokines), followed by skeletal muscle (myokines). To date, there have been fewer studies on proteins released from the heart (cardiokines) implicated with organ cross‐talk. Early evidence for the secretion of cardiac‐specific factors facilitating organ cross‐talk came in the form of natriuretic peptides which are secreted via the classical endoplasmic reticulum–Golgi pathway. More recently, studies in cardiomyocyte‐specific genetic mouse models have revealed cardiac‐initiated organ cross‐talk. Cardiomyocyte‐specific modulation of microRNAs (miR‐208a and miR‐23‐27‐24 cluster) and proteins such as the mediator complex subunit 13 (MED13), G‐protein‐coupled receptor kinase 2 (GRK2), mutant α‐myosin heavy‐chain (αMHC), ubiquitin‐like modifier‐activating enzyme (ATG7), oestrogen receptor alpha (ERα) and fibroblast growth factor 21 (FGF21) have resulted in metabolic and renal phenotypes. These studies have implicated a variety of factors which can be secreted via the classical pathway or via non‐classical mechanisms including the release of extracellular vesicles. Cross‐talk between the heart and the brain has also been described (e.g. via miR‐1 and an emerging concept, interoception: detection of internal neural signals). Here we summarize these studies taking into consideration that factors may be secreted in both settings of health and in disease. image
The impact of plakophilin‐2 deficiency on the atrial myocardium: electrophysiological insights and therapeutic implications
Gladkikh S., Cheng J.
Q1
Wiley
Journal of Physiology 2025 citations by CoLab: 0

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