The Journal of Physiology最新文献

{"title":"Diaphragm fatigue: Similarities and differences between sexes.","authors":"Ken D O'Halloran","doi":"10.1113/JP281081","DOIUrl":"https://doi.org/10.1113/JP281081","url":null,"abstract":"The inspiratory muscles of breathing are uniquely adapted for endurance. Nevertheless, akin to other striated muscles, inspiratory muscle fatigue occurs, even in the primary muscle of inspiration, during high-intensity exercise and inspiratory loading. Diaphragm fatigue has implications for respiratory system performance in health and disease. There are reports of sex differences in muscle fatigue characteristics in different muscle groups, including the inspiratory muscles, which is revealed as greater fatigue tolerance in women compared to men. Yet, interestingly, studies of diaphragm function in various species indicate similar force-generating and fatigue characteristics, suggesting that sex differences, where they exist, may reside at one or more sites within the complex integrative control of muscle behaviour and/or may be revealed in the (dys)functional response to stressors. Acute exposure to hypoxia can enhance diaphragm fatigue. There are reports of greater hypoxic tolerance in respiratory muscles of female rodents, purportedly as a result of the protective effects of oestrogen, particularly relevant to chronic exposure to hypoxia in the context of disease (O’Halloran & Lewis, 2017). In this issue of The Journal of Physiology, Archiza et al. (2021) sought to characterize diaphragm fatigue during inspiratory loading in acute hypoxia, aiming to determine whether differences exist between healthy men and women. In a technical tour de force, Archiza et al. (2021) elicited diaphragm fatigue in eight men and eight women by isocapnic inspiratory pressure-threshold loading at equivalent target workloads between sexes. Inspiratory loading trials were performed during exposure to normoxia and hypoxia (8%O2) performed on separate experimental days in a randomized fashion. Diaphragm fatigue was quantified by assessing the twitch transdiaphragmatic pressure elicited by cervical magnetic stimulation. Bilateral surface electromyogram recordings of the diaphragm allowed the assessment of M-waves to quantify diaphragm activation. Heart rate and non-invasive blood pressure were recorded to determine the cardiovascular consequences of the respiratory muscle metaboreflex. Peak transdiaphragmatic pressure at rest was equivalent between sexes. In normoxia, the magnitude of diaphragm fatigue was equivalent in men and women, confirming and extending previous work by this group (Geary et al. 2019). Conversely, and unexpectedly, greater fatigue was expressed in female diaphragm compared to males during equivalent cumulative work in hypoxia. Remarkably, the sex difference is characterized by robust hypoxic tolerance inmen, such that diaphragm fatiguewas not significantly greater in hypoxia compared to normoxia, whereas diaphragm fatigue in women was significantly enhanced in hypoxia compared to normoxia. The study by Archiza et al. (2021) contributes important observations and adds to the continued debate on similarities and differences in muscle fatigue between ","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1023-1024"},"PeriodicalIF":5.5,"publicationDate":"2021-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38734586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sympathetic reactivity and inflammation: another joint problem in rheumatoid arthritis?","authors":"James P Fisher","doi":"10.1113/JP281084","DOIUrl":"https://doi.org/10.1113/JP281084","url":null,"abstract":"Rheumatoid arthritis (RA) is a chronic inflammatory condition characterised by inflammation of the synovial joints and a systemic increase in inflammatory cytokines [e.g. tumour necrosis factor α, interleukins (IL)]. The risk of premature death is increased in RA, with cardiovascular disease accounting for up to 50% of the elevated mortality (Nurmohamed et al. 2015). Traditional risk factors do not wholly explain the increased cardiovascular risk (Nurmohamed et al. 2015) and the contribution of novel mechanisms, such as autonomic dysregulation (i.e. heightened sympathetic activation and attenuated cardiovagal control (Adlan et al. 2014, 2017), have also been highlighted. The study by Peçanha et al. (2021), published recently in the Journal of Physiology, extends the study of the autonomic nervous system in RA to exercise, which is recommended for symptomatic relief and improving cardio-metabolic outcomes in this population (Metsios & Kitas, 2018). Patients with RA exhibit exaggerated blood pressure (BP) responses to exercise, and although such exercise-induced BP surges may increase the risk of cardiovascular events, the study of Peçanha et al. (2021) is the first to examine the underlying neural mechanisms. The cardiovascular responses to isometric quadriceps exercise were compared in post-menopausal women with a diagnosis of RA (n = 33) and ageand sex-matched control participants (n= 10). As anticipated, and despite similar resting values, the mean BP response to exercise was greater in RA. Recordings of sympathetic vasoconstrictor outflow to the skeletal muscle vasculature (MSNA, muscle sympathetic nerve activity) were also obtained. Not only was resting MSNA elevated in RA, as previously reported (Adlan et al. 2017), but increases in MSNA during exercise were augmented. The pressor responses to exercise are mediated by several neural control mechanisms. These include feedforward signals arising from higher brain centres, known as ‘central command’, and sensory feedback from group III and IV skeletal muscle afferents in response to mechanical (mechanoreflex) and metabolic (metaboreflex) stimulation. The isolated activation of the latter is commonly achieved by the supra-systolic inflation of a pneumatic cuff, placed proximal to the exercising muscles, just before the cessation of exercise and then during a recovery period (i.e. post-exercise ischaemia). Peçanha et al. (2021) observed that the RA group exhibited a more pronounced elevation in BP and MSNA during post-exercise ischaemia than the control participants. This is indicative of an augmented muscle metaboreflex in RA and is probably an important driver of the elevated pressor response to exercise. So what might be the mechanism for the augmented muscle metaboreflex in RA? The inflammatory sequelae to which the metabolically sensitive skeletal muscle afferents are exposed is a likely candidate. Chronic exposure to such conditions may enhance the sensitivity of the metabolically sensitive","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1025-1026"},"PeriodicalIF":5.5,"publicationDate":"2021-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1113/JP281084","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38736513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pushing the needle forward on the relationship between autoimmunity and autonomic dysfunction.","authors":"Nina L Stute, P J Koopmans","doi":"10.1113/JP281197","DOIUrl":"https://doi.org/10.1113/JP281197","url":null,"abstract":"Immune-mediated diseases (IMDs) impact 4% of the global population, making them of great clinical and economic importance. They are a physical, emotional and economic burden for patients, oftentimes decreasing quality of life in multiple facets. The IMD burden impacts more than just patients: it overflows into the medical community, as the great majority of IMDs are accompanied by numerous comorbidities. Rheumatoid arthritis (RA) falls under the IMD umbrella as a chronic-inflammatory autoimmune disease: it is characterized by systemic inflammation, severe joint pain and an increased risk of serious comorbidities. Of these comorbid conditions, the most alarming is cardiovascular disease (CVD), which accounts for 40–50% of deaths in RA. Patients with RA experience high incidence of myocardial infarction and cerebrovascular stroke. The proposed mechanisms connecting RA and CVD are wide ranging: chronic systemic inflammation, which can wreak havoc on endothelial function; adverse interactions and side effects of disease-altering drugs and biologic therapies; as well as lifestyle and environmental factors that predispose patients to a plethora of CVD risk factors. Over the past five decades, using the technique of microneurography to investigate afferent and efferent nerve impulses has been a staple in autonomic function research. As such, this gold standard assessment of autonomic function, which allows for direct recording of muscle sympathetic nerve activity (MSNA), has been employed to elucidate the ambiguous relationship between RA and CVD. RA is hypothesized to be somewhat unique, as autonomic dysfunction may occur prior to RA development, as found by observational studies (Koopman et al. 2016). Autonomic dysfunction, like that seen in RA, wherein MSNA is elevated in both basal and reactivity measures, is recognized as one of the mechanisms contributing to adverse cardiovascular outcomes in RA. In a disease where early detection can save one from irreparable joint damage, such information is powerful in helping identify risk factors earlier rather than later. Autonomic and haemodynamic reactivity to exercise is complex. The muscle metaboreflex, which responds to an accumulation of metabolites in exercising skeletal muscle when O2 demands are not met, sparks a reflex to increase blood pressure (BP). An increase inMSNA during muscle metaboreflex activation, which can be stimulated via post-exercise ischaemia (PEI), has been shown to contribute to compromised haemodynamic control in various disease states (heart failure, hypertension, etc.). Isolating the metabolic portion of the exercise pressor response provides valuable insight into the neural and metabolic mechanisms contributing to RA. While autonomic dysfunction is clearly a key player in RA, just how much it pervades homeostatic processes has been unclear. This gap in the literature was addressed in a recent article in the Journal of Physiology by Peçanha et al. (2021). The authors recruited","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1039-1040"},"PeriodicalIF":5.5,"publicationDate":"2021-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38817567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"\"To measure is to know\": no relationship between cerebrovascular and peripheral shear-mediated dilation in young adults.","authors":"Max E Weston","doi":"10.1113/JP280784","DOIUrl":"https://doi.org/10.1113/JP280784","url":null,"abstract":"Endothelial dysfunction is the first detectable manifestation of the atherosclerotic process, and its measurement is of both clinical and research importance. Vascular function in conduit arteries is promoted through shear-mediated dilation, where increases in shear-stress induce vasodilation through nitric oxide (NO) production. This is known as endothelium-dependent dilation, and is assessed in the peripheral vasculature through flow mediated dilation (FMD) of the brachial artery. This technique is associated with coronary artery endothelium-dependent vasodilation and is predictive of cardiovascular events. Endothelial dysfunction of the internal carotid artery (ICA) is a risk factor for cerebrovascular diseases (such as stroke, dementia and Alzheimer’s disease), but whether brachial FMD is associated with cerebral endothelium-dependent vasodilation is unknown. Typically, cerebrovascular function is assessed by cerebrovascular reactivity (CVR) of middle cerebral artery blood velocity (MCAv) to carbon dioxide (CO2). Although linked to FMD (Ainslie et al., 2007), this approach has poor predictive value in healthy populations, measures only blood velocity (not vessel dilation) and does not isolate a shear-mediated response. In a recent issue of The Journal of Physiology, Carr et al. (2020) explored the relationships between ICA and brachial artery shear-mediated dilation in 19 healthy adults (23±6 years). They also explored the endothelium-independent responses of these arteries, through glyceryl trinitrate (GTN) administration. Brachial artery shear-mediated dilation was assessed by FMD, and the authors utilised a cerebral-FMD protocol (cFMD) developed by Hoiland et al. (2017) for the ICA. In short, the cFMD test involved Duplex ultrasound imaging of the ICA during and following a rapid +9 mmHg increase in end-tidal CO2 (PETCO2) for 30 seconds. This test has been shown to be predominantly shear-stress mediated, with the subsequent ICA dilation significantly related to shear-rate area under the curve (SRAUC) (Hoiland et al., 2017). This provides a suitable “FMD-equivalent” for the cerebrovasculature, where ischemia-induced hyperaemia is not possible. This is in contrast to “traditional” CVR tests involving sustained hypercapnia (typically 3–5 minutes), where the relationships between shear stress and ICA diameter can be secondary to other confounding factors (e.g. increases in blood pressure and cardiac output). Indeed, another strength of the study by Carr et al., was the inclusion of a 5-minute hypercapnic CVR test to explore the relationships between ICA cFMD and commonly-used outcomes of MCAvand ICA-CVR. The primary finding was that ICA and brachial artery responses were not correlated in both the endotheliumdependent (FMD, r = 0.00, P = 0.93) and independent (GTN, r = 0.12, P = 0.19) tests, and this was maintained when data were allometrically scaled to account for between-artery differences in baseline diameter. Furthermore, ICA cFMD was not","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1035-1036"},"PeriodicalIF":5.5,"publicationDate":"2021-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1113/JP280784","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38480216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial dysfunction in placental trophoblast cells experiencing gestational diabetes mellitus.","authors":"Joshua J Fisher,&nbsp;Chelsea L Vanderpeet,&nbsp;Lucy A Bartho,&nbsp;Daniel R McKeating,&nbsp;James S M Cuffe,&nbsp;Olivia J Holland,&nbsp;Anthony V Perkins","doi":"10.1113/JP280593","DOIUrl":"https://doi.org/10.1113/JP280593","url":null,"abstract":"<p><strong>Key points: </strong>Mitochondrial dysfunction is known to occur in diabetic phenotypes including type 1 and 2 diabetes mellitus. The incidence of gestational diabetes mellitus (GDM) is increasing and defined as the onset of a diabetic phenotype during pregnancy. The role of placental mitochondria in the aetiology of GDM remains unclear and is an emerging area of research. Differing mitochondrial morphologies within the placenta may influence the pathogenesis of the disorder. This study observed mitochondrial dysfunction in GDM placenta when assessing whole tissue. Upon further investigation into mitochondrial isolates from the cytotrophoblast and syncytiotrophoblast, mitochondrial dysfunction appears exaggerated in syncytiotrophoblast. Assessing mitochondrial populations individually enabled the determination of differences between cell lineages of the placenta and established varying levels of mitochondrial dysfunction in GDM, in some instances establishing significance in pathways previously inconclusive or confounded when assessing whole tissue. This research lays the foundation for future work into mitochondrial dysfunction in the placenta and the role it may play in the aetiology of GDM.</p><p><strong>Abstract: </strong>Mitochondrial dysfunction has been associated with diabetic phenotypes, yet the involvement of placental mitochondria in gestational diabetes mellitus (GDM) remains inconclusive. This is in part complicated by the different mitochondrial subpopulations present in the two major trophoblast cell lineages of the placenta. To better elucidate the role of mitochondria in this pathology, this study examined key aspects of mitochondrial function in placentas from healthy pregnancies and those complicated by GDM in both whole tissue and isolated mitochondria. Mitochondrial content, citrate synthase activity, reactive oxygen species production and gene expression regulating metabolic, hormonal and antioxidant control was examined in placental tissue, before examining functional differences between mitochondrial isolates from cytotrophoblast (Cyto-Mito) and syncytiotrophoblast (Syncytio-Mito). Our study observed evidence of mitochondrial dysfunction across multiple pathways when assessing whole placental tissue from GDM pregnancies compared with healthy controls. Furthermore, by examining isolated mitochondria from the cytotrophoblast and syncytiotrophoblast cell lineages of the placenta we established that although both mitochondrial populations were dysfunctional, they were differentially impacted. These data highlight the need to consider changes in mitochondrial subpopulations at the feto-maternal interface when studying pregnancy pathologies.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1291-1305"},"PeriodicalIF":5.5,"publicationDate":"2021-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1113/JP280593","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38558988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Contribution of retrotrapezoid nucleus neurons to CO₂ -amplified cardiorespiratory activity in spontaneously hypertensive rats.","authors":"Yanming Tian,&nbsp;Danyang Geng,&nbsp;Yakun Wang,&nbsp;Luo Shi,&nbsp;Hongxiao Yu,&nbsp;Wei He,&nbsp;Yufang Zhu,&nbsp;Shirui Jun,&nbsp;Congrui Fu,&nbsp;Xin Wang,&nbsp;Xiangjian Zhang,&nbsp;Fang Yuan,&nbsp;Sheng Wang","doi":"10.1113/JP280246","DOIUrl":"https://doi.org/10.1113/JP280246","url":null,"abstract":"<p><strong>Key points: </strong>This study demonstrates that both CO₂ -induced respiratory and cardiovascular responses are augmented in spontaneously hypertensive rats (SHRs). Genetic ablation of the retrotrapezoid nucleus (RTN) neurons depresses enhanced hypercapnic ventilatory response and eliminates CO₂ -stimulated increase in arterial pressure and heart rate in SHRs. SHRs have a high protein level of pH-sensitive channels in the RTN, including the TASK-2 channel, Kv12.1 channel and acid-sensing ion channel 3. The inhibition of putative TASK-2 channel activity by clofilium diminishes amplified hypercapnic ventilatory and cardiovascular responses, and reduces the number of CO₂ -activated RTN neurons in SHRs. These results indicate that RTN neurons contribute to enhanced CO₂ -stimulated respiratory and cardiovascular responses in SHRs.</p><p><strong>Abstract: </strong>The respiratory regulation of cardiovascular activity is essential for maintaining an efficient ventilation and perfusion ratio. Activation of central respiratory chemoreceptors not only elicits a ventilatory response but also regulates sympathetic nerve activity and arterial blood pressure (ABP). The retrotrapezoid nucleus (RTN) is the most completely characterized cluster of central respiratory chemoreceptors. We hypothesize that RTN neurons contribute to augmented CO₂ -stimulated respiratory and cardiovascular responses in adult spontaneously hypertensive rats (SHRs). Our findings indicate that SHRs exhibit more enhanced hypercapnic cardiorespiratory responses than age-matched normotensive Wistar-Kyoto rats. Genetic ablation of RTN neurons notably depresses an enhanced hypercapnic ventilatory response (HCVR) and eliminates a CO₂ -stimulated greater increase in ABP and heart rate in SHRs. In addition, SHRs have a higher protein level of pH-sensitive channels in the RTN, including TASK-2 channels, Kv12.1 channels and acid-sensing ion channel 3. Administration of clofilium (i.p.), an unselective inhibitor of TASK-2 channels, not only significantly reduces the enhanced HCVR but also inhibits CO₂ -amplified increases in ABP and heart rate in SHRs. Moreover, clofilium significantly decreases the number of CO₂ -activated RTN neurons in SHRs. Taken together, we suggest that RTN neurons play an important role in enhanced hypercapnic ventilatory and cardiovascular responses in SHRs and the putative mechanism involved is associated with TASK-2 channel activity in the RTN.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1115-1130"},"PeriodicalIF":5.5,"publicationDate":"2021-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1113/JP280246","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38397439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PKCε stimulation of TRPV1 orchestrates carotid body responses to asthmakines.","authors":"Nicholas G Jendzjowsky,&nbsp;Arijit Roy,&nbsp;Mircea Iftinca,&nbsp;Nicole O Barioni,&nbsp;Margaret M Kelly,&nbsp;Brittney A Herrington,&nbsp;Frank Visser,&nbsp;Christophe Altier,&nbsp;Richard J A Wilson","doi":"10.1113/JP280749","DOIUrl":"https://doi.org/10.1113/JP280749","url":null,"abstract":"<p><strong>Key points: </strong>We have previously shown that carotid body stimulation by lysophosphatidic acid elicits a reflex stimulation of vagal efferent activity sufficient to cause bronchoconstriction in asthmatic rats. Here, we show that pathophysiological concentrations of asthma-associated prototypical Th2 cytokines also stimulate the carotid bodies. Stimulation of the carotid bodies by these asthmakines involves a PKCε-transient receptor potential vanilloid 1 (TRPV1) signalling mechanism likely dependent on TRPV1 S502 and T704 phosphorylation sites. As the carotid bodies' oxygen sensitivity is independent of PKCε-TRPV1 signalling, systemic blockade of PKCε may provide a novel therapeutic target to reduce allergen-induced asthmatic bronchoconstriction. Consistent with the therapeutic potential of blocking the PKCε-TRPV1 pathway, systemic delivery of a PKCε-blocking peptide suppresses asthmatic respiratory distress in response to allergen and reduces airway hyperresponsiveness to bradykinin.</p><p><strong>Abstract: </strong>The autonomic nervous system orchestrates organ-specific, systemic and behavioural responses to inflammation. Recently, we demonstrated a vital role for lysophosphatidic acid in stimulating the primary autonomic oxygen chemoreceptors, the carotid bodies, in parasympathetic-mediated asthmatic airway hyperresponsiveness. However, the cacophony of stimulatory factors and cellular mechanisms of carotid body activation are unknown. Therefore, we set out to determine the intracellular signalling involved in carotid body-mediated sensing of asthmatic blood-borne inflammatory mediators. We employed a range of in vitro and rat in situ preparations, site-directed mutagenesis, patch-clamp, nerve recordings and pharmacological inhibition to assess cellular signalling. We show that the carotid bodies are also sensitive to asthma-associated prototypical Th2 cytokines which elicit sensory nerve excitation. This provides additional asthmatic ligands contributing to the previously established reflex arc resulting in efferent vagal activity and asthmatic bronchoconstriction. This novel sensing role for the carotid body is mediated by a PKCε-dependent stimulation of transient receptor potential vanilloid 1 (TRPV1), likely via TRPV1 phosphorylation at sites T704 and S502. Importantly, carotid body oxygen sensing was unaffected by blocking either PKCε or TRPV1. Further, we demonstrate that systemic PKCε blockade reduces asthmatic respiratory distress in response to allergen and airway hyperresponsiveness. These discoveries support an inflammation-dependent, oxygen-independent function for the carotid body and suggest that targeting PKCε provides a novel therapeutic option to abate allergic airway disease without altering life-saving autonomic hypoxic reflexes.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1335-1354"},"PeriodicalIF":5.5,"publicationDate":"2021-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1113/JP280749","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38689429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of glycolysis by the hypoxia-inducible factor (HIF): implications for cellular physiology.","authors":"S J Kierans,&nbsp;C T Taylor","doi":"10.1113/JP280572","DOIUrl":"https://doi.org/10.1113/JP280572","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"23-37"},"PeriodicalIF":5.5,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1113/JP280572","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38546530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exertional heat stroke leads to concurrent long-term epigenetic memory, immunosuppression and altered heat shock response in female mice.","authors":"Kevin O Murray,&nbsp;Jason O Brant,&nbsp;John D Iwaniec,&nbsp;Laila H Sheikh,&nbsp;Lucas de Carvalho,&nbsp;Christian K Garcia,&nbsp;Gerard P Robinson,&nbsp;Jamal M Alzahrani,&nbsp;Alberto Riva,&nbsp;Orlando Laitano,&nbsp;Michael P Kladde,&nbsp;Thomas L Clanton","doi":"10.1113/JP280518","DOIUrl":"https://doi.org/10.1113/JP280518","url":null,"abstract":"<p><strong>Key points: </strong>Exposure to exertional heat stroke (EHS) has been linked to increased long-term decrements of health. Epigenetic reprogramming is involved in the response to heat acclimation; however, whether the long-term effects of EHS are mediated by epigenetic reprogramming is unknown. In female mice, we observed DNA methylation reprogramming in bone marrow-derived (BMD) monocytes as early as 4 days of recovery from EHS and as late as 30 days compared with sham exercise controls. Whole blood, collected after 30 days of recovery from EHS, exhibited an immunosuppressive phenotype when challenged in vitro by lipopolysaccharide. After 30 days of recovery from EHS, BMD monocytes exhibited an altered in vitro heat shock response. The location of differentially methylated CpGs are predictive of both the immunosuppressive phenotype and altered heat shock responses.</p><p><strong>Abstract: </strong>Exposure to exertional heat stroke (EHS) has been linked to increased susceptibility to a second heat stroke, infection and cardiovascular disease. Whether these clinical outcomes are mediated by an epigenetic memory is unknown. Using a preclinical mouse model of EHS, we investigated whether EHS exposure produces a lasting epigenetic memory in monocytes and whether there are phenotypic alterations that may be consistent with these epigenetic changes. Female mice underwent forced wheel running at 37.5°C/40% relative humidity until symptom limitation, characterized by CNS dysfunction. Results were compared with matched exercise controls at 22.5°C. Monocytes were isolated from bone marrow after 4 or 30 days of recovery to extract DNA and analyse methylation. Broad-ranging alterations to the DNA methylome were observed at both time points. At 30 days, very specific alterations were observed to the promoter regions of genes involved with immune responsiveness. To test whether these changes might be related to phenotype, whole blood at 30 days was challenged with lipopolysaccharide (LPS) to measure cytokine secretion; monocytes were also challenged with heat shock to quantify mRNA expression. Whole blood collected from EHS mice showed markedly attenuated inflammatory responses to LPS challenge. Furthermore, monocyte mRNA from EHS mice showed significantly altered responses to heat shock challenge. These results demonstrate that EHS leads to a unique DNA methylation pattern in monocytes and altered immune and heat shock responsiveness after 30 days. These data support the hypothesis that EHS exposure can induce long-term physiological changes that may be linked to altered epigenetic profiles.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"119-141"},"PeriodicalIF":5.5,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1113/JP280518","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38475333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A single, clinically relevant dose of the GABA_B agonist baclofen impairs visuomotor learning.","authors":"Ainslie Johnstone, Ioana Grigoras, Pierre Petitet, Liliana P Capitão, Charlotte J Stagg","doi":"10.1113/JP280378","DOIUrl":"10.1113/JP280378","url":null,"abstract":"<p><strong>Key points: </strong>Baclofen is a GABA_B agonist prescribed as a treatment for spasticity in stroke, brain injury and multiple sclerosis patients, who are often undergoing concurrent motor rehabilitation. Decreasing GABAergic inhibition is a key feature of motor learning and so there is a possibility that GABA agonist drugs, such as baclofen, could impair these processes, potentially impacting rehabilitation. Here, we examined the effect of 10 mg of baclofen, in 20 young healthy individuals, and found that the drug impaired retention of visuomotor learning with no significant effect on motor sequence learning. Overall baclofen did not alter transcranial magnetic stimulation-measured GABA_B inhibition, although the change in GABA_B inhibition correlated with aspects of visuomotor learning retention. Further work is needed to investigate whether taking baclofen impacts motor rehabilitation in patients.</p><p><strong>Abstract: </strong>The GABA_B agonist baclofen is taken daily as a treatment for spasticity by millions of stroke, brain injury and multiple sclerosis patients, many of whom are also undergoing motor rehabilitation. However, decreases in GABA are suggested to be a key feature of human motor learning, which raises questions about whether drugs increasing GABAergic activity may impair motor learning and rehabilitation. In this double-blind, placebo-controlled study, we investigated whether a single 10 mg dose of the GABA_B agonist baclofen impaired motor sequence learning and visuomotor learning in 20 young healthy participants of both sexes. Participants trained on visuomotor and sequence learning tasks using their right hand. Transcranial magnetic stimulation (TMS) measures of corticospinal excitability, GABA_A (short-interval intracortical inhibition_, 2.5 ms) and GABA_B (long-interval intracortical inhibition_, 150 ms) receptor activation were recorded from left M1. Behaviourally, baclofen caused a significant reduction of visuomotor aftereffect (F_1,137.8  = 6.133, P = 0.014) and retention (F_1,130.7  = 4.138, P = 0.044), with no significant changes to sequence learning. There were no overall changes to TMS measured GABAergic inhibition with this low dose of baclofen. This result confirms the causal importance of GABA_B inhibition in mediating visuomotor learning and suggests that chronic baclofen use could negatively impact aspects of motor rehabilitation.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"307-322"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38609082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}