The 50 most-cited articles in The Journal of Physiology, 2020

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…

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…

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…

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 (O 2 ) delivery to exercising muscle→increased glycolysis, La − and H + production→decreased muscle and blood pH→with increased H + buffered by blood [HCO 3 − ]→increased CO 2 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 O 2 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…

Key points 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. Abstract 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…

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…

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…

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…

Regular exercise has a central role in human health by reducing the risk of type 2 diabetes, obesity, stroke and cancer. How exercise is able to promote such systemic benefits has remained somewhat of a mystery but has been thought to be in part mediated by the release of myokines, skeletal muscle-specific cytokines, in response to exercise. Recent studies have revealed skeletal muscle can also release extracellular vesicles (EVs) into circulation following a bout of exercise. EVs are small membrane-bound vesicles capable of delivering biomolecules to recipient cells and subsequently altering their metabolism. The notion that EVs may have a role in both skeletal muscle and systemic adaptation to exercise has generated a great deal of excitement within a number of different fields including exercise physiology, neuroscience and metabolism. The purpose of this review is to provide an introduction to EV biology and what is currently known about skeletal muscle EVs and their potential role in the response of muscle and other tissues to exercise.

Fast excitatory synaptic transmission in the mammalian brain is largely mediated by AMPA-type ionotropic glutamate receptors (AMPARs), which are activated by the neurotransmitter glutamate. In synapses, the function of AMPARs is tuned by their auxiliary subunits, a diverse set of membrane proteins associated with the core pore-forming subunits of the AMPARs. Each auxiliary subunit provides distinct functional modulation of AMPARs, ranging from regulation of trafficking to shaping ion channel gating kinetics. Understanding the molecular mechanism of the function of these complexes is key to decoding synaptic modulation and their global roles in cognitive activities, such as learning and memory. Here, we review the structural and molecular complexity of AMPAR-auxiliary subunit complexes, as well as their functional diversity in different brain regions. We suggest that the recent structural information provides new insights into the molecular mechanisms underlying synaptic functions of AMPAR-auxiliary subunit complexes.

Abstract The ability of ketogenic low‐carbohydrate (CHO) high‐fat (K‐LCHF) diets to enhance muscle fat oxidation has led to claims that it is the ‘future of elite endurance sport’. There is robust evidence that substantial increases in fat oxidation occur, even in elite athletes, within 3–4 weeks and possibly 5–10 days of adherence to a K‐LCHF diet. Retooling of the muscle can double exercise fat use to ∼1.5 g min−1, with the intensity of maximal rates of oxidation shifting from ∼45% to ∼70% of maximal aerobic capacity. Reciprocal reductions in CHO oxidation during exercise are clear, but current evidence to support the hypothesis of the normalization of muscle glycogen content with longer‐term adaptation is weak. Importantly, keto‐adaptation may impair the muscle's ability to use glycogen for oxidative fates, compromising the use of a more economical energy source when the oxygen supply becomes limiting and, thus, the performance of higher‐intensity exercise (>80% maximal aerobic capacity). Even with moderate intensity exercise, individual responsiveness to K‐LCHF is varied, with…

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced cardiac channelopathy that has a high mortality in untreated patients. Our understanding has grown tremendously since CPVT was first described as a clinical syndrome in 1995. It is now established that the deadly arrhythmias are caused by unregulated 'pathological' calcium release from the sarcoplasmic reticulum (SR), the major calcium storage organelle in striated muscle. Important questions remain regarding the molecular mechanisms that are responsible for the pathological calcium release, regarding the tissue origin of the arrhythmic beats that initiate ventricular tachycardia, and regarding optimal therapeutic approaches. At present, mutations in six genes involved in SR calcium release have been identified as the genetic cause of CPVT: RYR2 (encoding ryanodine receptor calcium release channel), CASQ2 (encoding cardiac calsequestrin), TRDN (encoding triadin), CALM1, CALM2 and CALM3 (encoding identical calmodulin protein). Here, we review each CPVT subtype and how CPVT mutations alter protein…

KEY POINTS: Alzheimer's disease (AD) patients and transgenic mice have beta-amyloid (Aβ) aggregation in the gastrointestinal (GI) tract. It is possible that Aβ from the periphery contributes to the load of Aβ in the brain, as Aβ has prion-like properties. The present investigations demonstrate that Aβ injected into the GI tract of ICR mice is internalised into enteric cholinergic neurons; at 1 month, administration of Aβ into the body of the stomach and the proximal colon was observed to partly redistribute to the fundus and jejunum; at 1 year, vagal and cerebral β-amyloidosis was present, and mice exhibited GI dysfunction and cognitive deficits. These data reveal a previously undiscovered mechanism that potentially contributes to the development of AD. ABSTRACT: Alzheimer's disease (AD) is the most common age-related cause of dementia, characterised by extracellular beta-amyloid (Aβ) plaques and intracellular phosphorylated tau tangles in the brain. Aβ deposits have also been observed in the gastrointestinal (GI) tract of AD patients and transgenic mice, with overexpression of…

Key points Brief (5–6 days) adaptation to a low carbohydrate high fat diet in elite athletes increased exercise fat oxidation to rates previously observed with medium (3–4 weeks) or chronic (>12 months) adherence to this diet, with metabolic changes being washed out in a similar time frame. Increased fat utilisation during exercise was associated with a 5–8% increase in oxygen cost at speeds related to Olympic Programme races. Acute restoration of endogenous carbohydrate (CHO) availability (24 h high CHO diet, pre‐race CHO) only partially restored substrate utilisation during a race warm‐up. Fat oxidation continued to be elevated above baseline values although it was lower than achieved by 5–6 days’ keto adaptation; CHO oxidation only reached 61% and 78% of values previously seen at exercise intensities related to race events. Acute restoration of CHO availability failed to overturn the impairment of high‐intensity endurance performance previously associated with low carbohydrate high fat adaptation, potentially due to the blunted capacity for CHO oxidation. Abstract We investigated…

'Inter-hemispheric inhibition' is used frequently to describe the action of one hemisphere in suppressing or impeding processing in its counterpart. It is widely believed that this is required in order to prevent a bilateral cerebrum giving rise to simultaneous and potentially competing outputs. It is argued here that a fundamental role of inter-hemispheric inhibition is to support contrast enhancing and integrative functions by co-opting the capacities of the two cerebral hemispheres. Drawing upon an extensive body of empirical data, derived largely from animal models, and associated theoretical modelling, it is demonstrated that inter-hemispheric projections act via mechanisms such as surround/lateral inhibition. The principal functional unit of callosal influence comprises a facilitatory centre and a depressing peripheral zone, which together shape the influence of converging inputs to pyramidal neurons. Inter-hemispheric inhibition is an instance of a more general feature of mammalian neural systems, whereby inhibitory interneurons act not simply to prevent over-excitation but…

KEY POINTS: We used the idea of synergic control and the framework of the uncontrolled manifold hypothesis to explore the synergic control of a single muscle. Individual motor units in flexor digitorum superficialis formed two-three groups (MU-modes) with parallel changes in firing frequency, robust over force-up and force-down segments. There were strong force-stabilizing synergies in the MU-mode space during accurate cyclical force production. The results show, for the first time, that the idea of synergic control is applicable to individual muscles. The results suggest that segmental spinal mechanisms, such as recurrent inhibition and stretch reflex, probably play a major role in the synergic control of action. ABSTRACT: In the present study, for the first time, we have used the idea of synergic control and the framework of the uncontrolled manifold (UCM) hypothesis to test two hypotheses: (i) individual motor units are organized into stable groups (MU-modes) with parallel scaling of firing rates with changes in the muscle force, and (ii) the gains of MU-mode involvement co-vary…

Key points Knee‐extensors demonstrate greater fatigue resistance in females compared to males during single‐limb and whole‐body exercise. For single‐limb exercise, the intensity–duration relationship is different between sexes, with females sustaining a greater relative intensity of exercise. This study established the power–duration relationship during cycling, then assessed fatigability during critical power‐matched exercise within the heavy and severe intensity domains. When critical power and the curvature constant were expressed relative to maximal ramp test power, no sex difference was observed. No sex difference in time to task failure was observed in either trial. During heavy and severe intensity cycling, females experienced lesser muscle de‐oxygenation. Following both trials, females experienced lesser reductions in knee‐extensor contractile function, and following heavy intensity exercise, females experienced less reduction in voluntary activation. These data demonstrate that whilst the relative power–duration relationship is not different between males and females, the…

Nevertheless, some physiological responses such as the erythropoietic (Hauser et al. 2016) and the cerebral oxygenation/perfusion (DiPasquale et al. 2016) do seem unaffected by the differential PB. Overall, there are currently (November 2019) >50 peer reviewed scientific publications reporting different responses between HH vs. NH and most support the conclusion that 'NH is not a surrogate of HH' and 'cannot be used interchangeably' (Fulco et al. 2011), with HH representing a more severe physiological stimulus than NH at the same . Whilst the exact mechanisms by which the lower PB in HH independently modulates the observed NH vs. HH differences remain elusive, some potential underlying factors have been identified previously. In particular, hypobaria per se has been suggested to provoke higher hypoxic pulmonary vasoconstriction that could result in changes of alveolar dead space and altered ventilation–perfusion ratio (Loeppky et al. 1997). Increased physiological dead space has also been suggested as one of the potential -independent mechanisms of hypobaria (Savourey et al. 2003)…

The clinical presentation of COVID-19 due to infection with SARS-CoV-2 is highly variable with the majority of patients having mild symptoms while others develop severe respiratory failure. The reason for this variability is unclear but is in critical need of investigation. Some COVID-19 patients have been labelled with 'happy hypoxia', in which patient complaints of dyspnoea and observable signs of respiratory distress are reported to be absent. Based on ongoing debate, we highlight key respiratory and neurological components that could underlie variation in the presentation of silent hypoxaemia and define priorities for subsequent investigation.

KEY POINTS: The maintenance of optimal mitochondrial content and function is critical for muscle health. Mitochondrial dynamics play key roles in mitochondrial quality control; however, the exact role that mitochondrial fission plays in skeletal muscle health remains unclear. Here we report knocking down Drp1 (a protein regulating mitochondrial fission) for 4 months in adult mouse skeletal muscle resulted in severe muscle atrophy (40-50%). Drp1 knockdown also led to a reduction in ADP-stimulated respiration, an increase in markers of impaired autophagy and increased muscle regeneration, denervation, fibrosis and oxidative stress. Our data indicate that Drp1 is crucial for the maintenance of normal mitochondrial function and that Drp1 depletion severely impairs muscle health. ABSTRACT: Mitochondria play central roles in skeletal muscle physiology, including energy supply, regulation of energy-sensitive signalling pathways, reactive oxygen species production/signalling, calcium homeostasis and the regulation of apoptosis. The maintenance of optimal mitochondrial content and function…

KEY POINTS: The vagus nerve is the largest cranial nerve and innervates many structures in the neck, thorax and abdomen. Although single-unit recordings from the vagus nerve have been performed in experimental animals for several decades, no recordings have ever been made from the human vagus nerve. The vagus nerve is routinely stimulated clinically, yet we know little of its physiology in humans. We describe the methodology and provide preliminary results of the first intraneural single-unit recordings from the cervical vagus in awake humans, using tungsten microelectrodes inserted into the nerve through ultrasound guidance. ABSTRACT: Intraneural microelectrodes have been used extensively to record from single somatosensory axons supplying muscle, tendons, joints and skin, as well as to record from postganglionic sympathetic axons supplying muscle and skin, in accessible peripheral nerves in awake humans. However, the vagus nerve has never been targeted, probably because of its close proximity to the carotid artery and jugular vein in the neck. Here, we report the first unitary…

KEY POINTS: Trabecular meshwork (TM) is a highly mechanosensitive tissue in the eye that regulates intraocular pressure through the control of aqueous humour drainage. Its dysfunction underlies the progression of glaucoma but neither the mechanisms through which TM cells sense pressure nor their role in aqueous humour outflow are understood at the molecular level. We identified the Piezo1 channel as a key TM transducer of tensile stretch, shear flow and pressure. Its activation resulted in intracellular signals that altered organization of the cytoskeleton and cell-extracellular matrix contacts and modulated the trabecular component of aqueous outflow whereas another channel, TRPV4, mediated a delayed mechanoresponse. This study helps elucidate basic mechanotransduction properties that may contribute to intraocular pressure regulation in the vertebrate eye. ABSTRACT: Chronic elevations in intraocular pressure (IOP) can cause blindness by compromising the function of trabecular meshwork (TM) cells in the anterior eye, but how these cells sense and transduce pressure stimuli is poorly…

Key points We performed a prospective electrostimulation study of the motor homunculus in 100 patients without motor deficit or brain lesion in the precentral gyrus in order to acquire accurate Montreal Neurological Institute (MNI) coordinates of the functional areas. The analysis of 248 body coordinates in the precentral gyrus showed rare inter‐individual variations in the medial‐to‐lateral somatotopic movement organization with quite similar intensity thresholds. Electrostimulation only induced basic and stereotyped movements. We detected a relative medial‐to‐lateral somatotopy of the wrist/hand/global/individual fingers, with sometimes different sites for an individual muscle or movement. We found some similarities to, but also substantial differences from, the seminal work of Penfield and colleagues. We propose an updated version of the human motor homunculus and of its correlation with the somatosensory homunculus, previously defined in MNI space with a similar brain mapping technique. Abstract In this prospective electrostimulation study, based on 100 operated patients without…

KEY POINTS: Disruptions in circadian rhythms across an organism are associated with negative health outcomes, such as cardiometabolic and neurodegenerative diseases. Exercise has been proposed as a time cue for the circadian clock in rodents and humans. In this study, we assessed the effect of a single bout of endurance exercise on the skeletal muscle clock in vivo and a bout of muscle contractions in vitro. Timing of exercise or contractions influences the directional response of the muscle clock phase in vivo and in vitro. Our findings demonstrate that muscle contractions, as a component of exercise, can directly modulate the expression of muscle clock components in a time-of-day dependent manner. ABSTRACT: Exercise has been proposed to be a zeitgeber for the muscle circadian clock mechanism. However, this is not well defined and it is unknown if exercise timing induces directional shifts of the muscle clock. Our purpose herein was to assess the effect of one bout of treadmill exercise on skeletal muscle clock phase changes. We subjected PERIOD2::LUCIFERASE mice (n = 30F) to one…

KEY POINTS: 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…

Brain-computer interfaces (BCIs) aim to help paralysed patients to interact with their environment by controlling external devices using brain activity, thereby bypassing the dysfunctional motor system. Some neuronal disorders, such as amyotrophic lateral sclerosis (ALS), severely impair the communication capacity of patients. Several invasive and non-invasive brain-computer interfaces (BCIs), most notably using electroencephalography (EEG), have been developed to provide a means of communication to paralysed patients. However, except for a few reports, all available BCI literature for the paralysed (mostly ALS patients) describes patients with intact eye movement control, i.e. patients in a locked-in state (LIS) but not a completely locked-in state (CLIS). In this article we will discuss: (1) the fundamental neuropsychological learning factors and neurophysiological factors determining BCI performance in clinical applications; (2) the difference between LIS and CLIS; (3) recent development in BCIs for communication with patients in the completely locked-in state; (4) the effect of…

Tobacco smoking is highly addictive and causes respiratory disease, cardiovascular disease and multiple types of cancer. Electronic-cigarettes (e-cigarettes) are non-combustible tobacco alternatives that aerosolize nicotine and flavouring agents in a propylene glycol-vegetable glycerine vehicle. They were originally envisaged as a tobacco cessation aid, but whether or not they help people to quit tobacco use is controversial. In this review, we have compared and contrasted what is known regarding the effects of nicotine on the lungs vs. the effects of nicotine in the brain in the context of addiction. Critically, both combustible tobacco products and e-cigarettes contain nicotine, a highly addictive, plant-derived alkaloid that binds to nicotinic acetylcholine receptors (nAChRs). Nicotine's reinforcing properties are primarily mediated by activation of the brain's mesolimbic reward circuitry and release of the neurotransmitter dopamine that contribute to the development of addiction. Moreover, nicotine addiction drives repeated intake that results in chronic pulmonary exposure to…

KEY POINTS: The amount of fibrotic material in dystrophic mouse muscles relates to contractile function, but not passive function. Collagen fibres in skeletal muscle are associated with increased passive muscle stiffness in fibrotic muscles. The alignment of collagen is independently associated with passive stiffness in dystrophic skeletal muscles. These outcomes demonstrate that collagen architecture rather than collagen content should be a target of anti-fibrotic therapies to treat muscle stiffness. ABSTRACT: Fibrosis is prominent in many skeletal muscle pathologies including dystrophies, neurological disorders, cachexia, chronic kidney disease, sarcopenia and metabolic disorders. Fibrosis in muscle is associated with decreased contractile forces and increased passive stiffness that limits joint mobility leading to contractures. However, the assumption that more fibrotic material is directly related to decreased function has not held true. Here we utilize novel measurement of extracellular matrix (ECM) and collagen architecture to relate ECM form to muscle function. We used mdx…

Ionotropic glutamate receptors (iGluRs) are a major class of ligand-gated ion channels that are widespread in the living kingdom. Their critical role in excitatory neurotransmission and brain function of arthropods and vertebrates has made them a compelling subject of interest for neurophysiologists and pharmacologists. This is particularly true for NMDA receptor (NMDARs), a subclass of iGluRs that act as central drivers of synaptic plasticity in the CNS. How and when the unique properties of NMDARs arose during evolution, and how they relate to the evolution of the nervous system, remain open questions. Recent years have witnessed a boom in both genomic and structural data, such that it is now possible to analyse the evolution of iGluR genes on an unprecedented scale and within a solid molecular framework. In this review, combining insights from phylogeny, atomic structure and physiological and mechanistic data, we discuss how evolution of NMDAR motifs and sequences shaped their architecture and functionalities. We trace differences and commonalities between NMDARs and other…

KEY POINTS: The neural strategies behind the control of force during muscle pain are not well understood as previous research has been limited in assessing pain responses only during low-force contractions. Here we compared, for the first time, the behaviour of motor units recruited at low and high forces in response to pain. The results showed that motor units activated at low forces were inhibited while those recruited at higher forces increased their activity in response to pain. When analysing lower- and higher-threshold motor unit behaviour at high forces we observed differential changes in discharge rate and recruitment threshold across the motor unit pool. These adjustments allow the exertion of high forces in acutely painful conditions but could eventually lead to greater fatigue and stress of the muscle tissue. ABSTRACT: During low-force contractions, motor unit discharge rates decrease when muscle pain is induced by injecting nociceptive substances into the muscle. Despite this consistent observation, it is currently unknown how the central nervous system regulates motor…

Key points Preclinical models have demonstrated that nitric oxide is a key component of neurovascular coupling; this has yet to be translated to humans. We conducted two separate protocols utilizing intravenous infusion of a nitric oxide synthase inhibitor and isovolumic haemodilution to assess the influence of nitric oxide on neurovascular coupling in humans. Isovolumic haemodilution did not alter neurovascular coupling. Intravenous infusion of a nitric oxide synthase inhibitor reduced the neurovascular coupling response by ∼30%, indicating that nitric oxide is integral to neurovascular coupling in humans. Abstract Nitric oxide is a vital neurovascular signalling molecule in preclinical models, yet the mechanisms underlying neurovascular coupling (NVC) in humans have yet to be elucidated. To investigate the contribution of nitric oxide to NVC in humans, we utilized a visual stimulus paradigm to elicit an NVC response in the posterior cerebral circulation. Two distinct mechanistic interventions were conducted on young healthy males: (1) NVC was assessed during intravenous infusion…

Acid-sensing ion channels (ASICs) are a class of trimeric cation-selective ion channels activated by changes in pH within the physiological range. They are widely expressed in the central and peripheral nervous systems where they participate in a range of physiological and pathophysiological situations such as learning and memory, pain sensation, fear and anxiety, substance abuse and cell death. ASICs are localized to cell bodies and dendrites, including the postsynaptic density, and within the last 5 years several examples of proton-evoked ASIC excitatory postsynaptic currents have emerged. Thus, ASICs have become bona fide neurotransmitter-gated ion channels, activated by the smallest neurotransmitter possible: protons. Here we review how protons are thought to drive the conformational changes associated with ASIC activation and desensitization. In particular, we weigh the evidence for and against the so-called 'acidic pocket' being a vital proton sensor and discuss the emerging role of the β11-12 linker as a desensitization switch or 'molecular clutch'. We also examine how…

Key points Human fetal Doppler ultrasound and invasive blood gas measurements obtained by cordocentesis or at the time of delivery reveal similarities with sheep (an extensively used model for human fetal cardiovascular physiology). Oxygen saturation (SO 2 ) measurements in human fetuses have been limited to the umbilical and scalp vessels, providing little information about normal regional SO 2 differences in the fetus. Blood T2 MRI relaxometry presents a non‐invasive measure of SO 2 in the major fetal vessels. This study presents the first in vivo validation of fetal vessel T2 oximetry against the in vitro T2–SO 2 relationship using catheterized sheep fetuses and compares the normal SO 2 in the major vessels between the human and sheep fetal circulations. Human fetal vessel SO 2 by T2 MRI confirms many similarities with the sheep fetal circulation and is able to demonstrate regional differences in SO 2 ; in particular the significantly higher SO 2 in the left versus right heart. Abstract Blood T2 magnetic resonance imaging (MRI) relaxometry non‐invasively measures oxygen…

KEY POINTS: A decreased respiratory arousal threshold is one of the main contributors to obstructive sleep apnoea (OSA) pathogenesis. Several recent studies have sought to find a drug capable of increasing the respiratory arousal threshold without impairing pharyngeal muscle activity to reduce OSA severity, with variable success. Here we show that zolpidem increases the respiratory arousal threshold by ∼15%, an effect size which was insufficient to systematically decrease OSA severity as measured by the apnoea-hypopnoea index. Unlike recent physiological findings that showed paradoxical increases in pharyngeal muscle responsiveness during transient manipulations of airway pressure, zolpidem did not alter pharyngeal muscle responsiveness during natural sleep. It did, however, increase sleep efficiency without changing apnoea length, oxygen desaturation, next-day perceived sleepiness and alertness. These novel findings indicate that zolpidem was well tolerated and effective in promoting sleep in people with OSA, which may be therapeutically useful for people with OSA and comorbid…

Intermittent fasting has grown in popularity as a weight loss strategy in recent years. In particular, time restricted eating (TRE) has been popularized in the diet industry with dozens of books touting its ability to promote weight loss and improve glucose regulation. TRE involves confining the eating window to a specified number of hours per day (usually 4-10 h), and fasting (with zero-calorie beverages) for the remaining hours of the day. While several studies of TRE have been performed in rodent models, human studies are only now emerging. The goal of this review is to summarize the effects of TRE on body weight and cardiometabolic disease risk factors in human subjects. Accumulating evidence shows that TRE may spontaneously decrease energy intake by 20-30% under ad libitum conditions, producing small but statistically significant weight loss of 1-4%. In addition, TRE may significantly decrease systolic and diastolic blood pressure independent of weight loss. Further, improvements in fasting insulin and insulin resistance have also been reported. Taken together, these…

Abstract Three sentinel parameters of aerobic performance are the maximal oxygen uptake ( ), critical power (CP) and speed of the kinetics following exercise onset. Of these, the latter is, perhaps, the cardinal test of integrated function along the O2 transport pathway from lungs to skeletal muscle mitochondria. Fast kinetics demands that the cardiovascular system distributes exercise‐induced blood flow elevations among and within those vascular beds subserving the contracting muscle(s). Ideally, this process must occur at least as rapidly as mitochondrial metabolism elevates . Chronic disease and ageing create an O2 delivery (i.e. blood flow × arterial [O2], ) dependency that slows kinetics, decreasing CP and , increasing the O2 deficit and sowing the seeds of exercise intolerance. Exercise training, in contrast, does the opposite. Within the context of these three parameters (see Graphical Abstract), this brief review examines the training‐induced plasticity of key elements in the O2 transport pathway. It asks how structural and functional vascular adaptations accelerate and…

KEY POINTS: The results of the present study establish the temporal pattern of age-related vascular dysfunction across the adult lifespan in sedentary mice consuming a non-Western diet, and the underlying mechanisms The results demonstrate that consuming a Western diet accelerates and exacerbates vascular ageing across the lifespan in sedentary mice They also show that lifelong voluntary aerobic exercise has remarkable protective effects on vascular function throughout the lifespan, in the setting of ageing alone, as well as ageing compounded by Western diet consumption Overall, the results indicate that amelioration of mitochondrial oxidative stress and inflammation are key mechanisms underlying the voluntary aerobic exercise-associated preservation of vascular function across the lifespan in both the presence and absence of a Western dietary pattern ABSTRACT: Advancing age is the major risk factor for cardiovascular diseases, driven largely by vascular endothelial dysfunction (impaired endothelium-dependent dilatation, EDD) and aortic stiffening (increased aortic pulse wave…

Key points Sleep restriction has previously been associated with the loss of muscle mass in both human and animal models. The rate of myofibrillar protein synthesis (MyoPS) is a key variable in regulating skeletal muscle mass and can be increased by performing high‐intensity interval exercise (HIIE), although the effect of sleep restriction on MyoPS is unknown. In the present study, we demonstrate that participants undergoing a sleep restriction protocol (five nights, with 4 h in bed each night) had lower rates of skeletal muscle MyoPS; however, rates of MyoPS were maintained at control levels by performing HIIE during this period. Our data suggest that the lower rates of MyoPS in the sleep restriction group may contribute to the detrimental effects of sleep loss on muscle mass and that HIIE may be used as an intervention to counteract these effects. Abstract The present study aimed to investigate the effect of sleep restriction, with or without high‐intensity interval exercise (HIIE), on the potential mechanisms underpinning previously‐reported sleep‐loss‐induced reductions to…

Key points Endurance‐type training with blood flow restriction (BFR) increases maximum oxygen uptake ( ) and exercise endurance of humans. However, the physiological mechanisms behind this phenomenon remain uncertain. In the present study, we show that BFR‐interval training reduces the peripheral resistance to oxygen transport during dynamic, submaximal exercise in recreationally‐trained men, mainly by increasing convective oxygen delivery to contracting muscles. Accordingly, BFR‐training increased oxygen uptake by, and concomitantly reduced net lactate release from, the contracting muscles during relative‐intensity‐matched exercise, at the same time as invoking a similar increase in diffusional oxygen conductance compared to the training control. Only BFR‐training increased resting femoral artery diameter, whereas increases in oxygen transport and uptake were dissociated from changes in the skeletal muscle content of mitochondrial electron‐transport proteins. Thus, physically trained men benefit from BFR‐interval training by increasing leg convective oxygen transport and reducing…

Key points Respiration plays a key role in the circulation of cerebrospinal fluid (CSF) around the central nervous system. During inspiration increased venous return from the cranium is believed to draw CSF rostrally. However, this mechanism does not explain why CSF has also been observed to move caudally during inspiration. We show that during inspiration decreased intrathoracic pressure draws venous blood from the cranium and lumbar spine towards the thorax. We also show that the abdominal pressure was associated with rostral CSF displacement. However, a caudal shift of cervical CSF was seen with low abdominal pressure and comparably negative intrathoracic pressures. These results suggest that the effects of epidural blood flow within the spinal canal need to be considered, as well as the cranial blood volume balance, to understand respiratory‐related CSF flow. These results may prove useful for the treatment of CSF obstructive pathology and understanding the behaviour of intrathecal drug injections. Abstract It is accepted that during inspiration, cerebrospinal fluid (CSF) flows…

Key points Heart failure (HF), the leading cause of death in developed countries, occurs in the setting of reduced (HFrEF) or preserved (HFpEF) ejection fraction. Unlike HFrEF, there are no effective treatments for HFpEF, which accounts for ∼50% of heart failure. Abnormal intracellular calcium dynamics in cardiomyocytes have major implications for contractility and rhythm, but compared to HFrEF, very little is known about calcium cycling in HFpEF. We used rat models of HFpEF and HFrEF to reveal distinct differences in intracellular calcium regulation and excitation‐contraction (EC) coupling. While HFrEF is characterized by defective EC coupling at baseline, HFpEF exhibits enhanced coupling fidelity, further aggravated by a reduction in β‐adrenergic sensitivity. These differences in EC coupling and β‐adrenergic sensitivity may help explain why therapies that work in HFrEF are ineffective in HFpEF. Abstract Heart failure with reduced or preserved ejection fraction (respectively, HFrEF and HFpEF) is the leading cause of death in developed countries. Although numerous therapies improve…

KEY POINTS: The present study showed that anodal and cathodal transcranial direct current stimulation (tDCS) can respectively increase and decrease the amplitude of visually evoked field potentials in the stimulated visual cortex of cats, with the effect lasting for ∼60-70 min. We directly measured tDCS-induced changes in the concentration of inhibitory and excitatory neurotransmitters in the visual cortex using the enzyme-linked immunosorbent assay method and showed that anodal and cathodal tDCS can selectively decrease the concentration of GABA and glutamate in the stimulated cortical area. Anodal and cathodal tDCS can selectively inhibit the synthesis of GABA and glutamate by suppressing the expression of GABA- and glutamate-synthesizing enzymes, respectively. ABSTRACT: Transcranial direct current stimulation (tDCS) evokes long-lasting neuronal excitability in the target brain region. The underlying neural mechanisms remain poorly understood. The present study examined tDCS-induced alterations in neuronal activities, as well as the concentration and synthesis of GABA and…

The E-cigarette market continues to expand at an alarming rate with thousands of flavours available for purchase and continuously evolving devices. Now that it is a multi-billion dollar industry and one without stringent regulation, there is rising concern over the safety of vaping products. Since June 2019, over 2800 cases of E-cigarette-associated acute lung toxicity have been reported in the USA, over 60 of which resulted in death. Many argue that E-cigarettes offer a safer alternative to smoking, but we are evidently far from fully understanding the potential hazards that they pose to respiratory health. Although the risk of an outbreak in the UK has been considered low due to tighter E-cigarette regulations, we cannot fully eliminate the possibility of similar events occurring in the future. With evidence frequently emerging of the harmful effects of E-cigarettes to pulmonary health, there is an urgent need to define the long-term implications of vaping. Studies show that E-cigarette exposure can disrupt pulmonary homeostasis, with reports of gas exchange disturbance, reduced…

Key points The functional roles of the capsaicin receptor, TRPV1, outside of sensory nerves are unclear. We mapped TRPV1 in the mouse circulation, revealing extensive expression in the smooth muscle of resistance arterioles supplying skeletal muscle, heart and adipose tissue. Activation of TRPV1 in vascular myocytes constricted arteries, reduced coronary flow in isolated hearts and increased systemic blood pressure. These functional effects were retained after sensory nerve ablation, indicating specific signalling by arterial TRPV1. TRPV1 mediated the vasoconstrictive and blood pressure responses to the endogenous inflammatory lipid lysophosphatidic acid. These results show that TRPV1 in arteriolar myocytes modulates regional blood flow and systemic blood pressure, and suggest that TRPV1 may be a target of vasoactive inflammatory mediators. Abstract The capsaicin receptor, TRPV1, is a key ion channel involved in inflammatory pain signalling. Although mainly studied in sensory nerves, there are reports of TRPV1 expression in isolated segments of the vasculature, but whether the…

KEY POINTS: Reduced vitamin D receptor (VDR) expression prompts skeletal muscle atrophy. Atrophy occurs through catabolic processes, namely the induction of autophagy, while anabolism remains unchanged. In response to VDR-knockdown mitochondrial function and related gene-set expression is impaired. In vitro VDR knockdown induces myogenic dysregulation occurring through impaired differentiation. These results highlight the autonomous role the VDR has within skeletal muscle mass regulation. ABSTRACT: Vitamin D deficiency is estimated to affect ∼40% of the world's population and has been associated with impaired muscle maintenance. Vitamin D exerts its actions through the vitamin D receptor (VDR), the expression of which was recently confirmed in skeletal muscle, and its down-regulation is linked to reduced muscle mass and functional decline. To identify potential mechanisms underlying muscle atrophy, we studied the impact of VDR knockdown (KD) on mature skeletal muscle in vivo, and myogenic regulation in vitro in C2C12 cells. Male Wistar rats underwent in vivo electrotransfer (IVE) to…

Key points Endothelial cell TRPV4 (TRPV4 EC ) channels exert a dilatory effect on the resting diameter of resistance mesenteric and pulmonary arteries. Functional intermediate‐ and small‐conductance K + (IK and SK) channels and endothelial nitric oxide synthase (eNOS) are present in the endothelium of mesenteric and pulmonary arteries. TRPV4 EC sparklets preferentially couple with IK/SK channels in mesenteric arteries and with eNOS in pulmonary arteries. TRPV4 EC channels co‐localize with IK/SK channels in mesenteric arteries but not in pulmonary arteries, which may explain TRPV4 EC ‐IK/SK channel coupling in mesenteric arteries and its absence in pulmonary arteries. The presence of the nitric oxide‐scavenging protein, haemoglobin α, limits TRPV4 EC ‐eNOS signalling in mesenteric arteries. Spatial proximity of TRPV4 EC channels with eNOS and the absence of haemoglobin α favour TRPV4 EC ‐eNOS signalling in pulmonary arteries. Abstract Spatially localized Ca 2+ signals activate Ca 2+ ‐sensitive intermediate‐ and small‐conductance K + (IK and SK) channels in some vascular beds and…

Abstract August Krogh twice won the prestigious international Steegen Prize, for nitrogen metabolism (1906) and overturning the concept of active transport of gases across the pulmonary epithelium (1910). Despite this, at the beginning of 1920, the consummate experimentalist was relatively unknown worldwide and even among his own University of Copenhagen faculty. But, in early 1919, he had submitted three papers to Dr Langley, then editor ofThe Journal of Physiologyin England. These papers coalesced anatomical observations of skeletal muscle capillary numbers with O2diffusion theory to propose a novel active role for capillaries that explained the prodigious increase in blood‐muscle O2flux from rest to exercise. Despite his own appraisal of the first two papers as “rather dull” to his friend, the eminent Cambridge respiratory physiologist, Joseph Barcroft, Krogh believed that the third one, dealing with O2supply and capillary regulation, was“interesting”. These papers, which won Krogh an unopposed Nobel Prize for Physiology or Medicine in 1920, form the foundation for this review.…

Key points Nrf2 is a master regulator of endogenous cellular defences, governing the expression of more than 200 cytoprotective proteins, including a panel of antioxidant enzymes. Nrf2 plays an important role in redox haemostasis of skeletal muscle in response to the increased generation of reactive oxygen species during contraction. Employing skeletal muscle‐specific transgenic mouse models with unbiased‐omic approaches, we uncovered new target proteins, downstream pathways and molecular networks of Nrf2 in skeletal muscle following Nrf2 or Keap1 deletion. Based on the findings, we proposed a two‐way model to understand Nrf2 function: a tonic effect through a Keap1‐independent mechanism under basal conditions and an induced effect through a Keap1‐dependent mechanism in response to oxidative and other stresses. Abstract Although Nrf2 has been recognized as a master regulator of cytoprotection, its functional significance remains to be completely defined. We hypothesized that proteomic/bioinformatic analyses from Nrf2‐deficient or overexpressed skeletal muscle tissues will provide a…

Key points Spontaneous contractions are essential for normal lymph transport and these contractions are exquisitely sensitive to the KATP channel activator pinacidil. KATP channel Kir6.1 and SUR2B subunits are expressed in mouse lymphatic smooth muscle (LSM) and form functional KATP channels as verified by electrophysiological techniques. Global deletion of Kir6.1 or SUR2 subunits results in severely impaired lymphatic contractile responses to pinacidil. Smooth muscle‐specific expression of Kir6.1 gain‐of‐function mutant (GoF) subunits results in profound lymphatic contractile dysfunction and LSM hyperpolarization that is partially rescued by the KATP inhibitor glibenclamide. In contrast, lymphatic endothelial‐specific expression of Kir6.1 GoF has essentially no effect on lymphatic contractile function. The high sensitivity of LSM to KATP channel GoF offers an explanation for the lymphoedema observed in patients with Cantú syndrome, a disorder caused by gain‐of‐function mutations in genes encoding Kir6.1 or SUR2, and suggests that glibenclamide may be an appropriate therapeutic…

Key points When exercise was prescribed to elicit a fixed evaporative heat balance requirement (Ereq), no differences in steady‐state sweat rates were observed with different absolute oesophageal and/or skin temperatures, secondary to differences in time of the day (i.e. morning (AM) vs. afternoon (PM)) and ambient temperature (i.e. 23°C vs. 33°C). Exercise at a fixed metabolic heat production (Hprod), but a different Ereq (due to differences in air temperature), yielded higher steady‐state sweat rates with a higher Ereq, irrespective of absolute oesophageal temperature. Circadian rhythm did not alter the change in core temperature prior to the onset for sudomotor activation, nor the thermosensitivity, resulting in similar cumulative whole‐body sweat rates irrespective of time of day at a fixed Ereq. Collectively, these data indicate that during exercise in a compensable environment, steady‐state sudomotor responses are influenced by Ereq rather than absolute core and skin temperatures, or Hprod. Abstract The present study sought to determine whether absolute core temperature…