The 50 most-cited articles in The Journal of Physiology, 2021

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…

High-intensity interval training (HIIT) is characterised by short bouts of high-intensity submaximal exercise interspersed with rest periods. Low-volume HIIT, typically involving less than 15 min of high-intensity exercise per session, is being increasingly investigated in healthy and clinical populations due to its time-efficient nature and purported health benefits. The findings from recent trials suggest that low-volume HIIT can induce similar, and at times greater, improvements in cardiorespiratory fitness, glucose control, blood pressure, and cardiac function when compared to more traditional forms of aerobic exercise training including high-volume HIIT and moderate intensity continuous training, despite requiring less time commitment and lower energy expenditure. Although further studies are required to elucidate the precise mechanisms of action, metabolic improvements appear to be driven, in part, by enhanced mitochondrial function and insulin sensitivity, whereas certain cardiovascular improvements are linked to increased left ventricular function as well as greater central…

Sex differences in exercise physiology, such as substrate metabolism and skeletal muscle fatigability, stem from inherent biological factors, including endogenous hormones and genetics. Studies investigating exercise physiology frequently include only males or do not take sex differences into consideration. Although there is still an underrepresentation of female participants in exercise research, existing studies have identified sex differences in physiological and molecular responses to exercise training. The observed sex differences in exercise physiology are underpinned by the sex chromosome complement, sex hormones and, on a molecular level, the epigenome and transcriptome. Future research in the field should aim to include both sexes, control for menstrual cycle factors, conduct large-scale and ethnically diverse studies, conduct meta-analyses to consolidate findings from various studies, leverage unique cohorts (such as post-menopausal, transgender, and those with sex chromosome abnormalities), as well as integrate tissue and cell-specific -omics data. This knowledge is…

Key points Few days of unloading are sufficient to induce a decline of skeletal muscle mass and function; notably, contractile force is lost at a faster rate than muscle mass. The reasons behind this disproportionate loss of muscle force are still poorly understood. We provide strong evidence of two mechanisms only hypothesized until now for the rapid muscle force loss in only 10 days of bed rest. Our results show that an initial neuromuscular junction instability, accompanied by alterations in the innervation status and impairment of single fibre sarcoplasmic reticulum function contribute to the loss of contractile force in front of a preserved myofibrillar function and central activation capacity. Early onset of neuromuscular junction instability and impairment in calcium dynamics involved in excitation–contraction coupling are proposed as eligible determinants to the greater decline in muscle force than in muscle size during unloading. Abstract Unloading induces rapid skeletal muscle atrophy and functional decline. Importantly, force is lost at a much higher rate than muscle…

AMPA receptors are tetrameric glutamate-gated ion channels that mediate a majority of fast excitatory neurotransmission in the brain. They exist as calcium-impermeable (CI-) and calcium-permeable (CP-) subtypes, the latter of which lacks the GluA2 subunit. CP-AMPARs display an array of distinctive biophysical and pharmacological properties that allow them to be functionally identified. This has revealed that they play crucial roles in diverse forms of central synaptic plasticity. Here we summarise the functional hallmarks of CP-AMPARs and describe how these are modified by the presence of auxiliary subunits that have emerged as pivotal regulators of AMPARs. A lasting change in the prevalence of GluA2-containing AMPARs, and hence in the fraction of CP-AMPARs, is a feature in many maladaptive forms of synaptic plasticity and neurological disorders. These include modifications of glutamatergic transmission induced by inflammatory pain, fear conditioning, cocaine exposure, and anoxia-induced damage in neurons and glia. Furthermore, defective RNA editing of GluA2 can cause altered…

Key points The impact of SARS‐CoV‐2 infection on autonomic and cardiovascular function in otherwise healthy individuals is unknown. For the first time it is shown that young adults recovering from SARS‐CoV‐2 have elevated resting sympathetic activity, but similar heart rate and blood pressure, compared with control subjects. Survivors of SARS‐CoV‐2 also exhibit similar sympathetic nerve activity and haemodynamics, but decreased pain perception, during a cold pressor test compared with healthy controls. Further, these individuals display higher sympathetic nerve activity throughout an orthostatic challenge, as well as an exaggerated heart rate response to orthostasis. If similar autonomic dysregulation, like that found here in young individuals, is present in older adults following SARS‐CoV‐2 infection, there may be substantial adverse implications for cardiovascular health. Abstract The novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) can elicit systemic adverse physiological effects. However, the impact of SARS‐CoV‐2 on autonomic and cardiovascular function in…

Maternal metabolic adaptations during pregnancy ensure appropriate nutrient supply to the developing fetus. This is facilitated by reductions in maternal peripheral insulin sensitivity, which enables glucose to be available in the maternal circulation for transfer to the fetus for growth. To balance this process and avoid excessive hyperglycaemia and glucose intolerance in the mother during pregnancy, maternal pancreatic β-cells undergo remarkable changes in their function including increasing their proliferation and glucose-stimulated insulin secretion. In this review we examine how placental and maternal hormones work cooperatively to activate several signalling pathways, transcription factors and epigenetic regulators to drive adaptations in β-cell function during pregnancy. We also explore how adverse maternal environmental conditions, including malnutrition, obesity, circadian rhythm disruption and environmental pollutants, may impact the endocrine and molecular mechanisms controlling β-cell adaptations during pregnancy. The available data from human and experimental animal…

Physical inactivity, i.e. not reaching the recommended level of physical activity (PA), and sedentary behaviours (SB), i.e. sitting time, have been associated with increased risk for common metabolic diseases. Recent epidemiological data suggest that high volumes of SB are detrimental to metabolic health, even in the presence of regular exercise, i.e. moderate/vigorous PA. This suggests that the health effects of SB are independent from those of exercise. However, experimentally testing this hypothesis is complicated because of the difficulty in disassociating SB from PA. Bedrest studies, a traditional space science model, can offer new insights. In some bedrest studies, an exercise training protocol has been used to counteract the harmful effects of inactivity. While bedrest induces an inactive and sedentary state, exercise with bedrest represents a unique model of sedentary yet physically active people. Here, we review bedrest studies with and without exercise training. Although exercise training prevents the loss of muscle mass and function, even large volumes of exercise are not…

Understanding the contribution of the autonomic nervous system to cerebral blood flow (CBF) control is challenging, and interpretations are unclear. The identification of calcium channels and adrenoreceptors within cerebral vessels has led to common misconceptions that the function of these receptors and actions mirror those of the peripheral vasculature. This review outlines the fundamental differences and complex actions of cerebral autonomic activation compared with the peripheral circulation. Anatomical differences, including the closed nature of the cerebrovasculature, and differential adrenoreceptor subtypes, density, distribution and sensitivity, provide evidence that measures on peripheral sympathetic nerve activity cannot be extrapolated to the cerebrovasculature. Cerebral sympathetic nerve activity seems to act opposingly to the peripheral circulation, mediated at least in part by changes in intracranial pressure and cerebral blood volume. Additionally, heterogeneity in cerebral adrenoreceptor distribution highlights region-specific autonomic regulation of CBF.…

Ageing is a natural process causing alterations in the neuromuscular system, which contributes to reduced quality of life. Motor unit (MU) contributes to weakness, but the mechanisms underlying reduced firing rates are unclear. Persistent inward currents (PICs) are crucial for initiation, gain control and maintenance of motoneuron firing, and are directly proportional to the level of monoaminergic input. Since concentrations of monoamines (i.e. serotonin and noradrenaline) are reduced with age, we sought to determine if estimates of PICs are reduced in older (>60 years old) compared to younger adults (<35 years old). We decomposed MU spike trains from high-density surface electromyography over the biceps and triceps brachii during isometric ramp contractions to 20% of maximum. Estimates of PICs (ΔFrequency; or simply ΔF) were computed using the paired MU analysis technique. Regardless of the muscle, peak firing rates of older adults were reduced by ∼1.6 pulses per second (pps) (P = 0.0292), and ΔF was reduced by ∼1.9 pps (P < 0.0001), compared to younger adults. We further found…

The persistence of quadriceps weakness represents a major concern following anterior cruciate ligament reconstruction (ACLR). The underlying adaptations occurring in the activity of spinal motoneurons are still unexplored. This study examined the discharge patterns of large populations of motor units (MUs) in the vastus lateralis (VL) and vastus medialis muscles following ACLR. Nine ACLR individuals and 10 controls performed unilateral trapezoidal contractions of the knee extensor muscles at 35%, 50% and 70% of the maximal voluntary isometric force (MVIF). High-density surface electromyography (HDsEMG) was used to record the myoelectrical activity of the vasti muscles in both limbs. HDsEMG signals were decomposed with a convolutive blind source separation method and MU properties were extracted and compared between sides and groups. The ACLR group showed a lower MVIF on the reconstructed side compared to the contralateral side (28.1%; P < 0.001). This force deficit was accompanied by reduced MU discharge rates (∼21%; P < 0.05), lower absolute MU recruitment and derecruitment…

NMDA receptors (NMDARs) are glutamate-gated ion channels that play key roles in synaptic transmission and plasticity. Both hyper- and hypo-activation of NMDARs are deleterious to neuronal function. In particular, NMDAR hypofunction is involved in a wide range of neurological and psychiatric conditions like schizophrenia, intellectual disability, age-dependent cognitive decline, or Alzheimer's disease. While early medicinal chemistry efforts were mostly focused on the development of NMDAR antagonists, the last 10 years have seen a boom in the development of NMDAR positive allosteric modulators (PAMs). Here we review the currently developed NMDAR PAMs, their pharmacological profiles and mechanisms of action, as well as their physiological effects in healthy animals and animal models of NMDAR hypofunction. In light of the complexity of physiological outcomes of NMDAR PAMs in vivo, we discuss the remaining challenges and questions that need to be addressed to better grasp and predict the therapeutic potential of NMDAR positive allosteric modulation.

Passive mechanical properties of whole skeletal muscle are not as well understood as active mechanical properties. Both the structural basis for passive mechanical properties and the properties themselves are challenging to determine because it is not clear which structures within skeletal muscle actually bear passive loads and there are not established standards by which to make mechanical measurements. Evidence suggests that titin bears the majority of the passive load within the single muscle cell. However, at larger scales, such as fascicles and muscles, there is emerging evidence that the extracellular matrix bears the major part of the load. Complicating the ability to quantify and compare across size scales, muscles and species, definitions of muscle passive properties such as stress, strain, modulus and stiffness can be made relative to many reference parameters. These uncertainties make a full understanding of whole muscle passive mechanical properties and modelling these properties very difficult. Future studies defining the specific load bearing structures and their…

Key points We report a novel method for the transient expression of SARS‐CoV‐2 envelope (E) protein in intracellular organelles and the plasma membrane of mammalian cells and Xenopus oocytes. Intracellular expression of SARS‐CoV‐2 E protein increases intra‐Golgi pH. By targeting the SARS‐CoV‐2 E protein to the plasma membrane, we show that it forms a cation channel, viroporin, that is modulated by changes of pH. This method for studying the activity of viroporins may facilitate screening for new antiviral drugs to identify novel treatments for COVID‐19. Abstract The envelope (E) protein of coronaviruses such as SARS‐CoV‐1 is proposed to form an ion channel or viroporin that participates in viral propagation and pathogenesis. Here we developed a technique to study the E protein of SARS‐CoV‐2 in mammalian cells by directed targeting using a carboxyl‐terminal fluorescent protein tag, mKate2. The wild‐type SARS‐CoV‐2 E protein can be trafficked to intracellular organelles, notably the endoplasmic reticulum–Golgi intermediate complex, where its expression increases pH inside the…

Key points Recent animal and human physiology studies indicate that noradrenergic and muscarinic processes are key mechanisms that mediate pharyngeal muscle control during sleep. The noradrenergic agent reboxetine combined with the anti‐muscarinic hyoscine butylbromide has recently been shown to improve upper airway function during sleep in healthy individuals. However, whether these findings translate to the clinically relevant patient population of people with obstructive sleep apnoea (OSA), and the effects of the agents on OSA severity, are unknown. We found that reboxetine plus hyoscine butylbromide reduced OSA severity, including overnight hypoxaemia, via increases in pharyngeal muscle responsiveness, improvements in respiratory control and airway collapsibility without changing the respiratory arousal threshold. These findings provide mechanistic insight into the role of noradrenergic and anti‐muscarinic agents on upper airway stability and breathing during sleep and are important for pharmacotherapy development for OSA. Abstract The noradrenergic agent reboxetine combined…

Type 2 diabetes can potentially be prevented by targeted lifestyle and weight loss interventions. Time restricted eating (TRE) is a form of intermittent fasting that has emerged as a novel diet strategy to reduce body weight and improve glycaemic control. TRE involves eating within a certain window of time (usually 4 to 10 h), and water-fasting for the remaining hours of the day. The purpose of this review is to summarize the effects of TRE on body weight and markers of glycaemic control in human subjects. We also aim to provide mechanistic insights into the effect of TRE on insulin sensitivity and glucose tolerance. Results to date reveal that TRE produces mild weight loss (1%-4% from baseline) and energy restriction, when food consumption is restricted to 4-10 h/day. TRE also reduces fasting insulin and improves insulin sensitivity in individuals with prediabetes and those with obesity. Moreover, TRE improves glucose tolerance and decreases serum glucose excursions. The possible mechanisms underlying these benefits include increased autophagic flux, mild elevations in ketone…

ABSTRACT Ribosomes are the macromolecular engines of protein synthesis. Skeletal muscle ribosome biogenesis is stimulated by exercise, but the contribution of ribosomal DNA (rDNA) copy number and methylation to exercise-induced rDNA transcription is unclear. To investigate the genetic and epigenetic regulation of ribosome biogenesis with exercise, a time course of skeletal muscle biopsies was obtained from 30 participants (18 men and 12 women; 31 ±8 yrs, 25 ±4 kg/m 2 ) at rest and 30 min, 3h, 8h, and 24h after acute endurance (n=10, 45 min cycling, 70% VO 2 max) or resistance exercise (n=10, 4 x 7 x 2 exercises); 10 control participants underwent biopsies without exercise. rDNA transcription and dosage were assessed using qPCR and whole genome sequencing. rDNA promoter methylation was investigated using massARRAY EpiTYPER, and global rDNA CpG methylation was assessed using reduced-representation bisulfite sequencing. Ribosome biogenesis and MYC transcription were associated with resistance but not endurance exercise, indicating preferential up-regulation during hypertrophic…

Abstract Changes in cellular Ca 2+ levels have major influences on vascular function and blood pressure regulation. Vascular smooth muscle cells (SMCs) and endothelial cells (ECs) orchestrate vascular activity in distinct ways, often involving highly specific fluctuations in Ca 2+ signalling. Ageing is a major risk factor for cardiovascular diseases, but the impact of ageing per se on vascular Ca 2+ signalling has received insufficient attention. We reviewed the literature for age‐related changes in Ca 2+ signalling in relation to vascular structure and function. Vascular tone dysregulation in several vascular beds has been linked to abnormal expression or activity of SMC voltage‐gated Ca 2+ channels, Ca 2+ ‐activated K + channels or TRPC6 channels. Some of these effects were linked to altered caveolae density, microRNA expression or 20‐HETE abundance. Intracellular store Ca 2+ handling was suppressed in ageing mainly via reduced expression of intracellular Ca 2+ release channels, and Ca 2+ reuptake or efflux pumps. An increase in mitochondrial Ca 2+ uptake, leading to oxidative…

Extracellular miRNAs are found in a variety of body fluids and mediate intercellular and interorgan communication, thus regulating gene expression and cellular metabolism. These miRNAs are secreted either in small vesicles/exosomes (sEV) or bound to proteins such as Argonaute and high-density lipoprotein. Both exosomal and protein-bound circulating miRNAs are altered in obesity. Although all tissues can contribute to changes in circulating miRNAs, adipose tissue itself is an important source of these miRNAs, especially those in sEVs. These are derived from both adipocytes and macrophages and participate in crosstalk between these cells, as well as peripheral tissues, including liver, skeletal muscle and pancreas, whose function may be impaired in obesity. Changes in levels of circulating miRNAs have also been linked to the beneficial effects induced by weight loss interventions, including diet, exercise and bariatric surgery, further indicating a role for these miRNAs as mediators of disease pathogenesis. Here, we review the role of circulating miRNAs in the pathophysiology of…

KEY POINTS: Extracellular spikes recorded in the visual cortex (Area 17/18, V1) are commonly classified into either regular-spiking (RS) or fast-spiking (FS). Using multi-electrode arrays positioned in cat V1 and a broadband stimulus, we show that there is also a distinct class with positive-spiking (PS) waveforms. PS units were associated mainly with non-oriented receptive fields while RS and FS units had orientation-selective receptive fields. We suggest that PS units are recordings of axons originating from the thalamus. This conclusion was reinforced by our finding that we could record PS units after cortical silencing, but not record RS and FS units. The importance of our findings is that we were able to correlate spike shapes with receptive field characteristics with high precision using multi-electrode extracellular recording techniques. This allows considerable increases in the amount of information that can be extracted from future cortical experiments. ABSTRACT: Extracellular spike waveforms from recordings in the visual cortex have been classified into either…

Ribbon-class synapses in the ear achieve analog to digital transformation of a continuously graded membrane potential to all-or-none spikes. In mammals, several auditory nerve fibres (ANFs) carry information from each inner hair cell (IHC) to the brain in parallel. Heterogeneity of transmission among synapses contributes to the diversity of ANF sound-response properties. In addition to the place code for sound frequency and the rate code for sound level, there is also a temporal code. In series with cochlear amplification and frequency tuning, neural representation of temporal cues over a broad range of sound levels enables auditory comprehension in noisy multi-speaker settings. The IHC membrane time constant introduces a low-pass filter that attenuates fluctuations of the receptor potential above 1-2 kHz. The ANF spike generator adds a high-pass filter via its depolarization-rate threshold that rejects slow changes in the postsynaptic potential and its phasic response property that ensures one spike per depolarization. Synaptic transmission involves several stochastic subcellular…

Abstract Adults with obesity are at increased risk of neurocognitive impairments, partly as a result of reduced cerebral blood flow and brain‐derived neurotrophic factor (BDNF). Ketone supplements containing β‐hydroxybutyrate (β‐OHB) are a purported therapeutic strategy for improving brain health in at‐risk populations. We tested the hypothesis that short‐term β‐OHB supplementation will elevate cerebral blood flow and BDNF, as well as improve cognition in adults with obesity. In a placebo‐controlled double‐blind, cross‐over design, 14 adults with obesity (10 females; aged 56 ± 12 years; body mass index = 33.8 ± 6.9 kg m–2) consumed 30 mL (12 g) of β‐OHB or placebo thrice‐daily for 14 days. Blood flow (Q) and cerebrovascular conductance (CVC) were measured in the common carotid (CCA), internal carotid (ICA) and vertebral (VA) arteries by duplex ultrasound. BDNF was measured by an enzyme‐linked immunosorbent assay. Cognition was assessed by the digit‐symbol substitution (DSST), Stroop and task‐switching tests. Following 14 days of ketone supplementation, we observed significant…

Abstract The prevalence of non‐alcoholic fatty liver disease (NAFLD) is increasing worldwide, and new treatments are sorely needed. Nicotinamide adenine dinucleotide (NAD+) has been proposed as a potential target to prevent and reverse NAFLD. NAD+ is an important redox factor for energy metabolism and is used as a substrate by a range of enzymes, including sirtuins (SIRT), which regulates histone acetylation, transcription factor activity and mitochondrial function. NAD+ is also a precursor for reduced nicotinamide adenine dinucleotide phosphate (NADPH), which is an important component of the antioxidant defense system. NAD+ precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are available as over‐the‐counter dietary supplements, and oral supplementation with these precursors increases hepatic NAD+ levels and prevents hepatic lipid accumulation in pre‐clinical models of NAFLD. NAD+ precursors have also been found to improve hepatic mitochondrial function and decrease oxidative stress in pre‐clinical NAFLD models. NAD+ repletion also prevents NAFLD…

Abstract Circulating concentrations of canonically pro‐ and anti‐inflammatory cytokines are commonly measured when evaluating the anti‐inflammatory effects of exercise. An important caveat to interpreting systemic cytokine concentrations as evidence for the anti‐inflammatory effects of exercise is the observed dissociation between circulating cytokine concentrations and cytokine function at the tissue/cellular level. The dichotomization of cytokines as pro‐ or anti‐inflammatory also overlooks the context dependence of cytokine function, which can vary depending on the physiological state being studied, the cytokine's cellular source/target, and magnitude of cytokine responses. We re‐evaluate our current understanding of anti‐inflammatory cytokine responses to exercise by highlighting nuances surrounding the interpretation of altered systemic cytokine concentrations as evidence for changes in inflammatory processes occurring at the tissue/cellular level. We highlight the lesser known pro‐inflammatory and immunostimulatory actions of the prototypical anti‐inflammatory cytokine,…

Key points It has previously been shown that afferent and efferent vagal nerve stimulation potently inhibits lipopolysaccharide (LPS)‐induced inflammation Our data show inhibition of inflammation by efferent but not afferent vagal nerve stimulation requires T‐cell derived acetylcholine We show that afferent and efferent neuroimmune circuits require β2‐adrenergic receptor signalling Abstract Chronic inflammation due to inappropriate immune cell activation can have significant effects on a variety of organ systems, reducing lifespan and quality of life. As such, highly targeted control of immune cell activation is a major therapeutic goal. Vagus nerve stimulation (VNS) has emerged as a therapeutic modality that exploits neuroimmune communication to reduce immune cell activation and consequently inflammation. Although vagal efferent fibres were originally identified as the primary driver of anti‐inflammatory actions, the vagus nerve in most species of animals predominantly comprises afferent fibres. Stimulation of vagal afferent fibres can also reduce inflammation; it is, however,…

Abstract The regulation and defence of intracellular pH is essential for homeostasis. Indeed, alterations in cerebrovascular acid–base balance directly affect cerebral blood flow (CBF) which has implications for human health and disease. For example, changes in CBF regulation during acid–base disturbances are evident in conditions such as chronic obstructive pulmonary disease and diabetic ketoacidosis. The classic experimental studies from the past 75+ years are utilized to describe the integrative relationships between CBF, carbon dioxide tension ( P CO 2 ), bicarbonate (HCO 3 – ) and pH. These factors interact to influence (1) the time course of acid–base compensatory changes and the respective cerebrovascular responses (due to rapid exchange kinetics between arterial blood, extracellular fluid and intracellular brain tissue). We propose that alterations in arterial [HCO 3 – ] during acute respiratory acidosis/alkalosis contribute to cerebrovascular acid–base regulation; and (2) the regulation of CBF by direct changes in arterial vs . extravascular/interstitial P CO 2 and pH – the…

KEY POINTS: Adipocyte enlargement is a key feature of obesity and associated with insulin resistance and metabolic disease The cause and consequences of adipocyte enlargement have remained hard to study in vitro due to a lack of human cell models with representative morphology This paper provides an easily set up spheroid culture method, HUVAS (human unilocular vascularized adipocyte spheroids), for the differentiation and culturing of human adipocytes with a more unilocular morphology We show that providing adipocyte progenitors with a vascular differentiation niche is key for achieving in vitro differentiated adipocytes with large lipid droplets Lipid treatment of the HUVAS spheroids can further adipocyte enlargement and induce cellular dysfunction, mimicking the in vivo effects of weight gain The model will allow a wider research community to perform mechanistic studies of the factors impacting on human adipocyte differentiation and growth, increasing our understanding of how obesity develops and why it has such detrimental consequences on whole body metabolism ABSTRACT: The rise…

KEY POINTS: Damage to corticospinal axons has implications for the development of spasticity following spinal cord injury (SCI). Here, we examined to what extent residual corticospinal connections and spasticity are present in muscles below the injury (quadriceps femoris and soleus) in humans with motor complete thoracic SCI. We found three distinct subgroups of people: participants with spasticity and corticospinal responses in the quadriceps femoris and soleus; participants with spasticity and corticospinal responses in the quadriceps femoris only; and participants with no spasticity or corticospinal responses in either muscle. Spasticity and corticospinal responses were present in the quadriceps but never only in the soleus muscle, suggesting a proximal to distal gradient of symptoms of hyperreflexia. These results suggest that concomitant patterns of residual corticospinal connectivity and spasticity exist in humans with motor complete SCI and that a clinical examination of spasticity might be a good predictor of residual descending motor pathways in people with severe…

KEY POINTS: The maintenance of mitochondrial integrity is critical for skeletal muscle health. Mitochondrial dynamics play key roles in mitochondrial quality control; however, the exact role that mitochondrial fission plays in the muscle ageing process remains unclear. Here we report that both Drp1 knockdown and Drp1 overexpression late in life in mice is detrimental to skeletal muscle function and mitochondrial health. Drp1 knockdown in 18-month-old mice resulted in severe skeletal muscle atrophy, mitochondrial dysfunction, muscle degeneration/regeneration, oxidative stress and impaired autophagy. Overexpressing Drp1 in 18-month-old mice resulted in mild skeletal muscle atrophy and decreased mitochondrial quality. Our data indicate that silencing or overexpressing Drp1 late in life is detrimental to skeletal muscle integrity. We conclude that modulating Drp1 expression is unlikely to be a viable approach to counter the muscle ageing process. ABSTRACT: Sarcopenia, the ageing-related loss of skeletal muscle mass and function, is a debilitating process negatively impacting the quality…

KEY POINTS: Maximal endurance performance is greater in the early daytime. Timed exercise differentially alters the muscle transcriptome and (phospho)-proteome. Early daytime exercise triggers energy provisioning and tissue regeneration. Early night-time exercise activates stress-related and catabolic pathways. Scheduled training has limited effects on the muscle and liver circadian clocks. ABSTRACT: Timed physical activity might potentiate the health benefits of training. The underlying signalling events triggered by exercise at different times of day are, however, poorly understood. Here, we found that time-dependent variations in maximal treadmill exercise capacity of naïve mice were associated with energy stores, mostly hepatic glycogen levels. Importantly, running at different times of day resulted in a vastly different activation of signalling pathways, e.g. related to stress response, vesicular trafficking, repair and regeneration. Second, voluntary wheel running at the opposite phase of the dark, feeding period surprisingly revealed a minimal zeitgeber (i.e. phase-shifting)…

Abstract In order to identify peripheral biomarkers of impaired oxidative metabolism during exercise following a 10‐day bed rest, 10 males performed an incremental exercise (to determine peak pulmonary V̇O 2 (V̇O 2 p )) and moderate‐intensity exercises, before (PRE) and after (POST) bed rest. Blood flow response was evaluated in the common femoral artery by Eco‐Doppler during 1 min of passive leg movements (PLM). The intramuscular matching between O 2 delivery and O 2 utilization was evaluated by near‐infrared spectroscopy (NIRS). Mitochondrial respiration was evaluated ex vivo by high‐resolution respirometry in isolated muscle fibres, and in vivo by NIRS by the evaluation of skeletal muscle V̇O 2 (V̇O 2 m ) recovery kinetics. Resting V̇O 2 m was estimated by NIRS. Peak V̇O 2 p was lower in POST vs . PRE. The area under the blood flow vs . time curve during PLM was smaller ( P = 0.03) in POST (274 ± 233 mL) vs . PRE (427 ± 291). An increased ( P = 0.03) overshoot of muscle deoxygenation during a metabolic transition was identified in POST. Skeletal muscle citrate synthase activity…

Vagus nerve stimulation (VNS) treats patients with drug-resistant epilepsy, depression and heart failure, but the mechanisms responsible are uncertain. The mild stimulus intensities used in chronic VNS suggest activation of myelinated primary visceral afferents projecting to the nucleus of the solitary tract (NTS). Here, we monitored the activity of second and higher order NTS neurons in response to peripheral vagal activation using therapeutic VNS criteria. A bipolar stimulating electrode activated the left cervical vagus nerve, and stereotaxically placed single tungsten electrodes recorded unit activity from the left caudomedial NTS of chloralose-anaesthetized rats. High-intensity single electrical stimuli established vagal afferent conduction velocity (myelinated A-type or unmyelinated C-type) as well as synaptic order (second vs. higher order using paired electrical stimuli) for inputs to single NTS neurons. Then, VNS treatment was applied. A mid-collicular knife cut (KC) divided the brainstem from all supramedullary regions to determine their contribution to NTS activity. Our…

There is emerging evidence of a gut microbiome-skeletal muscle axis. The purpose of this study was to determine if an intact gut microbiome was necessary for skeletal muscle adaptation to exercise. Forty-two 4-month-old female C57BL/6J mice were randomly assigned to untreated (U) or antibiotic-treated (T) non-running controls (CU or CT, respectively) or progressive weighted wheel running (PoWeR, P) untreated (PU) or antibiotic-treated (PT) groups. Antibiotic treatment resulted in disruption of the gut microbiome as indicated by a significant depletion of gut microbiome bacterial species in both CT and PT groups. The training stimulus was the same between PU and PT groups as assessed by weekly (12.35 ± 2.06 vs. 11.09 ± 1.76 km/week, respectively) and total (778.9 ± 130.5 vs. 703.8 ± 112.9 km, respectively) running activity. In response to PoWeR, PT showed less hypertrophy of soleus type 1 and 2a fibres and plantaris type 2b/x fibres compared to PU. The higher satellite cell and myonuclei abundance of PU plantaris muscle after PoWeR was not observed in PT. The fibre-type shift of PU…

Brain-computer interfaces (BCIs) designed for motor rehabilitation use brain signals associated with motor-processing states to guide neuroplastic changes in a state-dependent manner. These technologies are uniquely positioned to induce targeted and functionally relevant plastic changes in the human motor nervous system. However, while several studies have shown that BCI-based neuromodulation interventions may improve motor function in patients with lesions in the central nervous system, the neurophysiological structures and processes targeted with the BCI interventions have not been identified. In this review, we first summarize current knowledge of the changes in the central nervous system associated with learning new motor skills. Then, we propose a classification of current BCI paradigms for plasticity induction and motor rehabilitation based on the expected neural plastic changes promoted. This classification proposes four paradigms based on two criteria: the plasticity induction methods and the brain states targeted. The existing evidence regarding the brain circuits and…

Key points Endoplasmic reticulum (ER) stress promotes placental dysmorphogenesis and is associated with poor pregnancy outcomes. We show that unfolded protein response signalling pathways located in the ER drive differentiation of mouse trophoblast stem cells into trophoblast subtypes involved in development of the placental labyrinth zone and trophoblast invasion. In a mouse model of chronic ER stress (Eif2s1tm1RjK), higher ER stress in homozygous blastocysts is accompanied by reduced trophectoderm cell number and developmental delay and also is associated with an increased incidence of early pregnancy loss. Administration of the chemical chaperone, tauroursodeoxycholic acid, to Eif2s1+/tm1RjK heterozygous females during pregnancy alleviated ER stress in the mutant placenta, restored normal trophoblast populations and reduced the frequency of early pregnancy loss. Our results suggest that alleviation of intrauterine ER stress could provide a potential therapeutic target to improve pregnancy outcome in women with pre‐gestational metabolic or gynaecological conditions. Abstract Women…

Non-conventional N-methyl-d-aspartate receptors (NMDARs) containing GluN3A subunits have unique biophysical, signalling and localization properties within the NMDAR family, and are typically thought to counterbalance functions of classical NMDARs made up of GluN1/2 subunits. Beyond their recognized roles in synapse refinement during postnatal development, recent evidence is building a wider perspective for GluN3A functions. Here we draw particular attention to the latest developments for this multifaceted and unusual subunit: from finely timed expression patterns that correlate with plasticity windows in developing brains or functional hierarchies in the mature brain to new insight onto presynaptic GluN3A-NMDARs, excitatory glycine receptors and behavioural impacts, alongside further connections to a range of brain disorders.

Key points Patients with mild chronic obstructive pulmonary disease (COPD) have an elevated ventilatory equivalent to CO 2 production ( / ) during exercise, secondary to increased dead space ventilation. The reason for the increased dead space is unclear, although pulmonary microvascular dysfunction and the corresponding capillary hypoperfusion is a potential mechanism. Despite emerging evidence that mild COPD is associated with pulmonary microvascular dysfunction, limited research has focused on experimentally modulating the pulmonary microvasculature during exercise in mild COPD. The present study sought to examine the effect of inhaled nitric oxide (iNO), a selective pulmonary vasodilator, on / , dyspnoea and exercise capacity in patients with mild COPD. Experimental iNO increased peak oxygen uptake in mild COPD, secondary to reduced / and dyspnoea. This is the first study to demonstrate that experimental manipulation of the pulmonary circulation alone, can positively impact dyspnoea and exercise capacity in mild COPD. Abstract Patients with mild chronic obstructive pulmonary…

Key points Time‐restricted feeding (TRF, in which energy intake is restricted to 8 h/day during the dark phase) alone or combined with aerobic exercise (AE) training can prevent weight gain and metabolic disorders in Swiss mice fed a high‐fat diet. The benefits of TRF combined with AE are associated with improved hepatic metabolism and decreased hepatic lipid accumulation. TRF combined with AE training increased fatty acid oxidation and decreased expression of lipogenic and gluconeogenic genes in the liver of young male Swiss mice. TRF combined with AE training attenuated the detrimental effects of high‐fat diet feeding on the insulin signalling pathway in the liver. Abstract Time‐restricted feeding (TRF) or physical exercise have been shown to be efficient in the prevention and treatment of metabolic disorders; however, the additive effects of TRF combined with aerobic exercise (AE) training on liver metabolism have not been widely explored. In this study TRF (8 h in the active phase) and TRF combined with AE (TRF+Exe) were compared in male Swiss mice fed a high‐fat diet, with…

Abstract To determine the underlying mechanistic differences between diagnoses of Heart Failure (HF) and specifically heart failure with reduced and preserved ejection fraction (HFrEF & HFpEF), a closed loop model of the cardiovascular system coupled with patient specific transthoracic echocardiography (TTE) and right heart catheterization (RHC) measures was used to identify key parameters representing cardiovascular hemodynamics. Thirty-one patient records (10 HFrEF, 21 HFpEF) were obtained from the Cardiovascular Health Improvement Project (CHIP) database at the University of Michigan. Model simulations were tuned to match RHC and TTE pressure, volume and cardiac output measures in each patient with average error between data and model of 4.87 ± 2%. The underlying physiological model parameters were then plotted against model-based norms and compared between the HFrEF and HFpEF group. Our results confirm that the main mechanistic parameter driving HFrEF is reduced left ventricular contractility, while for HFpEF a much wider underlying phenotype is presented. Conducting principal…

There is a strict interaction between the autonomic nervous system (ANS) and pain, which might involve descending pain modulatory mechanisms. The periaqueductal grey (PAG) is involved both in descending pain modulation and ANS, but its role in mediating this relationship has not yet been explored. Here, we sought to determine brain regions mediating ANS and descending pain control associations. Thirty participants underwent conditioned pain modulation (CPM) assessments, in which they rated painful pressure stimuli applied to their thumbnail, either alone or with a painful cold contralateral stimulation. Differences in pain ratings between 'pressure-only' and 'pressure + cold' stimuli provided a measure of descending pain control. In 18 of the 30 participants, structural scans and two functional MRI assessments, one pain-free and one during cold-pain were acquired. Heart rate variability (HRV) was simultaneously recorded. Normalised low-frequency HRV (LF-HRVnu) and the CPM score were negatively correlated; individuals with higher LF-HRVnu during pain reported reductions in pain…

Abstract Oral supplementation of the NAD + precursor Nicotinamide Riboside (NR) has been reported to increase Sirtuin (SIRT) signalling, mitochondrial biogenesis and endurance capacity in rodent skeletal muscle. However, whether NR supplementation can elicit a similar response in human skeletal muscle is unclear. This study aimed to assess the effect of 7-day NR supplementation on exercise-induced transduction and transcriptional responses in skeletal muscle of young, healthy, recreationally active human volunteers. In a double-blinded, randomised, counter-balanced, crossover design, eight male participants (age: 23 ± 4 years, VO 2 peak: 46.5 ± 4.4 mL·kg -1 ·min -1 ) received one week of NR or cellulose placebo (PLA) supplementation (1000 mg·d -1 ) before performing one hour of cycling at 60% Wmax. Muscle biopsies were collected prior to supplementation and pre-, immediately and three-hours post-exercise from the medial vastus lateralis, whilst venous blood samples were collected throughout the trial. Global acetylation, auto-PARylation of PARP1, acetylation of p53 Lys382 and MnSOD…

Key points Sound information is transmitted by different subtypes of spiral ganglion neurons (SGN) from the ear to the brain. Selective damage of SGN peripheral synapses (cochlear synaptopathy) is widely recognized as one of the primary mechanisms of hearing loss, whereas the mechanisms at the SGN central synapses remain unclear. We report that different subtypes of SGN central synapses converge at different ratios onto individual target cochlear nucleus neurons with distinct physiological properties, and show biased morphological and physiological changes during age‐related hearing loss (ARHL). The results reveal a new dimension in cochlear nucleus neural circuitry that systematically reassembles and processes auditory information from different SGN subtypes, which is altered during ageing and probably contributes to the development of ARHL. In addition to known cochlear synaptopathy, the present study shows that SGN central synapses are also pathologically changed during ageing, which collectively helps us better understand the structure and function of SGNs during ARHL. Abstract…

Progressive improvements in perinatal care and respiratory management of preterm infants have resulted in increased survival of newborns of extremely low gestational age over the past few decades. However, the incidence of bronchopulmonary dysplasia, the chronic lung disease after preterm birth, has not changed. Studies of the long-term follow-up of adults born preterm have shown persistent abnormalities of respiratory, cardiovascular and cardiopulmonary function, possibly leading to a lower exercise capacity. The underlying causes of these abnormalities are incompletely known, but we hypothesize that dysanapsis, i.e. discordant growth and development, in the respiratory and cardiovascular systems is a central structural feature that leads to a lower exercise capacity in young adults born preterm than those born at term. We discuss how the hypothesized system dysanapsis underscores the observed respiratory, cardiovascular and cardiopulmonary limitations. Specifically, adults born preterm have: (1) normal lung volumes but smaller airways, which causes expiratory airflow limitation…

Abstract Although automated patch clamp (APC) devices have been around for many years and have become an integral part of many aspects of drug discovery, high throughput instruments with gigaohm seal data quality are relatively new. Experiments where a large number of compounds are screened against ion channels are ideally suited to high throughput APC, particularly when the amount of compound available is low. Here we evaluate different APC approaches using a variety of ion channels and screening settings. We have performed a screen of 1920 compounds on GluN1/GluN2A NMDA receptors for negative allosteric modulation using both the SyncroPatch 384 and FLIPR. Additionally, we tested the effect of 36 arthropod venoms on NaV1.9 using a single 384‐well plate on the SyncroPatch 384. As an example for mutant screening, a range of acid‐sensing ion channel variants were tested and the success rate increased through fluorescence‐activated cell sorting (FACS) prior to APC experiments. Gigaohm seal data quality makes the 384‐format accessible to recording of primary and stem cell‐derived cells…

KEY POINTS: Gait-related arm swing in humans supports efficient lower limb muscle activation, indicating a neural coupling between the upper and lower limbs during gait. Intermuscular coherence analyses of gait-related electromyography from upper and lower limbs in 20 healthy participants identified significant coherence in alpha and beta/gamma bands indicating that upper and lower limbs share common subcortical and cortical drivers that coordinate the rhythmic four-limb gait pattern. Additional directed connectivity analyses revealed that upper limb muscles drive and shape lower limb muscle activity during gait via subcortical and cortical pathways and to a lesser extent vice versa. The results provide a neural underpinning that arm swing may serve as an effective rehabilitation therapy concerning impaired gait in neurological diseases. ABSTRACT: Human gait benefits from arm swing, as it enhances efficient lower limb muscle activation in healthy participants as well as patients suffering from neurological impairment. The underlying neuronal mechanisms of such coupling between upper…

KEY POINTS: TMS is commonly used to study excitatory/inhibitory neurotransmission in cortical circuits. Changes in cortical excitability following TMS are typically measured from hand (using EMG; limited to motor cortex) or scalp (using EEG); however, it is unclear whether these two measures represent the same activity when assessing motor cortex. We found that TMS-EMG and TMS-EEG measures of motor cortex excitability are differentially affected by sensory confounds at different time points, masking any actual relationship between them in the time domain. In the frequency domain, local high-frequency oscillations in EEG recordings were minimally confounded by sensory artefacts and demonstrated strong correlations with EMG measures of cortical excitability across time, regardless of TMS intensity or waveform. Therefore, despite the effects of sensory artefacts, the two measures of motor cortex excitability share a response component, suggesting that they index a similar cortical activity and perhaps the same neuronal population. ABSTRACT: Transcranial magnetic stimulation (TMS) is a…

In recent years, the gut microbiota has been increasingly implicated in the development of many extraintestinal disorders, including neurodevelopmental and neurodegenerative disorders. Despite this growing connection, our understanding of the precise mechanisms behind these effects is currently lacking. Pattern recognition receptors (PRRs) are important innate immune proteins expressed on the surface and within the cytoplasm of a multitude of cells, both immune and otherwise, including epithelial, endothelial and neuronal. PRRs comprise four major subfamilies: the Toll-like receptors (TLRs), the nucleotide-binding oligomerization domain leucine rich repeats-containing receptors (NLRs), the retinoic acid inducible gene 1-like receptors and the C-type lectin receptors. Recognition of commensal bacteria by PRRs is critical for maintaining host-microbe interactions and homeostasis, including behaviour. The expression of PRRs on multiple cell types makes them a highly interesting and novel target for regulation of host-microbe signalling, which may lead to gut-brain signalling. Emerging…

Abstract Treatment of obesity with repurposed or novel drugs is an expanding research field. One approach is to target beta2‐adrenergic receptors because they regulate the metabolism and phenotype of adipose and skeletal muscle tissue. Several observations support a role for the beta2‐adrenergic receptor in obesity. Specific human beta2‐adrenergic receptor polymorphisms are associated with body composition and obesity, for which the Gln27Glu polymorphism is associated with obesity, while the Arg16Gly polymorphism is associated with lean mass in men and the development of obesity in specific populations. Individuals with obesity also have lower abundance of beta2‐adrenergic receptors in adipose tissue and are less sensitive to catecholamines. In addition, studies in livestock and rodents demonstrate that selective beta2‐agonists induce a so‐called ‘repartitioning effect’ characterized by muscle accretion and reduced fat deposition. In humans, beta2‐agonists dose‐dependently increase resting metabolic rate by 10–50%. And like that observed in other mammals, only a few weeks of…

Obesity is a medical disorder caused by multiple mechanisms of dysregulated energy balance. A major consequence of obesity is an increased risk to develop diabetes, diabetic complications and cardiovascular disease. While a better understanding of the molecular mechanisms linking obesity, insulin resistance and cardiovascular disease is needed, translational research of the human pathology is hampered by the available cellular and rodent model systems. Major barriers are the species-specific differences in energy balance, vascular biology and adipose tissue physiology, especially related to white and brown adipocytes, and adipose tissue browning. In rodents, non-shivering thermogenesis is responsible for a large part of energy expenditure, but humans possess much less thermogenic fat, which means temperature is an important variable in translational research. Mouse models with predisposition to dyslipidaemia housed at thermoneutrality and fed a high-fat diet more closely reflect human physiology. Also, adipocytes play a key role in the endocrine regulation of cardiovascular…

The number of people living with obesity has tripled worldwide since 1975 with serious implications for public health, as obesity is linked to a significantly higher chance of early death from associated comorbidities (metabolic syndrome, type 2 diabetes, cardiovascular disease and cancer). As obesity is a consequence of food intake exceeding the demands of energy expenditure, efforts are being made to better understand the homeostatic and hedonic mechanisms governing food intake. Gastrointestinal peptides are secreted from enteroendocrine cells in response to nutrient and energy intake, and modulate food intake either via afferent nerves, including the vagus nerve, or directly within the central nervous system, predominantly gaining access at circumventricular organs. Enteroendocrine hormones modulate homeostatic control centres at hypothalamic nuclei and the dorso-vagal complex. Additional roles of these peptides in modulating hedonic food intake and/or preference via the neural systems of reward are starting to be elucidated, with both peripheral and central peptide sources…