The 50 most-cited articles in The Journal of Physiology, 2019

KEY POINTS: Previous studies have indicated that several weeks of strength training is sufficient to elicit significant adaptations in the neural drive sent to the muscles. There are few data, however, on the changes elicited by strength training in the recruitment and rate coding of motor units during voluntary contractions. We show for the first time that the discharge characteristics of motor units in the tibialis anterior muscle tracked across the intervention are changed by 4 weeks of strength training with isometric voluntary contractions. The specific adaptations included significant increases in motor unit discharge rate, decreases in the recruitment-threshold force of motor units and a similar input-output gain of the motor neurons. The findings suggest that the adaptations in motor unit function may be attributable to changes in synaptic input to the motor neuron pool or to adaptations in intrinsic motor neuron properties. ABSTRACT: The strength of a muscle typically begins to increase after only a few sessions of strength training. This increase is usually attributed to…

Key points We propose and validate a method for accurately identifying the activity of populations of motor neurons during contractions at maximal rate of force development in humans. The behaviour of the motor neuron pool during rapid voluntary contractions in humans is presented. We show with this approach that the motor neuron recruitment speed and maximal motor unit discharge rate largely explains the individual ability in generating rapid force contractions. The results also indicate that the synaptic inputs received by the motor neurons before force is generated dictate human potential to generate force rapidly. This is the first characterization of the discharge behaviour of a representative sample of human motor neurons during rapid contractions. Abstract During rapid contractions, motor neurons are recruited in a short burst and begin to discharge at high frequencies (up to >200 Hz). In the present study, we investigated the behaviour of relatively large populations of motor neurons during rapid (explosive) contractions in humans, applying a new approach to accurately…

Mitochondrial health is an important mediator of cellular function across a range of tissues, and as a result contributes to whole-body vitality in health and disease. Our understanding of the regulation and function of these organelles is of great interest to scientists and clinicians across many disciplines within our healthcare system. Skeletal muscle is a useful model tissue for the study of mitochondrial adaptations because of its mass and contribution to whole body metabolism. The remarkable plasticity of mitochondria allows them to adjust their volume, structure and capacity under conditions such as exercise, which is useful or improving metabolic health in individuals with various diseases and/or advancing age. Mitochondria exist within muscle as a functional reticulum which is maintained by dynamic processes of biogenesis and fusion, and is balanced by opposing processes of fission and mitophagy. The sophisticated coordination of these events is incompletely understood, but is imperative for organelle function and essential for the maintenance of an interconnected organelle…

The prevalence of obesity, insulin resistance and diabetes is increasing rapidly. Most patients with these disorders have hypertriglyceridaemia and increased plasma levels of fatty acids, which are taken up and stored in lipid droplets in the heart. Intramyocardial lipids that exceed the capacity for storage and oxidation can be lipotoxic and induce non-ischaemic and non-hypertensive cardiomyopathy, termed diabetic or lipotoxic cardiomyopathy. The clinical features of diabetic cardiomyopathy are cardiac hypertrophy and diastolic dysfunction, which lead to heart failure, especially heart failure with preserved ejection fraction. Although the pathogenesis of the cardiomyopathy is multifactorial, diabetic dyslipidaemia and intramyocardial lipid accumulation are the key pathological features, triggering cellular signalling and modifications of proteins and lipids via generation of toxic metabolic intermediates. Most clinical studies have shown no beneficial effect of anti-diabetic agents and statins on outcomes in heart failure patients without atherosclerotic diseases, indicating the…

KEY POINTS: Exercise elicits circadian phase-shifting effects, but additional information is needed. The phase-response curve describing the magnitude and direction of circadian rhythm phase shifts, depending on the time of the zeigeber (time cue) stimulus, is the most fundamental chronobiological tool for alleviating circadian misalignment and related morbidity. Fifty-one older and 48 young adults followed a circadian rhythms measurement protocol for up to 5.5 days, and performed 1 h of moderate treadmill exercise for 3 consecutive days at one of eight times of the day/night. Temporal changes in the phase of 6-sulphatoxymelatonin (aMT6s) were measured from evening onset, cosine acrophase, morning offset and duration of excretion. Significant phase-response curves were established for aMT6 onset and acrophase with large phase delays from 7:00 pm to 10:00 pm and large phase advances at both 7:00 am and from 1:00 pm to 4:00 pm. Delays or advances would be desired, for example, for adjustment to westward or eastward air travel, respectively. Along with known synergism with bright…

Cardiovascular diseases (CVD) remain the leading cause of morbidity and mortality in both men and women in developed societies. Age is the greatest risk factor for CVD due largely to adverse changes to arteries that include stiffening of the large elastic arteries (aortic and carotid arteries) and endothelial dysfunction. Vascular ageing is driven by oxidative stress, which reduces nitric oxide (NO) bioavailability and stimulates changes in the extracellular matrix. In women, reductions in circulating oestrogens with menopause interact with ageing processes to induce vascular dysfunction. Regular aerobic exercise is the most evidence-based strategy for reducing CVD risk with ageing in both men and women. Much of this cardiovascular-protective effect of aerobic exercise is likely due to its vascular health-enhancing influence. Large elastic artery stiffening with advancing age is attenuated in healthy adults engaged in aerobic exercise training, and aerobic exercise interventions improve arterial stiffness in previously sedentary middle-aged and older men and postmenopausal women.…

Key points Age‐related arterial dysfunction, characterized by oxidative stress‐ and inflammation‐mediated endothelial dysfunction and arterial stiffening, is the primary risk factor for cardiovascular diseases. To investigate whether age‐related changes in the gut microbiome may mediate arterial dysfunction, we suppressed gut microbiota in young and old mice with a cocktail of broad‐spectrum, poorly‐absorbed antibiotics in drinking water for 3–4 weeks. In old mice, antibiotic treatment reversed endothelial dysfunction and arterial stiffening and attenuated vascular oxidative stress and inflammation. To provide insight into age‐related changes in gut microbiota that may underlie these observations, we show that ageing altered the abundance of microbial taxa associated with gut dysbiosis and increased plasma levels of the adverse gut‐derived metabolite trimethylamine N ‐oxide. The results of the present study provide the first proof‐of‐concept evidence that the gut microbiome is an important mediator of age‐related arterial dysfunction and therefore may be a promising therapeutic…

Air pollution is associated with detrimental effects on human health, including decreased cardiovascular function. However, the causative mechanisms behind these effects have yet to be fully elucidated. Here we review the current epidemiological, clinical and experimental evidence linking pollution with cardiovascular dysfunction. Our focus is on particulate matter (PM) and the associated low molecular weight polycyclic aromatic hydrocarbons (PAHs) as key mediators of cardiotoxicity. We begin by reviewing the growing epidemiological evidence linking air pollution to cardiovascular dysfunction in humans. We next address the pollution-based cardiotoxic mechanisms first identified in fish following the release of large quantities of PAHs into the marine environment from point oil spills (e.g. Deepwater Horizon). We finish by discussing the current state of mechanistic knowledge linking PM and PAH exposure to mammalian cardiovascular patho-physiologies such as atherosclerosis, cardiac hypertrophy, arrhythmias, contractile dysfunction and the underlying alterations in gene regulation.…

The crosstalk between endothelial cells and cardiomyocytes has emerged as a requisite for normal cardiac development, but also a key pathogenic player during the onset and progression of cardiac disease. Endothelial cells and cardiomyocytes are in close proximity and communicate through the secretion of paracrine signals, as well as through direct cell-to-cell contact. Here, we provide an overview of the endothelial cell-cardiomyocyte interactions controlling heart development and the main processes affecting the heart in normal and pathological conditions, including ischaemia, remodelling and metabolic dysfunction. We also discuss the possible role of these interactions in cardiac regeneration and encourage the further improvement of in vitro models able to reproduce the complex environment of the cardiac tissue, in order to better define the mechanisms by which endothelial cells and cardiomyocytes interact with a final aim of developing novel therapeutic opportunities.

KEY POINTS: Females demonstrate greater fatigue resistance than males during contractions at intensities relative to maximum force. However, previous studies have not accounted for the influence of metabolic thresholds on fatigability. This study is the first to test whether sex differences in fatigability exist when exercise intensity is normalised relative to a metabolic threshold: the critical intensity derived from assessment of the intensity-duration relationship during intermittent, isometric knee extensor contractions. We show that critical intensity in females occurred at a higher percentage of maximum force compared to males. Furthermore, females demonstrated greater fatigue resistance at exercise intensities above and below this metabolic threshold. Our data suggest that the sex difference was mediated by lesser deoxygenation of the knee extensors during exercise. These data highlight the importance of accounting for metabolic thresholds when comparing fatigability between sexes, whilst emphasising the notion that male data are not generalisable to female populations.…

The application of neuromuscular electrical stimulation (NMES) to paretic limbs has demonstrated utility for motor rehabilitation following brain injury. When NMES is delivered to a mixed peripheral nerve, typically both efferent and afferent fibres are recruited. Muscle contractions brought about by the excitation of motor neurons are often used to compensate for disability by assisting actions such as the formation of hand aperture, or by preventing others including foot drop. In this context, exogenous stimulation provides a direct substitute for endogenous neural drive. The goal of the present narrative review is to describe the means through which NMES may also promote sustained adaptations within central motor pathways, leading ultimately to increases in (intrinsic) functional capacity. There is an obvious practical motivation, in that detailed knowledge concerning the mechanisms of adaptation has the potential to inform neurorehabilitation practice. In addition, responses to NMES provide a means of studying CNS plasticity at a systems level in humans. We summarize the…

Key points This is the first long‐term human clinical trial to report on effects of nicotinamide riboside (NR) on skeletal muscle mitochondrial function, content and morphology. NR supplementation decreases nicotinamide phosphoribosyltransferase (NAMPT) protein abundance in skeletal muscle. NR supplementation does not affect NAD metabolite concentrations in skeletal muscle. Respiration, distribution and quantity of muscle mitochondria are unaffected by NR. NAMPT in skeletal muscle correlates positively with oxidative phosphorylation Complex I, sirtuin 3 and succinate dehydrogenase. Abstract Preclinical evidence suggests that the nicotinamide adenine dinucleotide (NAD + ) precursor nicotinamide riboside (NR) boosts NAD + levels and improves diseases associated with mitochondrial dysfunction. We aimed to determine if dietary NR supplementation in middle‐aged, obese, insulin‐resistant men affects mitochondrial respiration, content and morphology in skeletal muscle. In a randomized, placebo‐controlled clinical trial, 40 participants received 1000 mg NR or placebo twice daily for 12…

Key points In a cold environment, mammals increase their food intake while fish decrease or stop feeding. However, the physiological value of fasting during cold resistance in fish is currently unknown. Fasting for more than 48 h enhanced acute cold resistance in zebrafish, which correlated with lipid catabolism and cell damage attenuation. Lipid catabolism and autophagy were necessary for cold resistance in fish and the inhibition of mitochondrial fatty acid β‐oxidation or autophagy weakened the fasting‐induced cold resistance. Repression of mechanistic target of rapamycin (mTOR) signalling pathway by rapamycin largely mimicked the beneficial effects of fasting in promoting cold resistance, suggesting mTOR signalling may be involved in the fasting‐induced cold resistance in fish. Our study demonstrates that fasting may be a protective strategy for fish to survive under cold stress. Abstract In cold environments, most homeothermic animals increase their food intake to supply more energy to maintain body temperature, whereas most poikilothermic animals such as fishes decrease or even…

KEY POINTS: Performing resistance exercise with heavier loads is often proposed to be necessary for the recruitment of larger motor units and activation of type II muscle fibres, leading to type II fibre hypertrophy. Indirect measures [surface electromyography (EMG)] have been used to support this thesis, although we propose that lighter loads lifted to task failure (i.e. volitional fatigue) result in the similar activation of type II fibres. In the present study, participants performed resistance exercise to task failure with heavier and lighter loads with both a normal and longer repetition duration (i.e. time under tension). Type I and type II muscle fibre glycogen depletion was determined by neither load, nor repetition duration during resistance exercise performed to task failure. Surface EMG amplitude was not related to muscle fibre glycogen depletion or anabolic signalling; however, muscle fibre glycogen depletion and anabolic signalling were related. Performing resistance exercise to task failure, regardless of load lifted or repetition duration, necessitates the activation…

KEY POINTS: The main cause of death from opioid overdose is respiratory depression due to the activation of µ-opioid receptors (MORs). We conditionally deleted MORs from neurons in two key areas of the brainstem respiratory circuitry (the Kölliker-Fuse nucleus (KF) and pre-Bötzinger complex (preBötC)) to determine their role in opioid-induced respiratory disturbances in adult, awake mice. Deletion of MORs from KF neurons attenuated respiratory rate depression at all doses of morphine. Deletion of MORs from preBötC neurons attenuated rate depression at the low dose, but had no effect on rate following high doses of morphine. Instead, high doses of morphine increased the occurrence of apnoeas. The results indicate that opioids affect distributed key areas of the respiratory network in a dose-dependent manner and countering the respiratory effects of high dose opioids via the KF may be an effective approach to combat overdose. ABSTRACT: The primary cause of death from opioid overdose is respiratory failure. High doses of opioids cause severe rate depression and increased risk of fatal…

KEY POINTS: Non-alcoholic fatty liver disease, characterized in part by elevated liver triglycerides (i.e. hepatic steatosis), is a growing health problem. In this study, we found that hepatic steatosis is associated with robust hepatic sympathetic overactivity. Removal of hepatic sympathetic nerves reduced obesity-induced hepatic steatosis. Liver sympathetic innervation modulated hepatic lipid acquisition pathways during obesity. ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) affects 1 in 3 Americans and is a significant risk factor for type II diabetes mellitus, insulin resistance and hepatic carcinoma. Characterized in part by excessive hepatic triglyceride accumulation (i.e. hepatic steatosis), the incidence of NAFLD is increasing - in line with the growing obesity epidemic. The role of the autonomic nervous system in NAFLD remains unclear. Here, we show that chronic hepatic sympathetic overactivity mediates hepatic steatosis. Direct multiunit recordings of hepatic sympathetic nerve activity were obtained in high fat diet and normal chow fed male C57BL/6J mice. To reduce…

KEY POINTS: Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) capture patient-specific genotype-phenotype relationships, as well as cell-to-cell variability of cardiac electrical activity Computational modelling and simulation provide a high throughput approach to reconcile multiple datasets describing physiological variability, and also identify vulnerable parameter regimes We have developed a whole-cell model of iPSC-CMs, composed of single exponential voltage-dependent gating variable rate constants, parameterized to fit experimental iPSC-CM outputs We have utilized experimental data across multiple laboratories to model experimental variability and investigate subcellular phenotypic mechanisms in iPSC-CMs This framework links molecular mechanisms to cellular-level outputs by revealing unique subsets of model parameters linked to known iPSC-CM phenotypes ABSTRACT: There is a profound need to develop a strategy for predicting patient-to-patient vulnerability in the emergence of cardiac arrhythmia. A promising in vitro method to address patient-specific proclivity to…

KEY POINTS: Maternal obesity has been associated with shifts in intestinal microbiota, which may contribute to impaired barrier function Impaired barrier function may expose the placenta and fetus to pro-inflammatory mediators We investigated the impacts of diet-induced obesity in mice on maternal and fetal intestinal structure and placental vascularization Diet-induced obesity decreased maternal intestinal short chain fatty acids and their receptors, impaired gut barrier integrity and was associated with fetal intestinal inflammation. Placenta from obese mothers showed blood vessel immaturity, hypoxia, increased transcript levels of inflammation, autophagy and altered levels of endoplasmic reticulum stress markers. These data suggest that maternal intestinal changes probably contribute to adverse placental adaptations and also impart an increased risk of obesity in the offspring via alterations in fetal gut development. ABSTRACT: Shifts in maternal intestinal microbiota have been implicated in metabolic adaptations to pregnancy. In the present study, we generated cohorts of female…

Key points This work confirms previous reports that CM4620, a small molecule inhibitor of Ca2+ entry via store operated Ca2+ entry (SOCE) channels formed by stromal interaction molecule 1 (STIM1)/Orai complexes, attenuates acinar cell pathology and acute pancreatitis in mouse experimental models. Here we report that intravenous administration of CM4620 reduces the severity of acute pancreatitis in the rat, a hitherto untested species. Using CM4620, we probe further the mechanisms whereby SOCE via STIM1/Orai complexes contributes to the disease in pancreatic acinar cells, supporting a role for endoplasmic reticulum stress/cell death pathways in these cells. Using CM4620, we show that SOCE via STIM1/Orai complexes promotes neutrophil oxidative burst and inflammatory gene expression during acute pancreatitis, including in immune cells which may be either circulating or invading the pancreas. Using CM4620, we show that SOCE via STIM1/Orai complexes promotes activation and fibroinflammatory gene expression within pancreatic stellate cells. Abstract Key features of acute pancreatitis…

KEY POINTS: Recent evidence suggests that impaired mitophagy, a process in charge of removing damaged/dysfunctional mitochondria and in part regulated by Parkin, could contribute to the ageing-related loss of muscle mass and function. In the present study, we show that Parkin overexpression attenuates ageing-related loss of muscle mass and strength and unexpectedly causes hypertrophy in adult skeletal muscles. We also show that Parkin overexpression leads to increases in mitochondrial content and enzymatic activities. Finally, our results show that Parkin overexpression protects from ageing-related increases in markers of oxidative stress, fibrosis and apoptosis. Our findings place Parkin as a potential therapeutic target to attenuate sarcopenia and improve skeletal muscle health and performance. ABSTRACT: The ageing-related loss of muscle mass and strength, a process called sarcopenia, is one of the most deleterious hallmarks of ageing. Solid experimental evidence indicates that mitochondrial dysfunctions accumulate with ageing and are critical in the sarcopenic process. Recent…

KEY POINTS: Nitric oxide (NO), a potent vasodilator and a regulator of many physiological processes, is produced in mammals both enzymatically and by reduction of nitrite and nitrate ions. We have previously reported that, in rodents, skeletal muscle serves as a nitrate reservoir, with nitrate levels greatly exceeding those in blood or other internal organs, and with nitrate being reduced to NO during exercise. In the current study, we show that nitrate concentration is substantially greater in skeletal muscle than in blood and is elevated further by dietary nitrate ingestion in human volunteers. We also show that high-intensity exercise results in a reduction in the skeletal muscle nitrate store following supplementation, likely as a consequence of its reduction to nitrite and NO. We also report the presence of sialin, a nitrate transporter, and xanthine oxidoreductase in human skeletal muscle, indicating that muscle has the necessary apparatus for nitrate transport, storage and metabolism. ABSTRACT: Rodent skeletal muscle contains a large store of nitrate that can be augmented by…

KEY POINTS: Overload training is required for sustained performance gain in athletes (functional overreaching). However, excess overload may result in a catabolic state which causes performance decrements for weeks (non-functional overreaching) up to months (overtraining). Blood ketone bodies can attenuate training- or fasting-induced catabolic events. Therefore, we investigated whether increasing blood ketone levels by oral ketone ester (KE) intake can protect against endurance training-induced overreaching. We show for the first time that KE intake following exercise markedly blunts the development of physiological symptoms indicating overreaching, and at the same time significantly enhances endurance exercise performance. We provide preliminary data to indicate that growth differentiation factor 15 (GDF15) may be a relevant hormonal marker to diagnose the development of overtraining. Collectively, our data indicate that ketone ester intake is a potent nutritional strategy to prevent the development of non-functional overreaching and to stimulate endurance exercise performance.…

Heart failure (HF) is a complex clinical syndrome affecting roughly 26 million people worldwide. Increased sympathetic drive is a hallmark of HF and is associated with disease progression and higher mortality risk. Several mechanisms contribute to enhanced sympathetic activity in HF, but these pathways are still incompletely understood. Previous work suggests that inflammation and activation of the renin-angiotensin system (RAS) increases sympathetic drive. Importantly, chronic inflammation in several brain regions is commonly observed in aged populations, and a growing body of evidence suggests neuroinflammation plays a crucial role in HF. In animal models of HF, central inhibition of RAS and pro-inflammatory cytokines normalizes sympathetic drive and improves cardiac function. The precise molecular and cellular mechanisms that lead to neuroinflammation and its effect on HF progression remain undetermined. This review summarizes the most recent advances in the field of neuroinflammation and autonomic control in HF. In addition, it focuses on cellular and molecular mediators of…

Abstract Astrocytes are homeostatic and protective cells of the central nervous system. Astroglial homeostatic responses are tightly coordinated with neuronal activity. Astrocytes maintain neuronal excitability through regulation of extracellular ion concentrations, as well as assisting and modulating synaptic transmission by uptake and catabolism of major neurotransmitters. Moreover, they support neuronal metabolism and detoxify ammonium and reactive oxygen species. Astroglial homeostatic actions are initiated and controlled by intercellular signalling of ions, including Ca2+, Na+, Cl−, H+ and possibly K+. This review summarises current knowledge on ionic signals mediated by the major monovalent ions, which occur in microdomains, as global events, or as propagating intercellular waves and thereby represent the substrate for astroglial excitability. image

Key points For individuals showing suboptimal adaptations to resistance training, manipulation of training volume is a potential measure to facilitate responses. This remains unexplored. Here, 34 untrained individuals performed contralateral resistance training with moderate and low volume for 12 weeks. Moderate volume led to larger increases in muscle cross‐sectional area, strength and type II fibre‐type transitions. These changes coincided with greater activation of signalling pathways controlling muscle growth and greater induction of ribosome synthesis. Out of 34 participants, thirteen displayed clear benefit of MOD on muscle hypertrophy and sixteen showed clear benefit of MOD on muscle strength gains. This coincided with greater total RNA accumulation in the early phase of the training period, suggesting that ribosomal biogenesis regulates the dose–response relationship between training volume and muscle hypertrophy. These results demonstrate that there is a dose‐dependent relationship between training volume and outcomes. On the individual level, benefits of higher training…

Funder: \n British Heart Foundation\n https://doi.org/10.13039/501100000274

KEY POINTS: Women with polycystic ovary syndrome (PCOS) commonly suffer from miscarriage, but the underlying mechanisms remain unknown. Herein, pregnant rats chronically treated with 5α-dihydrotestosterone (DHT) and insulin exhibited hyperandrogenism and insulin resistance, as well as increased fetal loss, and these features are strikingly similar to those observed in pregnant PCOS patients. Fetal loss in our DHT+insulin-treated pregnant rats was associated with mitochondrial dysfunction, disturbed superoxide dismutase 1 and Keap1/Nrf2 antioxidant responses, over-production of reactive oxygen species (ROS) and impaired formation of the placenta. Chronic treatment of pregnant rats with DHT or insulin alone indicated that DHT triggered many of the molecular pathways leading to placental abnormalities and fetal loss, whereas insulin often exerted distinct effects on placental gene expression compared to co-treatment with DHT and insulin. Treatment of DHT+insulin-treated pregnant rats with the antioxidant N-acetylcysteine improved fetal survival but was deleterious in normal pregnant…

KEY POINTS: In people or animals with incomplete spinal cord injury (SCI), changing a spinal reflex through an operant conditioning protocol can improve locomotion. All previous studies conditioned the reflex during steady-state maintenance of a specific posture. By contrast, the present study down-conditioned the reflex during the swing-phase of locomotion in people with hyperreflexia as a result of chronic incomplete SCI. The aim was to modify the functioning of the reflex in a specific phase of a dynamic movement. This novel swing-phase conditioning protocol decreased the reflex much faster and farther than did the steady-state protocol in people or animals with or without SCI, and it also improved locomotion. The reflex decrease persisted for at least 6 months after conditioning ended. The results suggest that conditioning reflex function in a specific phase of a dynamic movement offers a new approach to enhancing and/or accelerating recovery after SCI or in other disorders. ABSTRACT: In animals and people with incomplete spinal cord injury, appropriate operant conditioning of a…

KEY POINTS: Mice are commonly housed at room temperatures below their thermoneutral zone meaning they are exposed to chronic thermal stress. Endurance exercise induces browning and mitochondrial biogenesis in white adipose tissue of rodents, but there are conflicting reports of this phenomenon in humans. We hypothesized that the ambient room temperature at which mice are housed could partially explain these discrepant reports between humans and rodents. We housed mice at room temperature or thermoneutrality and studied their physiological responses to acute and chronic exercise. We found that thermoneutral housing altered running behaviour and glucose homeostasis, and further, that exercise-induced markers of mitochondrial biogenesis and the browning of white adipose tissue were reduced in mice housed at thermoneutrality. ABSTRACT: Mice are often housed at temperatures below their thermoneutral zone resulting in compensatory increases in thermogenesis. Despite this, many studies report housing mice at room temperature (RT), likely for the convenience of the researchers studying…

Abstract This review considers the physiological basis of brief vigorous exercise to improve health, with a focus on cardiorespiratory fitness (CRF) and glycaemic control, and the potential underlying mechanisms involved. We defined ‘brief’ as a protocol lasting ≤15 min including warm‐up, cool‐down and recovery, and involving a total of ≤5 min of ‘vigorous’ exercise, which was classified as meeting or exceeding the lower end of the range for this relative intensity as per the criteria from the American College of Sports Medicine. The physiological mechanisms responsible for the increase in CRF, as measured by maximal oxygen update ( ), after brief vigorous exercise are unclear and likely depend on various factors including the specific nature of the intervention as well as the time course of the response. Limited available evidence suggests the potential for an increased oxygen extraction by active muscle (i.e. greater arterio‐venous oxygen difference), since an increase in has been reported after several weeks of brief vigorous exercise despite no measurable change in cardiac…

KEY POINTS: Maternal exercise improves the metabolic health of maternal mice challenged with a high-fat diet. Exercise intervention of obese mothers prevents fetal overgrowth. Exercise intervention reverses impaired placental vascularization in obese mice. Maternal exercise activates placental AMP-activated protein kinase, which was inhibited as a result of maternal obesity. ABSTRACT: More than one-third of pregnant women in the USA are obese and maternal obesity (MO) negatively affects fetal development, which predisposes offspring to metabolic diseases. The placenta mediates nutrient delivery to fetuses and its function is impaired as a result of MO. Exercise ameliorates metabolic dysfunction resulting from obesity, although its effect on placental function of obese mothers has not been explored. In the present study, C57BL/6J female mice were randomly assigned into two groups fed either a control or a high-fat diet (HFD) and then the mice on each diet were further divided into two subgroups with/without exercise. In HFD-induced obese mice, daily treadmill exercise during…

Key points Polycystic ovary syndrome (PCOS) is a complex syndrome with cardiovascular risk factors, including obesity and insulin resistance. PCOS is also associated with high androgens, increases the risk of cardiovascular dysfunction in women. Due to the complexity of PCOS, had it has been challenging to isolate specific causes of the cardiovascular dysfunction. Our measure of cardiovascular dysfunction (endothelial dysfunction) was most profound in lean women with PCOS. The endothelin‐1‐induced vasodilation in these PCOS subject, was dependent on the ET B R but was not NO‐dependent. We also demonstrated oestrogen administration improved endothelial function in lean and obese women with PCOS likely because oestrogen increased NO availability. Our studies indicate a primary role for androgens in cardiovascular dysfunction in PCOS. Abstract Endothelin‐1 (ET‐1) is an indicator of endothelial injury and dysfunction and is elevated in women with androgen excess polycystic ovary syndrome (AE‐PCOS). The endothelin B receptor (ET B R) subtype mediates vasodilatation, but is blunted in…

The past decade has witnessed growing scientific and commercial interest in the identification of bioactive oral compounds that mimic or potentiate the effects of exercise, so-called 'exercise pills' or 'exercise mimetics.' These compounds have, to date, typically targeted skeletal muscle in an attempt to stimulate some of the adaptations to exercise induced by endurance training. Accordingly, they fail to impart many of the broad health protecting effects of exercise that are seen in tissues and organs other than skeletal muscle. In the context that multiple integrative regulatory and often redundant pathways have evolved to detect and respond to human movement, here we consider the complex challenges of designing a pill that might mimic the extensive range of exercise benefits. In particular, we consider the limits of the current 'myocentric' paradigm given the wide-ranging array of impacts that exercise exerts on atherosclerosis and the cardiovascular system. We discuss the validity and limitations of the concept that low dose cardiovascular polypills, already in large scale…

Women show a lower incidence of cardiovascular diseases than age-matched men, but this benefit disappears after menopause. Oestrogen-mediated vascular actions are mainly attributed to oestradiol and exerted by oestrogen receptors (ERα, ERβ and G protein-coupled oestrogen receptor), through rapid and/or genomic mechanisms, but these effects depend on ageing and inflammation. A cardiovascular approach in women's health has arisen due to controversy regarding oestrogen's beneficial impact as reported in experimental and observational studies and large randomized trials. These can be explained, in part, by two mutually non-exclusive hypotheses. On the one hand, the timing hypothesis, which states that oestrogen-mediated benefits occur before the detrimental effects of ageing are established in the vasculature; on the other hand, ageing and/or hormonal-associated changes in ER expression that could lead to a deleterious imbalance in favour of ERβ over ERα, generally associated with higher inflammation and endothelial dysfunction. In experimental studies, oestradiol acting on ERα promotes…

KEY POINTS: Susceptibility to age-related muscle atrophy relates to the degree of muscle denervation and the capacity of successful reinnervation. However, the specific role of denervation as a determinant of the severity of muscle aging between populations with low versus high physical function has not been addressed. We show that prefrail/frail elderly women exhibited marked features of muscle denervation, whereas world class octogenarian female master athletes showed attenuated indices of denervation and greater reinnervation capacity. These findings suggest that the difference in age-related muscle impact between low- and high-functioning elderly women is the robustness of the response to denervation of myofibers. ABSTRACT: Ageing muscle degeneration is a key contributor to physical frailty; however, the factors responsible for exacerbated vs. muted ageing muscle impact are largely unknown. Based upon evidence that susceptibility to neurogenic impact is an important determinant of the severity of ageing muscle degeneration, we aimed to determine the presence and extent of…

Abstract We examined if blood flow restriction (BFR) would augment training-induced improvements in muscle K + handling and performance during intense exercise in men, and if these adaptations would be associated with an effect of muscle antioxidant function on thigh K + release and with fibre type-dependent modulation of Na + ,K + -ATPase-isoform abundance and FXYD1 phosphorylation. Ten recreationally-active men (25 ± 4 y, 49.7 ± 5.3 mL∙kg -1 ∙min -1 ) performed 6 weeks of interval cycling, where one leg trained without (control; CON-leg) and the other leg with BFR (BFR-leg, pressure: 178 mmHg). Before and after training, catheters were inserted into the femoral artery and vein, and blood flow was assessed during single-leg knee-extensions at 25% (Ex1) and 90% of leg peak aerobic power (Ex2) with intravenous infusion of N-acetylcysteine (NAC) or saline (placebo), and a resting muscle biopsy was collected. After training, performance during exhaustive exercise increased to a greater extent in BFR-leg (23%) than in CON-leg (12%, p<0.05), whereas thigh K + release during Ex2 was…

KEY POINTS: The neuromotor system generates flexible motor patterns that can adapt to changes in our bodies or environment and also take advantage of assistance provided by the environment. We ask how energy minimization influences adaptive learning during human locomotion to improve economy when walking on a split-belt treadmill. We use a model-based approach to predict how people should adjust their walking pattern to take advantage of the assistance provided by the treadmill, and we validate these predictions empirically. We show that adaptation to a split-belt treadmill can be explained as a process by which people reduce step length asymmetry to take advantage of the work performed by the treadmill to reduce metabolic cost. Our results also have implications for the evaluation of devices designed to reduce effort during walking, as locomotor adaptation may serve as a model approach to understand how people learn to take advantage of external assistance. ABSTRACT: In everyday tasks such as walking and running, we often exploit the work performed by external sources to reduce…

Key points Inappropriate intake of key micronutrients in pregnancy is known to alter maternal endocrine status, impair placental development and induce fetal growth restriction. Selenium is an essential micronutrient required for the function of approximately 25 important proteins. However, the specific effects of selenium deficiency during pregnancy on maternal, placental and fetal outcomes are poorly understood. The present study demonstrates that maternal selenium deficiency increases maternal triiodothyronine and tetraiodothyronine concentrations, reduces fetal blood glucose concentrations, and induces fetal growth restriction. Placental expression of key selenium‐dependent thyroid hormone converting enzymes were reduced, whereas the expression of key placental nutrient transporters was dysregulated. Selenium deficiency had minimal impact on selenium‐dependent anti‐oxidants but increased placental copper concentrations and expression of superoxide dismutase 1. These results highlight the idea that selenium deficiency during pregnancy may contribute to thyroid dysfunction,…

KEY POINTS: Two groups of inexperienced brain-computer interface users underwent a purely mental EEG-BCI session that rapidly impacted on their brain. Modulations in structural and functional MRI were found after only 1 h of BCI training. Two different types of BCI (based on motor imagery or visually evoked potentials) were employed and analyses showed that the brain plastic changes are spatially specific for the respective neurofeedback. This spatial specificity promises tailored therapeutic interventions (e.g. for stroke patients). ABSTRACT: A brain-computer-interface (BCI) allows humans to control computational devices using only neural signals. However, it is still an open question, whether performing BCI also impacts on the brain itself, i.e. whether brain plasticity is induced. Here, we show rapid and spatially specific signs of brain plasticity measured with functional and structural MRI after only 1 h of purely mental BCI training in BCI-naive subjects. We employed two BCI approaches with neurofeedback based on (i) modulations of EEG rhythms by motor imagery (MI-BCI) or (ii)…

The 'glymphatic' system is a brain-wide network of perivascular pathways that supports exchange of cerebrospinal fluid (CSF) and brain interstitial fluid (ISF), contributing to the efflux of interstitial solutes including amyloid β (Iliff et al., 2012, 2013a,b). Importantly, this pathway emphasizes a role for astrocytes and the water channel aquaporin-4 (AQP4) in facilitating this exchange, setting it apart from earlier descriptions of perivascular clearance (Rennels et al., 1985). Since its initial characterization in 2012, it has garnered much attention and controversy, including a recent critique (Smith et al., 2017) centered on two discrete elements of the glymphatic system as it was initially described: (1) the occurrence of interstitial bulk flow and (2) the dependence of perivascular CSF–ISF exchange upon the AQP4. Here, we will elaborate the evidence supporting and opposing these points of controversy. Solute movement in tissue occurs principally by two processes: diffusion, thermally driven movement of solutes down their concentration gradients; and bulk flow, solute motion…

KEY POINTS: Physical activity is associated with reduced mortality rates for survivors of colorectal cancer. Acute high intensity interval exercise (HIIE) reduced colon cancer cell number in vitro and promoted increases in inflammatory cytokines immediately following exercise. This acute suppression of colon cancer cell number was transient and not observed at 120 minutes post-acute HIIE. The acute effects of exercise may constitute an important mechanism by which exercise can influence colorectal cancer outcomes. ABSTRACT: Physical activity is associated with significant reductions in colorectal cancer mortality. However, the mechanisms by which exercise mediates this anti-oncogenic effect are not clear. In the present study, colorectal cancer survivors completed acute (n = 10) or chronic (n = 10) exercise regimes. An acute high intensity interval exercise session (HIIE; 4 × 4 min at 85-95% peak heart rate) was completed with serum samples collected at baseline, as well as 0 and 120 min post-exercise. For the 'chronic' intervention, resting serum was sampled before and after 4…

Key points Triheteromeric NMDA receptors contain two GluN1 and two distinct GluN2 subunits and mediate excitatory neurotransmission in the CNS. Triheteromeric GluN1/2B/2D receptors have functional properties intermediate to those of diheteromeric GluN1/2B and GluN1/2D receptors. GluN1/2B/2D receptors are more sensitive to channel blockade by ketamine and memantine compared to GluN1/2B receptors in the presence of physiological Mg2+. GluN2B‐selective antagonists produce robust inhibition of GluN1/2B/2D receptors, and the GluN2B‐selective positive allosteric modulator spermine enhances responses from GluN1/2B/2D but not GluN1/2A/2B receptors. These insights into the properties of triheteromeric GluN1/2B/2D receptors are necessary to appreciate their physiological roles in neural circuit function and the actions of therapeutic agents targeting NMDA receptors. Abstract Triheteromeric NMDA‐type glutamate receptors that contain two GluN1 and two different GluN2 subunits contribute to excitatory neurotransmission in the adult CNS. In the present study, we report properties of the…

Key points The mechanisms for the age‐related increase in fatigability during dynamic exercise remain elusive. We tested whether age‐related impairments in muscle oxidative capacity would result in a greater accumulation of fatigue causing metabolites, inorganic phosphate (Pi), hydrogen (H+) and diprotonated phosphate (H2PO4−), in the muscle of old compared to young adults during a dynamic knee extension exercise. The age‐related increase in fatigability (reduction in mechanical power) of the knee extensors was closely associated with a greater accumulation of metabolites within the working muscle but could not be explained by age‐related differences in muscle oxidative capacity. These data suggest that the increased fatigability in old adults during dynamic exercise is primarily determined by age‐related impairments in skeletal muscle bioenergetics that result in a greater accumulation of metabolites. Abstract The present study aimed to determine whether the increased fatigability in old adults during dynamic exercise is associated with age‐related differences in skeletal muscle…

KEY POINTS: A low protein diet had minimal effects on paternal cardiovascular function or renin-angiotensin system activity. Paternal low protein diet modified F1 neonatal and adult offspring renin-angiotensin system activity and cardiovascular function in a sperm and/or seminal plasma specific manner. Paternal low protein diet modified F1 male offspring testicular expression of central epigenetic regulators. Significant changes in F2 neonatal offspring growth and tissue angiotensin-converting enzyme activity were programmed by paternal low protein diet in a sperm and/or seminal plasma specific manner. ABSTRACT: Although the impact of maternal diet on adult offspring health is well characterized, the role that a father's diet has on his offspring's health remains poorly defined. We establish the significance of a sup-optimal paternal low protein diet for offspring vascular homeostasis and define the sperm and seminal plasma specific programming effects on cardiovascular health. Male C57BL6 mice were fed either a control normal protein diet (NPD; 18% protein) or an isocaloric low…

Key points Central chemoreceptor stimulation, by hypercapnia (acidosis), and peripheral, by hypoxia plus hypercapnia, evoke reflex increases in ventilation and sympathetic outflow. The assumption that central or peripheral chemoreceptor‐mediated sympathetic activation elicited when increases parallels concurrent ventilatory responses is unproven. Applying a modified rebreathing protocol that equilibrates central and peripheral chemoreceptor whilst clamping O2 tension at either hypoxic or hyperoxic concentrations, the independent ventilatory and muscle sympathetic stimulus–response properties of the central and peripheral chemoreflexes were quantified and compared in young men. The novel findings were that ventilatory and sympathetic responses to central and peripheral chemoreflex stimulation are initiated at similar recruitment thresholds but individual specific sympathetic responsiveness cannot be predicted from the ventilatory sensitivities of either chemoreceptor reflex. Such findings in young men, if replicated in heart failure or hypertension, should temper present enthusiasm…

KEY POINTS: We have recently identified that a HECT domain E3 ubiquitin ligase, named UBR5, is altered epigenetically (via DNA methylation) after human skeletal muscle hypertrophy, where its gene expression is positively correlated with increasing lean leg mass after training and retraining. In the present study we extensively investigate this novel and uncharacterised E3 ubiquitin ligase (UBR5) in skeletal muscle atrophy, recovery from atrophy and injury, anabolism and hypertrophy. We demonstrated that UBR5 was epigenetically altered via DNA methylation during recovery from atrophy. We also determined that UBR5 was alternatively regulated versus well characterised E3 ligases, MuRF1/MAFbx, at the gene expression level during atrophy, recovery from atrophy and hypertrophy. UBR5 also increased at the protein level during recovery from atrophy and injury, hypertrophy and during human muscle cell differentiation. Finally, in humans, genetic variations of the UBR5 gene were strongly associated with larger fast-twitch muscle fibres and strength/power performance versus endurance/untrained…

Abstract Store‐operated Ca 2+ entry through Orai1 channels is a primary mechanism for Ca 2+ entry in many cells and mediates numerous cellular effector functions ranging from gene transcription to exocytosis. Orai1 channels are amongst the most Ca 2+ ‐selective channels known and are activated by direct physical interactions with the endoplasmic reticulum Ca 2+ sensor stromal interaction molecule 1 (STIM1) in response to store depletion triggered by stimulation of a variety of cell surface G‐protein coupled and tyrosine kinase receptors. Work in the last decade has revealed that the Orai1 gating process is highly cooperative and strongly allosteric, likely driven by a wave of interdependent conformational changes throughout the protein originating in the peripheral C‐terminal ligand binding site and culminating in pore opening. In this review, we survey the structural and molecular features in Orai1 that contribute to channel gating and consider how they give rise to the unique biophysical fingerprint of Orai1 currents. image

KEY POINTS: Oestrogen has been shown to play an important role in the regulation of metabolic homeostasis and insulin sensitivity in both human and rodent studies. Insulin sensitivity is greater in premenopausal women compared with age-matched men, and metabolism-related cardiovascular diseases and type 2 diabetes are less frequent in these same women. Both female and male mice treated with oestradiol are protected against obesity-induced insulin resistance. The protection against obesity-induced insulin resistance is associated with reduced ectopic lipid content in liver and skeletal muscle. These results were associated with increased insulin-stimulated suppression of white adipose tissue lipolysis and reduced inflammation. ABSTRACT: Oestrogen has been shown to play an important role in the regulation of metabolic homeostasis and insulin sensitivity in both human and rodent studies. Overall, females are protected against obesity-induced insulin resistance; yet, the mechanisms responsible for this protection are not well understood. Therefore, the aim of the present work was to…

KEY POINTS: Neural connectivity between distinct motor neuronal modules in the spinal cord is classically studied through electrical stimulation or multi-muscle EMG recordings. We quantified the strength of correlation in the activity of two distinct populations of motor neurons innervating the thenar and first dorsal interosseous muscles during tasks that required the two hand muscles to exert matched or un-matched forces in different directions. We show that when the two hand muscles are concurrently activated, synaptic input to the two motor neuron pools is shared across all frequency bandwidths (representing cortical and spinal input) associated with force control. The observed connectivity indicates that motor neuron pools receive common input even when digit actions do not belong to a common behavioural repertoire. ABSTRACT: Neural connectivity between distinct motor neuronal modules in the spinal cord is classically studied through electrical stimulation or multi-muscle EMG recordings. Here we quantify the strength of correlation in the activity of two distinct populations of…

Key points Hypoxia, a potent activator of the sympathetic nervous system, is known to increase muscle sympathetic nerve activity (MSNA) to the peripheral vasculature of native Lowlanders during sustained high altitude (HA) exposure. We show that the arterial baroreflex control of MSNA functions normally in healthy Lowlanders at HA, and that upward baroreflex resetting permits chronic activation of basal sympathetic vasomotor activity under this condition. The baroreflex MSNA operating point and resting sympathetic vasomotor outflow both are lower for highland Sherpa compared to acclimatizing Lowlanders; these lower levels may represent beneficial hypoxic adaptation in Sherpa. Acute hyperoxia at HA had minimal effect on baroreflex control of MSNA in Lowlanders and Sherpa, raising the possibility that mechanisms other than peripheral chemoreflex activation contribute to vascular sympathetic baroreflex resetting and sympathoexcitation. These findings provide a better understanding of sympathetic nervous system activation and the control of blood pressure during the physiological stress…