The Journal of Physiology最新文献

{"title":"Closing in on the heat-activation mechanisms of TRPV channels.","authors":"Leon D Islas","doi":"10.1113/JP282347","DOIUrl":"https://doi.org/10.1113/JP282347","url":null,"abstract":"The sensation of heat is mediated by cation-permeable ion channels of the thermoTRP kind. Among these, some of the principal heat-activated ion channels are formed by the TRPV1–4 members of the TRPV subfamily (Latorre et al. 2009). The mechanism by which these membrane proteins convert thermal energy to a channel-opening conformational change is still being intensely investigated and for the most part is not well understood. The availability of high-resolution structures provided by the cryo-EM revolution has made it easier to propose structure–function hypotheses to study heat activation.However, high quality functional studies based in electrophysiology are still the benchmark to prove mechanisms for ion channels. Quantifying the contribution of a channel region to the heat-absorbing step is a difficult task. So far, a good experimental approximation is the estimation of the activation enthalpy associated with the opening of the channel, measured from the steepness of the channel open probability as a function of temperature. In previous seminal work (Yao et al. 2011), the laboratory of Feng Qin identified a so-called membrane proximal domain (MPD), located between the first transmembrane domain and the N-terminal ankyrin repeat domains in all TRPV channels. The authors produced evidence which suggests that the MPD is a main determinant of the activation enthalpy in TRPV1–4 thermoTRP channels. Importantly, the suggestion that this region is involved in a heat-absorbing conformational change was supported by careful measurement of the apparent enthalpy. In the present work, Liu and Qin (2021) further dissect the contribution of the components of the MPD and of individual amino acid residues within the MPD to the apparent enthalpy of activation in TRPV1 and TRPV2 channels. These important new results begin to paint a detailed picture of the fine-tuning involved in channel activation by temperature. TRPV2 channels are the thermoTRP channels with the highest enthalpy of activation –more than double the activation enthalpy of TRPV1 – and are also activated by very high temperatures (>50°C compared to >40°C for TRPV1). Interestingly, the activation of TRPV2 is also different from TRPV1 in that it shows marked hysteresis. TRPV2 channels activate steeply after initial temperature stimuli that do not activate a large fraction of current. Regardless of these differences, Liu and Qin make use of a unique heat-activation technique that relies on rapid infrared laser activation of currents and of chimeric constructions in which parts of the MPD region are swapped between both types of channels to successfully identify a helix–turn–helix motif comprising 10 residues in TRPV2 and 11 residues in TRPV1 that is part of the MPD. Transplantation of this motif between the two channels is enough to produce chimaeras that activate with the enthalpy of activation of the donor channel. Further mutagenesis experiments identified single residues that are implicated in th","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"4733-4734"},"PeriodicalIF":5.5,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39453765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Edward Carmeliet: his contributions and scientific legacy.","authors":"Karin R Sipido, David A Eisner","doi":"10.1113/JP282357","DOIUrl":"https://doi.org/10.1113/JP282357","url":null,"abstract":"The death of Edward Carmeliet has robbed us of one of the founders of modern cardiac electrophysiology. Here we summarize his contributions and, equally importantly, consider the current situation of the fields which he helped to develop. It would, however, be remiss not to point out that from 1980 to 1987, he was a member of the Editorial Board of The Journal of Physiology, one of the many roles in which he contributed to helping others develop their science. The Journal has also been an important forum for his work and was his publication of choice for the full reports of his mechanistic studies of cardiac electrophysiology. The dazzling variety of topics which he contributed to is also noteworthy and ranges from the basic properties of Ca2+ and K+ currents, the control of action potential duration, excitation–contraction coupling, to translational aspects such as the effects of ischaemia, and antiarrhythmic therapy. Such breadth was perhaps more common in days gone by than today.","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"4727-4729"},"PeriodicalIF":5.5,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39428070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of waveform and amplitude of mouse rod and cone flash responses.","authors":"Annia Abtout,&nbsp;Gordon Fain,&nbsp;Jürgen Reingruber","doi":"10.1113/JP281225","DOIUrl":"https://doi.org/10.1113/JP281225","url":null,"abstract":"<p><strong>Key points: </strong>Most vertebrate eyes have rod and cone photoreceptors, which use a signal transduction pathway consisting of many biological processes to transform light into an electrical response. We dissect and quantify the contribution of each of these processes to the photoreceptor light response by using a novel method of analysis that provides an analytical solution for the entire time course of the dim-flash light response. We find that the shape of the light response is exclusively controlled by deactivation parameters. Activation parameters scale this shape and alter the response amplitude. We show that the rising phase of the response depends on Ca²⁺ feedback, and we identify the deactivation parameters that control the recovery phase of the response. We devise new methods to extract values for deactivation and activation parameters from a separate analysis of response shape and response amplitude.</p><p><strong>Abstract: </strong>Vertebrate eyes have rod and cone photoreceptors, which use a complex transduction pathway comprising many biological processes to transform the absorption of light into an electrical response. A fundamental question in sensory transduction is how these processes contribute to the response. To study this question, we use a well-accepted phototransduction model, which we analyse with a novel method based on the log transform of the current. We derive an analytical solution that describes the entire time course of the photoreceptor response to dim flashes of light. We use this solution to dissect and quantify the contribution of each process to the response. We find that the entire dim-flash response is proportional to the flash intensity. By normalizing responses to unit amplitude, we define a waveform that is independent of the light intensity and characterizes the invariant shape of dim-flash responses. We show that this waveform is exclusively determined by deactivation rates; activation rates only scale the waveform and affect the amplitude. This analysis corrects a previous assumption that the rising phase is determined entirely by activation rates. We further show that the rising phase depends on Ca²⁺ feedback to the cyclase, contrary to current belief. We identify the deactivation rates that control the recovery phase of the response, and we devise new methods to extract activation and deactivation rates from an analysis of response shape and response amplitude. In summary, we provide a comprehensive understanding of how the various transduction processes produce the cellular response.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"3295-3312"},"PeriodicalIF":5.5,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259453/pdf/nihms-1703510.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38983602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Temporal control of muscle synergies is linked with alpha-band neural drive.","authors":"Christopher M Laine,&nbsp;Brian A Cohn,&nbsp;Francisco J Valero-Cuevas","doi":"10.1113/JP281232","DOIUrl":"https://doi.org/10.1113/JP281232","url":null,"abstract":"<p><strong>Key points: </strong>It is theorized that the nervous system controls groups of muscles together as functional units, or 'synergies', resulting in correlated electromyographic (EMG) signals among muscles. However, such correlation does not necessarily imply group-level neural control. Oscillatory synchronization (coherence) among EMG signals implies neural coupling, but it is not clear how this relates to control of muscle synergies. EMG was recorded from seven arm muscles of 10 adult participants rotating an upper limb ergometer, and EMG-EMG coherence, EMG amplitude correlations and their relationship with each other were characterized. A novel method to derive multi-muscle synergies from EMG-EMG coherence is presented and these are compared with classically defined synergies. Coherent alpha-band (8-16 Hz) drive was strongest among muscles whose gross activity levels are well correlated within a given task. The cross-muscle distribution and temporal modulation of coherent alpha-band drive suggests a possible role in the neural coordination/monitoring of synergies.</p><p><strong>Abstract: </strong>During movement, groups of muscles may be controlled together by the nervous system as an adaptable functional entity, or 'synergy'. The rules governing when (or if) this occurs during voluntary behaviour in humans are not well understood, at least in part because synergies are usually defined by correlated patterns of muscle activity without regard for the underlying structure of their neural control. In this study, we investigated the extent to which comodulation of muscle output (i.e. correlation of electromyographic (EMG) amplitudes) implies that muscles share intermuscular neural input (assessed via EMG-EMG coherence analysis). We first examined this relationship among pairs of upper limb muscles engaged in an arm cycling task. We then applied a novel multidimensional EMG-EMG coherence analysis allowing synergies to be characterized on the basis of shared neural drive. We found that alpha-band coherence (8-16 Hz) is related to the degree to which overall muscle activity levels correlate over time. The extension of this coherence analysis to describe the cross-muscle distribution and temporal modulation of alpha-band drive revealed a close match to the temporal and structural features of traditionally defined muscle synergies. Interestingly, the coherence-derived neural drive was inversely associated with, and preceded, changes in EMG amplitudes by ∼200 ms. Our novel characterization of how alpha-band neural drive is dynamically distributed among muscles is a fundamental step forward in understanding the neural origins and correlates of muscle synergies.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"3385-3402"},"PeriodicalIF":5.5,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9009735/pdf/nihms-1703509.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38961620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Delayed KCNQ1/KCNE1 assembly on the cell surface helps I_Ks fulfil its function as a repolarization reserve in the heart.","authors":"Zachary T Wilson,&nbsp;Min Jiang,&nbsp;Jing Geng,&nbsp;Sukhleen Kaur,&nbsp;Samuel W Workman,&nbsp;Jon Hao,&nbsp;Tytus Bernas,&nbsp;Gea-Ny Tseng","doi":"10.1113/JP281773","DOIUrl":"https://doi.org/10.1113/JP281773","url":null,"abstract":"<p><strong>Key points: </strong>In adult ventricular myocytes, the slow delayed rectifier (I_Ks ) channels are distributed on the surface sarcolemma, not t-tubules. In adult ventricular myocytes, KCNQ1 and KCNE1 have distinct cell surface and cytoplasmic pools. KCNQ1 and KCNE1 traffic from the endoplasmic reticulum to the plasma membrane by separate routes, and assemble into I_Ks channels on the cell surface. Liquid chromatography/tandem mass spectrometry applied to affinity-purified KCNQ1 and KCNE1 interacting proteins reveals novel interactors involved in protein trafficking and assembly. Microtubule plus-end binding protein 1 (EB1) binds KCNQ1 preferentially in its dimer form, and promotes KCNQ1 to reach the cell surface. An LQT1-associated mutation, Y111C, reduces KCNQ1 binding to EB1 dimer.</p><p><strong>Abstract: </strong>Slow delayed rectifier (I_Ks ) channels consist of KCNQ1 and KCNE1. I_Ks functions as a 'repolarization reserve' in the heart by providing extra current for ventricular action potential shortening during β-adrenergic stimulation. There has been much debate about how KCNQ1 and KCNE1 traffic in cells, where they associate to form I_Ks channels, and the distribution pattern of I_Ks channels relative to β-adrenergic signalling complex. We used experimental strategies not previously applied to KCNQ1, KCNE1 or I_Ks , to provide new insights into these issues. 'Retention-using-selected-hook' experiments showed that newly translated KCNE1 constitutively trafficked through the conventional secretory path to the cell surface. KCNQ1 largely stayed in the endoplasmic reticulum, although dynamic KCNQ1 vesicles were observed in the submembrane region. Disulphide-bonded KCNQ1/KCNE1 constructs reported preferential association after they had reached cell surface. An in situ proximity ligation assay detected I_Ks channels in surface sarcolemma but not t-tubules of ventricular myocytes, similar to the reported location of adenylate cyclase 9/yotiao. Fluorescent protein-tagged KCNQ1 and KCNE1, in conjunction with antibodies targeting their extracellular epitopes, detected distinct cell surface and cytoplasmic pools of both proteins in myocytes. We conclude that, in cardiomyocytes, KCNQ1 and KCNE1 traffic by different routes to surface sarcolemma where they assemble into I_Ks channels. This mode of delayed channel assembly helps I_Ks fulfil its function of repolarization reserve. Proteomic experiments revealed a novel KCNQ1 interactor, microtubule plus-end binding protein 1 (EB1). EB1 dimer (active form) bound KCNQ1 and increased its surface level. An LQT1 mutation, Y111C, reduced KCNQ1 binding to EB1 dimer.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"3337-3361"},"PeriodicalIF":5.5,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411300/pdf/nihms-1716517.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38971630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic and epigenetic regulation of skeletal muscle ribosome biogenesis with exercise.","authors":"Vandré C Figueiredo,&nbsp;Yuan Wen,&nbsp;Björn Alkner,&nbsp;Rodrigo Fernandez-Gonzalo,&nbsp;Jessica Norrbom,&nbsp;Ivan J Vechetti,&nbsp;Taylor Valentino,&nbsp;C Brooks Mobley,&nbsp;Gabriel E Zentner,&nbsp;Charlotte A Peterson,&nbsp;John J McCarthy,&nbsp;Kevin A Murach,&nbsp;Ferdinand von Walden","doi":"10.1113/JP281244","DOIUrl":"https://doi.org/10.1113/JP281244","url":null,"abstract":"<p><strong>Key points: </strong>Ribosome biogenesis and MYC transcription are associated with acute resistance exercise (RE) and are distinct from endurance exercise in human skeletal muscle throughout a 24 h time course of recovery. A PCR-based method for relative ribosomal DNA (rDNA) copy number estimation was validated by whole genome sequencing and revealed that rDNA dosage is positively correlated with ribosome biogenesis in response to RE. Acute RE modifies rDNA methylation patterns in enhancer, intergenic spacer and non-canonical MYC-associated regions, but not the promoter. Myonuclear-specific rDNA methylation patterns with acute mechanical overload in mice corroborate and expand on rDNA findings with RE in humans. A genetic predisposition for hypertrophic responsiveness may exist based on rDNA gene dosage.</p><p><strong>Abstract: </strong>Ribosomes are the macromolecular engines of protein synthesis. Skeletal muscle ribosome biogenesis is stimulated by exercise, although 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 years, 25 ± 4 kg m^-2 ) at rest and 30 min, 3 h, 8 h and 24 h after acute endurance (n = 10, 45 min cycling, 70% <math><msub><mover><mi>V</mi><mo>̇</mo></mover><mrow><msub><mi>O</mi><mn>2</mn></msub><mi>max</mi></mrow></msub></math> ) or resistance exercise (n = 10, 4 × 7 × 2 exercises); 10 control participants underwent biopsies without exercise. rDNA transcription and dosage were assessed using quantitative PCR and whole genome sequencing. rDNA promoter methylation was investigated using massARRAY EpiTYPER and global rDNA CpG methylation was assessed using reduced-representation bisulphite sequencing. Ribosome biogenesis and MYC transcription were associated primarily with resistance but not endurance exercise, indicating preferential up-regulation during hypertrophic processes. With resistance exercise, ribosome biogenesis was associated with rDNA gene dosage, as well as epigenetic changes in enhancer and non-canonical MYC-associated areas in rDNA, but not the promoter. A mouse model of in vivo metabolic RNA labelling and genetic myonuclear fluorescence labelling validated the effects of an acute hypertrophic stimulus on ribosome biogenesis and Myc transcription, and also corroborated rDNA enhancer and Myc-associated methylation alterations specifically in myonuclei. The present study provides the first information on skeletal muscle genetic and rDNA gene-wide epigenetic regulation of ribosome biogenesis in response to exercise, revealing novel roles for rDNA dosage and CpG methylation.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"3363-3384"},"PeriodicalIF":5.5,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38852702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Late gestation fetal hyperglucagonaemia impairs placental function and results in diminished fetal protein accretion and decreased fetal growth.","authors":"Sarah N Cilvik,&nbsp;Stephanie R Wesolowski,&nbsp;Russ V Anthony,&nbsp;Laura D Brown,&nbsp;Paul J Rozance","doi":"10.1113/JP281288","DOIUrl":"https://doi.org/10.1113/JP281288","url":null,"abstract":"<p><strong>Key points: </strong>Fetal glucagon concentrations are elevated in the setting of placental insufficiency, hypoxia and elevated stress hormones. Chronically elevated glucagon concentrations in the adult result in profound decreases in amino acid concentrations and lean body mass. Experimental elevation of fetal glucagon concentrations in a late-gestation pregnant sheep results in lower fetal amino acid concentrations, lower protein accretion and lower fetal weight, in addition to decreased placental function. This study demonstrates a negative effect of glucagon on fetal protein accretion and growth, and also provides the first example of a fetal hormone that negatively regulates placental nutrient transport and blood flow.</p><p><strong>Abstract: </strong>Fetal glucagon concentrations are elevated in the setting of placental insufficiency and fetal stress. Postnatal studies have demonstrated the importance of glucagon in amino acid metabolism, and limited fetal studies have suggested that glucagon inhibits umbilical uptake of certain amino acids. We hypothesized that chronic fetal hyperglucagonaemia would decrease amino acid transfer and increase amino acid oxidation by the fetus. Late gestation singleton fetal sheep received a direct intravenous infusion of glucagon (GCG; 5 or 50 ng/kg/min; n = 7 and 5, respectively) or a vehicle control (n = 10) for 8-10 days. Fetal and maternal nutrient concentrations, uterine and umbilical blood flows, fetal leucine flux, nutrient uptake rates, placental secretion of chorionic somatomammotropin (CSH), and targeted placental gene expression were measured. GCG fetuses had 13% lower fetal weight compared to controls (P = 0.0239) and >28% lower concentrations of 16 out of 21 amino acids (P < 0.02). Additionally, protein synthesis was 49% lower (P = 0.0005), and protein accretion was 92% lower in GCG fetuses (P = 0.0006). Uterine blood flow was 33% lower in ewes with GCG fetuses (P = 0.0154), while umbilical blood flow was similar. Fetal hyperglucagonaemia lowered uterine uptake of 10 amino acids by >48% (P < 0.05) and umbilical uptake of seven amino acids by >29% (P < 0.04). Placental secretion of CSH into maternal circulation was reduced by 80% compared to controls (P = 0.0080). This study demonstrates a negative effect of glucagon on fetal protein accretion and growth. It also demonstrates that glucagon, a hormone of fetal origin, negatively regulates maternal placental nutrient transport function, placental CSH production and uterine blood flow.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"3403-3427"},"PeriodicalIF":5.5,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249343/pdf/nihms-1704984.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38892041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improving gas exchange and exercise tolerance in mild COPD patients.","authors":"Dylan C Sieck,&nbsp;Gary C Sieck","doi":"10.1113/JP281323","DOIUrl":"https://doi.org/10.1113/JP281323","url":null,"abstract":"In their recent study, Phillips et al. (2021) focused on patients with mild chronic obstructive pulmonary disease (COPD) who have an exaggerated ventilatory response to exercise contributing to exertional dyspnoea, resulting in exercise intolerance. This is an important area of research with huge translational potential because 3.6–11.7% of the adult population worldwide have been diagnosed with COPD with ∼30% of diagnosed cases considered mild (Anecchino et al. 2007; Adeloye et al. 2015). The progression of COPD from mild to severe in this population is probably affected by the patient’s aversion to exercise as a result of exertional dyspnoea. In addition, with reduced exercise capacity and less overall activity, these COPD patients are at greater risk of comorbidities related to obesity, diabetes, cardiovascular dysfunction and stroke, leading to higher mortality. Therapeutic strategies that target early intervention to avoid the vicious cycle of ineffective gas exchange and reduced exercise capacity in mild COPD patients are probably very beneficial. Previous research on mild COPD patients has uncovered an elevated ventilatory equivalent to CO2 production (V̇E/V̇CO2 ) during exercise, secondary to increased dead space ventilation. Currently, the cause of the increased dead space ventilation is unknown, although this is considered to be a result of microvascular dysfunction and corresponding pulmonary capillary hypoperfusion. Importantly, mild COPD patients have been found to have minor airflow obstruction but diminished gas exchange capacity and reduced pulmonary capillary blood volume, which appear to contribute to dyspnoea (Tedjasaputra et al. 2018). Phillips et al. (2021) took a novel approach to solving dyspnoea-related exercise intolerance in mild COPD patients by administering inhaled nitric oxide (NO) to selectively vasodilate the pulmonary circulation and thereby improve perfusion. This simple but novel approach targets pulmonary perfusion, whereas most COPD therapies have targeted improving ventilation with bronchodilation (Phillips et al. 2021). Mild COPD patients increased O2 uptake during exercise, with improved V̇E/V̇CO2 , reduced dyspnoea and improved exercise tolerance after they received inhaled NO. These positive results indicate that microvascular perfusion limits gas exchange and exercise capacity in mild COPD patients. Just as Phillips et al. (2021) took a simple but novel approach to exertional dyspnoea in mild COPD patients, a novel approach to understanding and treating COPD needs to be implemented clinically. Mild COPD is diagnosed by spirometry (forced expiratory volume in 1 s and forced vital capacity) thresholds but does not address the actual physiological basis underlying dyspnoea with exertion, which is impaired gas exchange. Inhaled NO was able to improve exertional dyspnoea inmildCOPD patients, although, however effective, this treatment is not practical as an intervention that can be continuously applied to lar","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1943-1944"},"PeriodicalIF":5.5,"publicationDate":"2021-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25364153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pick me, Pick me! Rationale for investigating persistent inward currents (PICs) and associated exercise effects in the ageing neuromuscular system.","authors":"Christopher Latella","doi":"10.1113/JP281324","DOIUrl":"https://doi.org/10.1113/JP281324","url":null,"abstract":"The loss of neuromuscular function with ageing has been extensively documented. Physiologically, muscular fibre atrophy, loss and denervation along with associated motor unit remodelling occur with, and continue into, ageing. Although motor unit remodelling serves to reinnervate and preserve local muscle fibres and thus function, overall reductions in muscle strength and power are linked to greater risk of falling, associated co-morbidities and all-cause mortality amongst elderly individuals. However, the neuromuscular system (muscle and neural motor pathways) displays remarkable plastic potential. In particular, exercise serves as an important stimulus to increase muscle mass, strength and power and to improve overall neuromuscular function across the lifespan. As such, there is an ever-growing focus on the implementation of appropriately structured and targeted exercise programmes to combat age-related declines in neuromuscular function in older adults. Despite this, the effects of chronic exercise over the course of much of the lifespan are less clear. This poor understanding is likely compounded by the obvious difficulties (e.g. time requirements, logistics, participant retention) in conducting extreme longitudinal intervention studies. Thus, current research has largely sought to investigate the effects of lifelong exercise on the neuromuscular system by adopting well-controlled cross-sectional methodological designs.","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1957-1959"},"PeriodicalIF":5.5,"publicationDate":"2021-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38856208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bötzinger inhibitory neurons and the control of active expiration.","authors":"Ana C Takakura","doi":"10.1113/JP281168","DOIUrl":"https://doi.org/10.1113/JP281168","url":null,"abstract":"Neural circuits controlling breathing in mammals are well organized within serially and functionally interacting brainstem compartments (Del Negro et al. 2018). The core circuit components that constitute the neural machinery for generating respiratory rhythm and shaping inspiratory and expiratory motor patterns are distributed within the ventral respiratory column with the following compartments: parafacial respiratory group and retrotrapezoid nucleus (pFRG and RTN), the Bötzinger complex (BötC), pre-Bötzinger complex (pre-BötC) and the premotor neurons in the rostral and caudal ventral respiratory groups (rVRG and cVRG) (Fig. 1). Additional structures essential for normal breathing include the dorsolateral pons (intertrigeminal region, the Kölliker-Fuse nucleus, and the lateral parabrachial complex) and the dorsal respiratory group (nucleus of the solitary tract) (Del Negro et al. 2018) (Fig. 1). The integrity of the connections between all these regions is necessary for the production of the physiological phases of the breathing pattern (inspiration, post inspiration, and late expiration) and for proper control of the airway muscles that are involved in the slow expiratory airflow after inspiration (Del Negro et al. 2018). Therefore, understanding the arrangement and connections of the respiratory circuitries is essential to know how breathing is generated and adjusted to attend to metabolic and behavioural demands. Under resting conditions, mammalian breathing exhibits a two-phase pattern in which the expiratory phase occurs passively","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1945-1947"},"PeriodicalIF":5.5,"publicationDate":"2021-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39154091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}