The Journal of Physiology最新文献

{"title":"Nitric oxide contributes to cerebrovascular shear-mediated dilatation but not steady-state cerebrovascular reactivity to carbon dioxide.","authors":"Ryan L Hoiland, Hannah G Caldwell, Jay M J R Carr, Connor A Howe, Benjamin S Stacey, Tony Dawkins, Denis J Wakeham, Joshua C Tremblay, Michael M Tymko, Alexander Patrician, Kurt J Smith, Mypinder S Sekhon, David B MacLeod, Daniel J Green, Damian M Bailey, Philip N Ainslie","doi":"10.1113/JP282427","DOIUrl":"https://doi.org/10.1113/JP282427","url":null,"abstract":"<p><p>Cerebrovascular CO<sub>2</sub> reactivity (CVR) is often considered a bioassay of cerebrovascular endothelial function. We recently introduced a test of cerebral shear-mediated dilatation (cSMD) that may better reflect endothelial function. We aimed to determine the nitric oxide (NO)-dependency of CVR and cSMD. Eleven volunteers underwent a steady-state CVR test and transient CO<sub>2</sub> test of cSMD during intravenous infusion of the NO synthase inhibitor N<sup>G</sup> -monomethyl-l-arginine (l-NMMA) or volume-matched saline (placebo; single-blinded and counter-balanced). We measured cerebral blood flow (CBF; duplex ultrasound), intra-arterial blood pressure and <math><semantics><msub><mi>P</mi><mrow><mi>aC</mi><msub><mi>O</mi><mn>2</mn></msub></mrow></msub><annotation>${P_{{rm{aC}}{{rm{O}}_{rm{2}}}}}$</annotation></semantics></math> . Paired arterial and jugular venous blood sampling allowed for the determination of trans-cerebral NO<sub>2</sub><sup>-</sup> exchange (ozone-based chemiluminescence). l-NMMA reduced arterial NO<sub>2</sub><sup>-</sup> by ∼25% versus saline (74.3 ± 39.9 vs. 98.1 ± 34.2 nM; P = 0.03). The steady-state CVR (20.1 ± 11.6 nM/min at baseline vs. 3.2 ± 16.7 nM/min at +9 mmHg <math><semantics><msub><mi>P</mi><mrow><mi>aC</mi><msub><mi>O</mi><mn>2</mn></msub></mrow></msub><annotation>${P_{{rm{aC}}{{rm{O}}_{rm{2}}}}}$</annotation></semantics></math> ; P = 0.017) and transient cSMD tests (3.4 ± 5.9 nM/min at baseline vs. -1.8 ± 8.2 nM/min at 120 s post-CO<sub>2</sub> ; P = 0.044) shifted trans-cerebral NO<sub>2</sub><sup>-</sup> exchange towards a greater net release (a negative value indicates release). Although this trans-cerebral NO<sub>2</sub><sup>-</sup> release was abolished by l-NMMA, CVR did not differ between the saline and l-NMMA trials (57.2 ± 14.6 vs. 54.1 ± 12.1 ml/min/mmHg; P = 0.49), nor did l-NMMA impact peak internal carotid artery dilatation during the steady-state CVR test (6.2 ± 4.5 vs. 6.2 ± 5.0% dilatation; P = 0.960). However, l-NMMA reduced cSMD by ∼37% compared to saline (2.91 ± 1.38 vs. 4.65 ± 2.50%; P = 0.009). Our findings indicate that NO is not an obligatory regulator of steady-state CVR. Further, our novel transient CO<sub>2</sub> test of cSMD is largely NO-dependent and provides an in vivo bioassay of NO-mediated cerebrovascular function in humans. KEY POINTS: Emerging evidence indicates that a transient CO<sub>2</sub> stimulus elicits shear-mediated dilatation of the internal carotid artery, termed cerebral shear-mediated dilatation. Whether or not cerebrovascular reactivity to a steady-state CO<sub>2</sub> stimulus is NO-dependent remains unclear in humans. During both a steady-state cerebrovascular reactivity test and a transient CO<sub>2</sub> test of cerebral shear-mediated dilatation, trans-cerebral nitrite exchange shifted towards a net release indicating cerebrovascular NO production; this response was not evident following intravenous infusion of the non-selective NO synthase ","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1385-1403"},"PeriodicalIF":5.5,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39835633","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":"Probing shear-stress-mediated cerebral vasodilatation in humans - it's a NO brainer.","authors":"Jui-Lin Fan, James P Fisher","doi":"10.1113/JP282707","DOIUrl":"https://doi.org/10.1113/JP282707","url":null,"abstract":"The burden of brain diseases (e.g. stroke, dementia, Alzheimer’s disease) is considerable and has grown substantially alongside the increased life expectancy of western industrialised nations. Disrupted cerebrovascular endothelial function contributes significantly to the pathogenesis and neurodegeneration of several of these conditions. The early identification of individuals with or at risk of cerebrovascular impairments, using tests with a robust mechanistic basis, may have clinical utility for guiding interventional strategies, thereby helping to ameliorate disease progression before it becomes firmly established. Some of the earliest measurements of cerebral blood flow in humans quantified the “striking and consistent” steady-state hyperaemic response to the inhalation of carbon dioxide (CO2) (5–7%) (Kety & Schmidt 1948), which is important for pH and thus neuronal homeostasis. Subsequently, the cerebrovascular response to a steady-state CO2 stimulus test has been reported to be diminished in several clinical conditions and has prognostic value (Juttukonda & Donahue 2019). In a recent issue of the Journal of Physiology, Hoiland and colleagues provided important new mechanistic insights into a novel test that potentially provides a targeted assessment of cerebrovascular endothelial function. A transient CO2 stimulus – provided by inspiring a CO2-enriched gas mixture to raise PETCO2 by +9 mmHg for 30 s – evokes an increase in shear stress within the internal carotid artery (ICA) that peaks at ∼20 s after CO2 onset and is followed by ICA vasodilatation at ∼80 s (Hoiland et al. 2017). Since this time course is akin to that observed in other conduit vessels during the flow-mediated dilatation test, the authors discounted any direct actions of CO2 and instead hypothesized that a shear-stress-mediated release of nitric oxide (NO) was responsible for the latent ICA vasodilatation. To explore this possibility, Hoiland et al. (2022) re-evaluated the ICA response to the transient CO2 stimulus both with a saline control and i.v. infusion of the non-selective NO synthase inhibitor, NG-monomethyl-l-arginine (l-NMMA, 5 mg/kg bolus and 50 μg/kg/ min maintenance dose). Notably, l-NMMA abolished the increase in the trans-cerebral release of nitrite (index of NO production) during the transient CO2 stimulus and reduced the increase in ICA vasodilatation (by ∼37%), while shear stress was not different between conditions. Such observations were interpreted as revealing the integral role of shear-stress-mediated endothelial NO release to the cerebrovascular response to a transient CO2 stimulus. In contrast, an NO synthasemechanismwas not observed to be obligatory for the cerebrovascular response to steady-state CO2 stimulus. Indeed, the magnitude of the ICA response, along with that of the vertebral artery (VA) and middle cerebral artery blood velocity (MCAv), to steady-state hypercapnia (5 min at +4.5 and +9 mmHg PaCO2 ) was not different in the l-NMMA and salin","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1283-1284"},"PeriodicalIF":5.5,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9303707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39912244","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":"Sensorimotor integration within the primary motor cortex by selective nerve fascicle stimulation.","authors":"Federico Ranieri, Giovanni Pellegrino, Anna Lisa Ciancio, Gabriella Musumeci, Emiliano Noce, Angelo Insola, Lorenzo Alirio Diaz Balzani, Vincenzo Di Lazzaro, Giovanni Di Pino","doi":"10.1113/JP282259","DOIUrl":"10.1113/JP282259","url":null,"abstract":"<p><p>The integration of sensory inputs in the motor cortex is crucial for dexterous movement. We recently demonstrated that a closed-loop control based on the feedback provided through intraneural multichannel electrodes implanted in the median and ulnar nerves of a participant with upper limb amputation improved manipulation skills and increased prosthesis embodiment. Here we assessed, in the same participant, whether and how selective intraneural sensory stimulation also elicits a measurable cortical activation and affects sensorimotor cortical circuits. After estimating the activation of the primary somatosensory cortex evoked by intraneural stimulation, sensorimotor integration was investigated by testing the inhibition of primary motor cortex (M1) output to transcranial magnetic stimulation, after both intraneural and perineural stimulation. Selective sensory intraneural stimulation evoked a low-amplitude, 16 ms-latency, parietal response in the same area of the earliest component evoked by whole-nerve stimulation, compatible with fast-conducting afferent fibre activation. For the first time, we show that the same intraneural stimulation was also capable of decreasing M1 output, at the same time range of the short-latency afferent inhibition effect of whole-nerve superficial stimulation. The inhibition generated by the stimulation of channels activating only sensory fibres was stronger than that due to intraneural or perineural stimulation of channels activating mixed fibres. We demonstrate in a human subject that the cortical sensorimotor integration inhibiting M1 output previously described after the experimental whole-nerve stimulation is present also with a more ecological selective sensory fibre stimulation. KEY POINTS: Cortical integration of sensory inputs is crucial for dexterous movement. Short-latency somatosensory afferent inhibition of motor cortical output is typically produced by peripheral whole-nerve stimulation. We exploited intraneural multichannel electrodes used to provide sensory feedback for prosthesis control to assess whether and how selective intraneural sensory stimulation affects sensorimotor cortical circuits in humans. Activation of the primary somatosensory cortex (S1) was explored by recording scalp somatosensory evoked potentials. Sensorimotor integration was tested by measuring the inhibitory effect of the afferent stimulation on the output of the primary motor cortex (M1) generated by transcranial magnetic stimulation. We demonstrate in humans that selective intraneural sensory stimulation elicits a measurable activation of S1 and that it inhibits the output of M1 at the same time range of whole-nerve superficial stimulation.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1497-1514"},"PeriodicalIF":0.0,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/26/49/TJP-600-1497.PMC9305922.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39736378","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":"Developing in a polluted atmosphere: A link between long-term exposure to elevated atmospheric CO₂ and hyperactivity.","authors":"Helen Stolp","doi":"10.1113/JP282577","DOIUrl":"https://doi.org/10.1113/JP282577","url":null,"abstract":"The World Health Organisation (WHO) estimates that 99% of people worldwide breathe polluted air on a day-to-day basis (i.e. air with pollutant levels higher than WHO guidelines) and that ambient air pollution causes more than 4 million premature deaths per year. These numbers reflect the effect of particulate matter on cardiovascular and respiratory disease (Cohen et al. 2017) and probably underestimate the importance of air pollution on health because the role of atmospheric carbon dioxide (CO2) has not been considered thus far. Furthermore, air pollution has neurotoxic effects that are increasingly recognised and elevated atmospheric CO2 has the potential to cause renal and bone disease, expanding the latent health impact of air pollution globally. In this issue of The Journal of Physiology, Wyrwoll et al. (2022) address this timely question, exploring both systemic and neurological outcomes of a life lived in a high CO2 environment. Comparing life-time exposure to current atmospheric CO2 (460 ppm) with the higher CO2 level of 890 ppm, a level predicted to occur by the year 2100, Wyrwoll et al. (2022) showed that mice exposed to elevated CO2 during gestation had a higher birth weight than their control counterparts. Abnormal birth weight can increase risk of later morbidity, although, in this case, weight normalised over the postnatal period and developmental milestones, such as righting reflex or eye opening, were not delayed. Dimorphism occurred between males and females at adulthood, with high CO2 exposed females having lower body weight compared to age-matched controls. It is well known that substantial acute increases in inspired, or decreases in expired, CO2 result in respiratory acidosis, where the pH of the blood falls below the normal physiological range. Short-term compensations include increased respiration or altered renal excretion of hydrogen and bicarbonate ions. Longer-term, excess hydrogen can be buffered by bicarbonate released from bone. This bicarbonate release may lead to osteoporosis, whereas the accompanying release of calcium and other ions can contribute to renal calcification. It has been unclear until now whether increased atmospheric CO2 could drive these pathologies. This question is pertinent given that the world is experiencing unprecedented increases in atmospheric CO2. Surprisingly, no pathological changes were observed in kidney structure at adulthood following exposure to the high CO2 environment for 3 months (i.e. from gestation to young adulthood) or using measures of renal function (Wyrwoll et al. 2022). Nor were differences in bone structural density identified, as would be expected if substantial physiological compensation was occurring. This may reflect the relatively short experimental period and the fact that blood pH was only borderline acidotic in this model, although it was sufficient to change the structure and function of the lungs, as detailed in a companion study (Larcombe et al. 2021). Particul","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1275-1276"},"PeriodicalIF":5.5,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9305783/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39663908","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":"Nasal epithelial cells as a gold-standard predictive model for personalized medicine in cystic fibrosis.","authors":"Nicoletta Pedemonte","doi":"10.1113/JP282586","DOIUrl":"https://doi.org/10.1113/JP282586","url":null,"abstract":"Cystic fibrosis (CF) is caused by mutations impairing CFTR channel function. Over the last decade, novel drugs, called modulators, have been developed to rescue the basic defect caused by specific mutations. Unprecedented clinical results have been achieved in patients with eligible genotypes. However, CF is characterized by a remarkable allelic heterogeneity. Many patients cannot benefit yet from these treatments as in the case of patients carrying rare biallelic mutations, potentially responsive to modulators, but unable to be included in clinical trials due to the rarity of their mutations (Castellani, 2020). The use of in vitro models can significantly contribute to personalized therapeutic approaches in CF. Rectal biopsy-derived cells can develop intestinal organoids having a fluid-filled lumen.CFTR activation causes organoid swelling, and thus modulator efficacy can be evaluated by assessing their ability to restore swelling in CF organoids (Dekkers et al. 2013), as an indirect measure of CFTR function. While these models may address gastrointestinal features of CF patients, their relevance with regards to the pulmonary phenotypes is not unanimously recognized and the most reliable model to predict efficacy of CF therapies remains the airway epithelium. Since the availability of human CF bronchial (hBE) cells relies on patients undergoing lung transplant, human nasal epithelial (hNE) cells have emerged as a surrogate of airway epithelial cells for ex vivo testing of CF modulators (Pranke et al. 2017; Brewington et al. 2018). Conditional reprogramming culture allows the amplification of hNE cell number to study the molecular mechanisms causing CFTR dysfunction and responsiveness to drugs. In their recent study, Noel and colleagues (2022) investigated the amplitude and characteristics of CFTR-mediated currents in freshly isolated vs. conditionally reprogrammed hNE cells and compared them to the results obtained using in vivo assays to assess CFTR function in nasal epithelium (nasal potential difference (NPD) assay) and sweat gland (sweat Cl− concentration measurements). The utility and validity of hNE cell testing is still debated since it is not clear whether reprogrammed cells maintain the same CFTR expression level and activity as compared to native cells. With this aim, the authors performed whole-cell Cl− current recordings on freshly isolated and cultured hNE cells from non-CF or CF subjects before and after conditional reprogramming culture and compared the results with short-circuit current recordings in reprogrammed cells. In this way, the authors clearly demonstrated that there is perfect agreement between the two measurements. Interestingly, the authors also found that the amount of CFTR-mediated whole-cell Cl− current recorded in hNE cells from non-CF subjects was variable, in agreement with previous reports on bronchial epithelia (Eckford et al. 2014). Differences in genetic background are the most plausible explanation for the o","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1285-1286"},"PeriodicalIF":5.5,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39941483","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":"Increasing SR Ca uptake: a double-edged sword.","authors":"Carlos A Valverde,&nbsp;Alicia Mattiazzi","doi":"10.1113/JP282659","DOIUrl":"https://doi.org/10.1113/JP282659","url":null,"abstract":"We read with great attention the recently published article by Sato et al. titled ‘Increasing SERCA function promotes initiation of calcium sparks and breakup of calcium waves’ (Sato et al. 2021). We believe that the opposing effects of increasing SR Ca uptake described in the paper is very significant, not only from the physiological point of view, but also because of the possible therapeutic consequences. It is very well known that different attempts have been made and are in course, to treat cardiac failure by improving SR Ca uptake and increasing systolic and diastolic function (Greenberg et al. 2014; Hulot et al. 2017; Lyon et al. 2020; Wasala et al. 2020). As is clear from Sato’s results, this constitutes a double-edged sword, because the increase in SR Ca content may also increase SR Ca leak and cardiac arrhythmias. However, if the increase in SR Ca uptake is high enough, SR Ca load and contractility may be improved, whereas SR Ca waves are aborted. Still, several questions remain to be discussed. One of them refers to the effects of a persistent and exacerbated increase in SR Ca leak. Although the increase in SR Ca uptake may be less arrhythmogenic because of Ca wave abortion, which is the consequence of the chronic exacerbated SR Ca leak? In our previous study (Mazzocchi et al. 2016), also published in the Journal of Physiology, we showed that phospholamban (PLN) ablation increased SR Ca leak but prevented arrhythmogenic Ca waves, by breaking them up into mini waves. Interestingly we also showed that decreasing SERCA2a activity by addition of CPA, reinstalled the previous arrhythmogenic full-calcium wave pattern, in complete agreement with Sato et al.’s results. We further showed that ablation of PLN was able to abort SR Ca waves observed in myocytes that, in addition to PLN ablation present an increase in RyR2 open probability produced by constitutive pseudo-phosphorylation of RyR2 at the CaMKII-dependent phosphorylation site Ser2814/15 (van Oort et al. 2010). These double mutant mice were named SDKO mice. In a following study (Valverde et al. 2019), we examined the role of PLN ablation on arrhythmogenic Ca waves in hearts submitted to a protocol of ischaemia/reperfusion. Under these conditions, we had the chance to investigate the effects that the increased SR Ca leak produced by PLN ablation, both in the presence and absence of RyR2 pseudo-phosphorylation at the Ser2814 site. The results indicated that, although able to reduce arrhythmogenic Ca waves, even when SR Ca leak was greatly enhanced in SDKO hearts, ablation of PLN altered mitochondria function and exacerbates cardiac damage. These results fully agree with earlier experiments by Joan Heller Brown and Don Bers ́ groups (Zhang et al. 2010), in which it was shown that ablation of PLN exacerbated cardiac damage in CaMKII-overexpressing mice, with enhanced phosphorylation of the Ser2814 site. Although, Sato et al. (2021), did not mention or discuss neither our results nor Bers and","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1533-1534"},"PeriodicalIF":5.5,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39912249","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":"Selective stimulation with intraneural electrodes for bionic limb prostheses can contribute to shed light on human touch sensorimotor integration.","authors":"Calogero Maria Oddo","doi":"10.1113/JP282734","DOIUrl":"https://doi.org/10.1113/JP282734","url":null,"abstract":"Stimulus delivery is a major challenge in the investigation of sensory physiology and physiopathology, with translational implications while targeting bionic substitution of impaired sensorimotor functions by means of neuroprostheses. The complexity represented by stimulus administration is generally valid for all senses, and particularly for touch among physical senses because of the distributed positioning of receptors throughout the large area of the whole skin and the intrinsically interactive characteristics of somatosensation. In touch studies, the experimental protocols typically involve the delivery of mechanothermal or electrical stimuli and the collection and analysis of stimulus-induced responses, either at perceptual level bymeans of psychophysical methods or by investigating peripheral or central bioelectronic activity in humans or animals via techniques such as microneurography and microstimulation, patch clamp, electrode arrays, functional magnetic resonance imaging, or electroencephalography. When the stimulus is delivered mechanically directly to the epidermis of intact subjects, such as with vibrotactile probes, extended textures or shapes, the spatiotemporal interaction with the skin should be carefully controlled over multiple sessions, for example by using custom biorobotic tools. Such automatic mechatronic platforms should be developed to allow gathering of repeatable responses of the somatosensory pathways in order to enable modelling attempts based on brain imaging or electrophysiological recordings at higher stages with respect to the cutaneous haptic stimulation site. Another suitable approach involves accessing directly the nervous system in order to release electrical pulses to the afferent pathways. The electrical delivery of the stimuli is extremely challenging because of the complexity of guaranteeing mechanical, electrical and biological stability of the electrode-nerve interface, the high number of stimulation sites, and selectivity, both spatially and temporally. Among the possible methods for releasing electrical patterns to the nervous system, microstimulation with needle electrodes is a technique used by trained neurophysiologists for eliciting action potentials with excellent axonal selectivity within a microneurographic session (Vallbo, 2018). While being minimally invasive, and thus applicable in trials involving either intact or amputee humans, microstimulation has the inherent constraint of single-site electrode placement and stability limited to short term protocols in acute subjects. However, progress with neurotechnologies and neurosurgical techniques has enabled over the past decade a series of studies that are demonstrating the feasibility of chronically implanting electrodes in the peripheral nerves of human subjects for neuroprosthetic applications, such as perineural cuffs or intraneural filament electrodes that are being applied in pilot clinical trials with limb amputees to partially restore sen","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1279-1280"},"PeriodicalIF":5.5,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9303773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39694212","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":"Nutrient timing and metabolic regulation.","authors":"Harry A Smith, James A Betts","doi":"10.1113/JP280756","DOIUrl":"10.1113/JP280756","url":null,"abstract":"<p><p>Daily (circadian) rhythms coordinate our physiology and behaviour with regular environmental changes. Molecular clocks in peripheral tissues (e.g. liver, skeletal muscle and adipose) give rise to rhythms in macronutrient metabolism, appetite regulation and the components of energy balance such that our bodies can align the periodic delivery of nutrients with ongoing metabolic requirements. The timing of meals both in absolute terms (i.e. relative to clock time) and in relative terms (i.e. relative to other daily events) is therefore relevant to metabolism and health. Experimental manipulation of feeding-fasting cycles can advance understanding of the effect of absolute and relative timing of meals on metabolism and health. Such studies have extended the overnight fast by regular breakfast omission and revealed that morning fasting can alter the metabolic response to subsequent meals later in the day, whilst also eliciting compensatory behavioural responses (i.e. reduced physical activity). Similarly, restricting energy intake via alternate-day fasting also has the potential to elicit a compensatory reduction in physical activity, and so can undermine weight-loss efforts (i.e. to preserve body fat stores). Interrupting the usual overnight fast (and therefore also the usual sleep cycle) by nocturnal feeding has also been examined and further research is needed to understand the importance of this period for either nutritional intervention or nutritional withdrawal. In summary, it is important for dietary guidelines for human health to consider nutrient timing (i.e. when we eat) alongside the conventional focus on nutrient quantity and nutrient quality (i.e. how much we eat and what we eat).</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1299-1312"},"PeriodicalIF":0.0,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9305539/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39827637","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":"GLOBAL REACH 2018: intra-arterial vitamin C improves endothelial-dependent vasodilatory function in humans at high altitude.","authors":"Rachel M Stone,&nbsp;Philip N Ainslie,&nbsp;Joshua C Tremblay,&nbsp;John D Akins,&nbsp;David B MacLeod,&nbsp;Michael M Tymko,&nbsp;Christopher A DeSouza,&nbsp;Anthony R Bain","doi":"10.1113/JP282281","DOIUrl":"https://doi.org/10.1113/JP282281","url":null,"abstract":"<p><p>High altitude-induced hypoxaemia is often associated with peripheral vascular dysfunction. However, the basic mechanism(s) underlying high-altitude vascular impairments remains unclear. This study tested the hypothesis that oxidative stress contributes to the impairments in endothelial function during early acclimatization to high altitude. Ten young healthy lowlanders were tested at sea level (344 m) and following 4-6 days at high altitude (4300 m). Vascular endothelial function was determined using the isolated perfused forearm technique with forearm blood flow (FBF) measured by strain-gauge venous occlusion plethysmography. FBF was quantified in response to acetylcholine (ACh), sodium nitroprusside (SNP) and a co-infusion of ACh with the antioxidant vitamin C (ACh+VitC). The total FBF response to ACh (area under the curve) was ∼30% lower at high altitude than at sea level (P = 0.048). There was no difference in the response to SNP at high altitude (P = 0.860). At sea level, the co-infusion of ACh+VitC had no influence on the FBF dose response (P = 0.268); however, at high altitude ACh+VitC resulted in an average increase in the FBF dose response by ∼20% (P = 0.019). At high altitude, the decreased FBF response to ACh, and the increase in FBF in response to ACh+VitC, were associated with the magnitude of arterial hypoxaemia (R² = 0.60, P = 0.008 and R² = 0.63, P = 0.006, respectively). Collectively, these data support the hypothesis that impairments in vascular endothelial function at high altitude are in part attributable to oxidative stress, a consequence of the magnitude of hypoxaemia. These data extend our basic understanding of vascular (mal)adaptation to high-altitude sojourns, with important implications for understanding the aetiology of high altitude-related vascular dysfunction. KEY POINTS: Vascular dysfunction has been demonstrated in lowlanders at high altitude (>4000 m). However, the extent of impairment and the delineation of contributing mechanisms have remained unclear. Using the gold-standard isolated perfused forearm model, we determined the extent of vasodilatory dysfunction and oxidative stress as a contributing mechanism in healthy lowlanders before and 4-6 days after rapid ascent to 4300 m. The total forearm blood flow response to acetylcholine at high altitude was decreased by ∼30%. Co-infusion of acetylcholine with the antioxidant vitamin C partially restored the total forearm blood flow by ∼20%. The magnitude of forearm blood flow reduction, as well as the impact of oxidative stress, was positively associated with the individual severity of hypoxaemia. These data extend our basic understanding of vascular (mal)adaptation to high-altitude sojourns, with important implications for understanding the aetiology of high altitude-related changes in endothelial-mediated vasodilatory function.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1373-1383"},"PeriodicalIF":5.5,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39684896","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":"Altered muscle mitochondrial, inflammatory and trophic markers, and reduced exercise training adaptations in type 1 diabetes.","authors":"Dean Minnock,&nbsp;Giosuè Annibalini,&nbsp;Giacomo Valli,&nbsp;Roberta Saltarelli,&nbsp;Mauricio Krause,&nbsp;Elena Barbieri,&nbsp;Giuseppe De Vito","doi":"10.1113/JP282433","DOIUrl":"https://doi.org/10.1113/JP282433","url":null,"abstract":"<p><p>Growing evidence of impaired skeletal muscle health in people with type 1 diabetes points toward the presence of a mild myopathy in this population. However, this myopathic condition is not yet well characterised and often overlooked, even though it might affect the whole-body glucose homeostasis and the development of comorbidities. This study aimed to compare skeletal muscle adaptations and changes in glycaemic control after 12 weeks of combined resistance and aerobic (COMB) training between people with type 1 diabetes and healthy controls, and to determine whether the impaired muscle health in type 1 diabetes can affect the exercise-induced adaptations. The COMB training intervention increased aerobic capacity and muscle strength in both healthy and type 1 diabetes sedentary participants, although these improvements were higher in the control group. Better glucose control, reduced glycaemic fluctuations and fewer hypoglycaemic events were recorded at post- compared to pre-intervention in type 1 diabetes. Analysis of muscle biopsies showed an alteration of muscle markers of mitochondrial functions, inflammation, ageing and growth/atrophy compared to the control group. These muscular molecular differences were only partially modified by the COMB training and might explain the reduced exercise adaptation observed in type 1 diabetes. In brief, type 1 diabetes impairs many aspects of skeletal muscle health and might affect the exercise-induced adaptations. Defining the magnitude of diabetic myopathy and the effect of exercise, including longer duration of the intervention, will drive the development of strategies to maximise muscle health in the type 1 diabetes population. KEY POINTS: Type 1 diabetes negatively affects skeletal muscle health; however, the effect of structured exercise training on markers of mitochondrial function, inflammation and regeneration is not known. Even though participants with type 1 diabetes and healthy control were comparable for cardiorespiratory fitness ( <math><semantics><msub><mover><mi>V</mi><mo>̇</mo></mover><mrow><msub><mi>O</mi><mn>2</mn></msub><mi>max</mi></mrow></msub><annotation>${dot{V}_{{{rm{O}}_{rm{2}}}{rm{max}}}}$</annotation></semantics></math> ) and muscle strength at baseline, molecular markers related to muscle health were decreased in type 1 diabetes. After training, both groups increased <math><semantics><msub><mover><mi>V</mi><mo>̇</mo></mover><mrow><msub><mi>O</mi><mn>2</mn></msub><mi>max</mi></mrow></msub><annotation>${dot{V}_{{{rm{O}}_{rm{2}}}{rm{max}}}}$</annotation></semantics></math> and muscle strength; however, a larger improvement was achieved by the control group. The training intervention decreased glucose fluctuations and occurrence of hypoglycaemic events in type 1 diabetes, while signs of mild myopathy found in the muscle of participants with type 1 diabetes only partially improved after training Improving muscle health by specific exercise protocols is of considerable clinical ","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1405-1418"},"PeriodicalIF":5.5,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9306774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39793678","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}