The Journal of Physiology最新文献

{"title":"Cortical dynamics of movement-evoked pain in chronic low back pain.","authors":"Wei-En Wang,&nbsp;Rachel L M Ho,&nbsp;Bryan Gatto,&nbsp;Susanne M van der Veen,&nbsp;Matthew K Underation,&nbsp;James S Thomas,&nbsp;Ajay B Antony,&nbsp;Stephen A Coombes","doi":"10.1113/JP280735","DOIUrl":"https://doi.org/10.1113/JP280735","url":null,"abstract":"<p><strong>Key points: </strong>Cortical activity underlying movement-evoked pain is not well understood, despite being a key symptom of chronic musculoskeletal pain. We combined high-density electroencephalography with a full-body reaching protocol in a virtual reality environment to assess cortical activity during movement-evoked pain in chronic low back pain. Movement-evoked pain in individuals with chronic low back pain was associated with longer reaction times, delayed peak velocity and greater movement variability. Movement-evoked pain was associated with attenuated disinhibition in prefrontal motor areas, as evidenced by an attenuated reduction in beta power in the premotor cortex and supplementary motor area.</p><p><strong>Abstract: </strong>Although experimental pain alters neural activity in the cortex, evidence of changes in neural activity in individuals with chronic low back pain (cLBP) remains scarce and results are inconsistent. One of the challenges in studying cLBP is that the clinical pain fluctuates over time and often changes during movement. The goal of the present study was to address this challenge by recording high-density electroencephalography (HD-EEG) data during a full-body reaching task to understand neural activity during movement-evoked pain. HD-EEG data were analysed using independent component analyses, source localization and measure projection analyses to compare neural oscillations between individuals with cLBP who experienced movement-evoked pain and pain-free controls. We report two novel findings. First, movement-evoked pain in individuals with cLBP was associated with longer reaction times, delayed peak velocity and greater movement variability. Second, movement-evoked pain was associated with an attenuated reduction in beta power in the premotor cortex and supplementary motor area. Our observations move the field forward by revealing attenuated disinhibition in prefrontal motor areas during movement-evoked pain in cLBP.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"289-305"},"PeriodicalIF":5.5,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1113/JP280735","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38497822","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":"Epigenetic imprinting of human skeletal muscle cells: From metabolic diseases to myopathy.","authors":"Cedric Moro","doi":"10.1113/JP280954","DOIUrl":"https://doi.org/10.1113/JP280954","url":null,"abstract":"Idiopathic inflammatory myopathies (IIM) are a group of rare, heterogeneous, acquired disorders characterized by muscle weakness, excessive muscle fatigue and poor aerobic fitness. They have been historically considered as autoimmune diseases and classified as dermatomyositis, polymyositis or inclusion body myositis (Gazeley & Cronin, 2011). Myositis-specific antibodies define subsets of patients with different responses to treatment and prognosis. IIM primarily affects skeletal muscles and is characterized by chronic inflammation and immune cell infiltration causing muscle damage and excessive fatigability. The primary line of treatment is corticosteroids with the addition of other immunosuppressive therapies in severe or refractory disease (Gazeley & Cronin, 2011). However, the suppression of inflammation with glucocorticoids does not always lead to clinical improvement. There is still a great need to find more effective and less toxic therapies. In this issue of The Journal of Physiology, Nemec et al. (2021) show that 6 months’ supervised training improves muscle functional capacity and the clinical state of IIM patients. Training included 1 h per week of activities of daily living and 1 h of strength training with three series of 10–15 repetitions at 50–70% of 1 repetition maximum. Adherence and compliance to the exercise training programme were excellent with 100% completers. Training improved functional index-2, a valid and reliable index of muscle function in IIM patients, by nearly 40%. The main aim of this study was to investigate disease-related metabolic disturbances in skeletal muscle cells of IIM patients before and after exercise training. Primary culture of human skeletal muscle cells from CD56-positive satellite cells differentiated into metabolically responsive myotubes has been widely used to investigate metabolic and signalling pathways as well as for mechanistic studies to gain insight into cause–effect relationship (Bourlier et al. 2013). Nemec et al. herein observed a defect of total palmitate oxidation rate in myotubes derived from IIM patients chronically treated with palmitate for 3 days to mimic lipid overload in muscle. This metabolic trait has been previously observed in myotubes derived from obese and type 2 diabetic donors and could have interesting clinical implication for IIM patients. They next observed a training-induced up-regulation of lipid oxidative capacity, i.e. measured by elevated palmitate oxidation rate, in primary myotubes of IIM patients cultured before and at the end of the 6 months’ training programme (Nemec et al. 2021). This finding agrees with previous studies showing that training-induced metabolic adaptations are retained in vitro in cultured human myotubes (Bourlier et al. 2013). Interestingly, chronic palmitate treatment for 3 days revealed training-induced molecular changes of lipid metabolism proteins such as mitochondrial respiratory complex proteins, 5′-AMP protein kinase and adipose trig","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"9-10"},"PeriodicalIF":5.5,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1113/JP280954","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38572512","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 dynamics of lipid metabolism in muscle cells from patients with idiopathic inflammatory myopathy is ameliorated by 6 months of training.","authors":"M Nemec,&nbsp;L Vernerová,&nbsp;N Laiferová,&nbsp;M Balážová,&nbsp;M Vokurková,&nbsp;T Kurdiová,&nbsp;S Oreská,&nbsp;K Kubínová,&nbsp;M Klein,&nbsp;M Špiritović,&nbsp;M Tomčík,&nbsp;J Vencovský,&nbsp;J Ukropec,&nbsp;B Ukropcová","doi":"10.1113/JP280468","DOIUrl":"https://doi.org/10.1113/JP280468","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Key points: &lt;/strong&gt;Regular exercise improves muscle functional capacity and clinical state of patients with idiopathic inflammatory myopathy (IIM). In our study, we used an in vitro model of human primary muscle cell cultures, derived from IIM patients before and after a 6-month intensive supervised training intervention to assess the impact of disease and exercise on lipid metabolism dynamics. We provide evidence that muscle cells from IIM patients display altered dynamics of lipid metabolism and impaired adaptive response to saturated fatty acid load compared to healthy controls. A 6-month intensive supervised exercise training intervention in patients with IIM mitigated disease effects in their cultured muscle cells, improving or normalizing their capacity to handle lipids. These findings highlight the putative role of intrinsic metabolic defects of skeletal muscle in the pathogenesis of IIM and the positive impact of exercise, maintained in vitro by yet unknown epigenetic mechanisms.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Abstract: &lt;/strong&gt;Exercise improves skeletal muscle function, clinical state and quality of life in patients with idiopathic inflammatory myopathy (IIM). Our aim was to identify disease-related metabolic perturbations and the impact of exercise in skeletal muscle cells of IIM patients. Patients underwent a 6-month intensive supervised training intervention. Muscle function, anthropometric and metabolic parameters were examined and muscle cell cultures were established (m. vastus lateralis; Bergström needle biopsy) before and after training from patients and sedentary age/sex/body mass index-matched controls. [&lt;sup&gt;14&lt;/sup&gt; C]Palmitate was used to determine fat oxidation and lipid synthesis (thin layer chromatography). Cells were exposed to a chronic (3 days) and acute (3 h) metabolic challenge (the saturated fatty acid palmitate, 100 μm). Reduced oxidative (intermediate metabolites, -49%, P = 0.034) and non-oxidative (diglycerides, -38%, P = 0.013) lipid metabolism was identified in palmitate-treated muscle cells from IIM patients compared to controls. Three days of palmitate exposure elicited distinct regulation of oxidative phosphorylation (OxPHOS) complex IV and complex V/ATP synthase (P = 0.012/0.005) and adipose triglyceride lipase in patients compared to controls (P = 0.045) (immunoblotting). Importantly, 6 months of training in IIM patients improved lipid metabolism (CO&lt;sub&gt;2&lt;/sub&gt; , P = 0.010; intermediate metabolites, P = 0.041) and activation of AMP kinase (P = 0.007), and nearly normalized palmitate-induced changes in OxPHOS proteins in myotubes from IIM patients, in parallel with improvements of patients' clinical state. Myotubes from IIM patients displayed altered dynamics of lipid metabolism and impaired response to metabolic challenge with saturated fatty acid. Our observations suggest that metabolic defects intrinsic to skeletal muscle could represent non-immune pathomechanisms, which can contribute to muscle weakness i","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"207-229"},"PeriodicalIF":5.5,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1113/JP280468","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38500069","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":"Predicting the protein composition of human urine in normal and pathological states: Quantitative description based on Dent1 disease (CLCN5 mutation).","authors":"Aurélie Edwards,&nbsp;Erik I Christensen,&nbsp;Robert J Unwin,&nbsp;Anthony G W Norden","doi":"10.1113/JP280740","DOIUrl":"https://doi.org/10.1113/JP280740","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Key points: &lt;/strong&gt;The presence of plasma proteins in urine is difficult to interpret quantitatively. It may be a result of impaired glomerular filtration or impaired proximal tubule (PT) reabsorption, or both. Dent1 disease (CLCN5 mutation) abolishes PT protein reabsorption leaving glomerular function intact. Using urine protein measurements from patients with Dent1 disease and normal individuals, we devised a mathematical model that incorporates two PT transport processes with distinct kinetics. This model predicts albumin, α&lt;sub&gt;1&lt;/sub&gt; -microglobulin (α&lt;sub&gt;1&lt;/sub&gt; -m), β&lt;sub&gt;2&lt;/sub&gt; -microglobulin (β&lt;sub&gt;2&lt;/sub&gt; -m) and retinol-binding protein 4 (RBP4) urine concentrations. Our results indicate that the urinary excretion of β&lt;sub&gt;2&lt;/sub&gt; -m and RBP4 differs from that of albumin and α&lt;sub&gt;1&lt;/sub&gt; -m in their sensitivity to changes in the glomerular filtration rate, glomerular protein leak, tubular protein uptake via endocytosis and PT water reabsorption. The model predicts quantitatively how hyperfiltration and glomerular leak interact to promote albuminuria. Our model should contribute to improved understanding and interpretation of urine protein measurements in renal disease.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Abstract: &lt;/strong&gt;To clarify the relative contributions of glomerular filtration and tubular uptake to urinary protein excretion, we developed a mathematical model of protein reabsorption in the human proximal tubule (PT) using Michaelis-Menten kinetics and molar urinary protein measurements taken from human Dent1 disease (CLCN5 loss-of-function mutation). β&lt;sub&gt;2&lt;/sub&gt; -Microglobulin (β&lt;sub&gt;2&lt;/sub&gt; -m) and retinol-binding protein 4 (RBP4) are normally reabsorbed with 'very high' efficiency uptake kinetics and fractional urinary excretion of 0.025%, whereas albumin and α&lt;sub&gt;1&lt;/sub&gt; -microglobulin (α&lt;sub&gt;1&lt;/sub&gt; -m) are reabsorbed by 'high' efficiency uptake kinetics and 50-fold higher fractional urinary excretion of 1.15%. Our model correctly predicts the urinary β&lt;sub&gt;2&lt;/sub&gt; -m, RBP4 and α&lt;sub&gt;1&lt;/sub&gt; -m content in aristolochic acid nephropathy, and elevated β&lt;sub&gt;2&lt;/sub&gt; -m excretion with increased single nephron glomerular filtration rate (SNGFR) following unilateral-nephrectomy. We explored how altered endocytic uptake, water reabsorption, SNGFR and glomerular protein filtration affect excretion. Our results help to explain why β&lt;sub&gt;2&lt;/sub&gt; -m and RBP4 are more sensitive markers of PT dysfunction than albumin or α&lt;sub&gt;1&lt;/sub&gt; -m, and suggest that reduced PT sodium and water reabsorption in Fanconi syndrome may contribute to proteinuria. Transition of albumin excretion from normal to microalbuminuria, a 5-fold increase, corresponds to a 3.5-fold elevation in albumin glomerular filtration, supporting the use of microalbuminuria screening to detect glomerular leak in diabetes. In macroalbuminuria, small albumin permeability changes produce large changes in excretion. However, changes in SNGFR can alter protein excretion, and hyperfiltrat","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"323-341"},"PeriodicalIF":5.5,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1113/JP280740","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38537445","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":"Circadian actions of orexins on the retinorecipient lateral geniculate complex in rat.","authors":"Lukasz Chrobok,&nbsp;Jagoda Stanislawa Jeczmien-Lazur,&nbsp;Kamil Pradel,&nbsp;Jasmin Daniela Klich,&nbsp;Monika Bubka,&nbsp;Michal Wojcik,&nbsp;Mariusz Kepczynski,&nbsp;Marian Henryk Lewandowski","doi":"10.1113/JP280275","DOIUrl":"https://doi.org/10.1113/JP280275","url":null,"abstract":"<p><strong>Key points: </strong>Rhythmic processes in living organisms are controlled by biological clocks. The orexinergic system of the lateral hypothalamus carries circadian information to provide arousal for the brain during the active phase. Here, we show that orexins exert an excitatory action in three parts of the lateral geniculate nucleus (LGN), in particular upon directly retinorecipient neurons in the non-image forming visual structures. We provide evidence for the high nocturnal levels of orexins with stable circadian expression of predominant orexin receptor 2 in the LGN. Our data additionally establish the convergence of orexinergic and pituitary adenylate cyclase (PAC)-activating peptide/PAC1 receptor systems (used by melanopsin-expressing retinal ganglion cells), which directly regulates responses to the retinal input. These results help us better understand circadian orexinergic control over the non-image forming subcortical visual system, forming the animal's preparedness for the behaviourally active night.</p><p><strong>Abstract: </strong>The orexinergic system of the lateral hypothalamus is tightly interlinked with the master circadian clock and displays daily variation in activity to provide arousal-related excitation for the plethora of brain structures in a circadian manner. Here, using a combination of electrophysiological, optogenetic, histological, molecular and neuronal tracing methods, we explore a particular link between orexinergic and visual systems in rat. The results of the present study demonstrate that orexinergic fibre density at the area of subcortical visual system exerts a clear day to night variability, reaching a maximum at behaviourally active night. We also show pronounced electrophysiological activations of neurons in the lateral geniculate nucleus by orexin A through 24 h, via identified distinct orexin receptors, with the ventrolateral geniculate displaying a daily cycle of responsiveness. In addition, for the first time, we provide a direct evidence for orexins to act on retinorecipient neurons with a high convergence of orexinergic and putatively retinal pituitary adenylate cyclase (PAC)-activating peptide/PAC1 receptor systems. Altogether, the present study ties orexins to non-image forming visual structures with implications for circadian orexinergic modulation of neurons, which process information on ambient light levels.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"231-252"},"PeriodicalIF":5.5,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1113/JP280275","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38438528","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":"Opposing modulation of Cx26 gap junctions and hemichannels by CO₂.","authors":"Sarbjit Nijjar, Daniel Maddison, Louise Meigh, Elizabeth de Wolf, Thomas Rodgers, Martin J Cann, Nicholas Dale","doi":"10.1113/JP280747","DOIUrl":"10.1113/JP280747","url":null,"abstract":"<p><strong>Key points: </strong>A moderate increase in <math><msub><mi>P</mi><mrow><mi>C</mi><msub><mi>O</mi><mn>2</mn></msub></mrow></msub></math> (55 mmHg) closes Cx26 gap junctions. This effect of CO₂ is independent of changes in intra- or extracellular pH. The CO₂ -dependent closing effect depends on the same residues (K125 and R104) that are required for the CO₂ -dependent opening of Cx26 hemichannels. Pathological mutations of Cx26 abolish the CO₂ -dependent closing of the gap junction. Elastic network modelling suggests that the effect of CO₂ on Cx26 hemichannels and gap junctions is mediated through changes in the lowest entropy state of the protein.</p><p><strong>Abstract: </strong>Cx26 hemichannels open in response to moderate elevations of CO₂ ( <math><msub><mi>P</mi><mrow><mi>C</mi><msub><mi>O</mi><mn>2</mn></msub></mrow></msub></math> 55 mmHg) via a carbamylation reaction that depends on residues K125 and R104. Here we investigate the action of CO₂ on Cx26 gap junctions. Using a dye transfer assay, we found that an elevated <math><msub><mi>P</mi><mrow><mi>C</mi><msub><mi>O</mi><mn>2</mn></msub></mrow></msub></math> of 55 mmHg greatly delayed the permeation of a fluorescent glucose analogue (NBDG) between HeLa cells coupled by Cx26 gap junctions. However, the mutations K125R or R104A abolished this effect of CO₂ . Whole cell recordings demonstrated that elevated CO₂ reduced the Cx26 gap junction conductance (median reduction 66.7%, 95% CI, 50.5-100.0%) but had no effect on Cx26^K125R or Cx31 gap junctions. CO₂ can cause intracellular acidification. Using 30 mm propionate, we found that acidification in the absence of a change in <math><msub><mi>P</mi><mrow><mi>C</mi><msub><mi>O</mi><mn>2</mn></msub></mrow></msub></math> caused a median reduction in the gap junction conductance of 41.7% (95% CI, 26.6-53.7%). This effect of propionate was unaffected by the K125R mutation (median reduction 48.1%, 95% CI, 28.0-86.3%). pH-dependent and CO₂ -dependent closure of the gap junction are thus mechanistically independent. Mutations of Cx26 associated with the keratitis ichthyosis deafness syndrome (N14K, A40V and A88V), in combination with the mutation M151L, also abolished the CO₂ -dependent gap junction closure. Elastic network modelling suggests that the lowest entropy state when CO₂ is bound is the closed configuration for the gap junction but the open state for the hemichannel. The opposing actions of CO₂ on Cx26 gap junctions and hemichannels thus depend on the same residues and presumed carbamylation reaction.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"103-118"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38561063","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":"Regulation of microRNA-221, -222, -21 and -27 in articular cartilage subjected to abnormal compressive forces.","authors":"Paulina S Stadnik, Sophie J Gilbert, Jessica Tarn, Sarah Charlton, Andrew J Skelton, Matthew J Barter, Victor C Duance, David A Young, Emma J Blain","doi":"10.1113/JP279810","DOIUrl":"10.1113/JP279810","url":null,"abstract":"<p><strong>Key points: </strong>microRNAs (miRs) are small non-coding molecules that regulate post-transcriptional target gene expression. miRs are involved in regulating cellular activities in response to mechanical loading in all physiological systems, although it is largely unknown whether this response differs with increasing magnitudes of load. miR-221, miR-222, miR-21-5p and miR-27a-5p were significantly increased in ex vivo cartilage explants subjected to increasing load magnitude and in in vivo joint cartilage exposed to abnormal loading. TIMP3 and CPEB3 are putative miR targets in chondrocytes Identification of mechanically regulated miRs that have potential to impact on tissue homeostasis provides a mechanism by which load-induced tissue behaviour is regulated, in both health and pathology, in all physiological systems.</p><p><strong>Abstract: </strong>MicroRNAs (miRs) are small non-coding molecules that regulate post-transcriptional target gene expression and are involved in mechano-regulation of cellular activities in all physiological systems. It is unknown whether such epigenetic mechanisms are regulated in response to increasing magnitudes of load. The present study investigated mechano-regulation of miRs in articular cartilage subjected to 'physiological' and 'non-physiological' compressive loads in vitro as a model system and validated findings in an in vivo model of abnormal joint loading. Bovine full-depth articular cartilage explants were loaded to 2.5 MPa (physiological) or 7 MPa (non-physiological) (1 Hz, 15 min) and mechanically-regulated miRs identified using next generation sequencing and verified using a quantitative PCR. Downstream targets were verified using miR-specific mimics or inhibitors in conjunction with 3'-UTR luciferase activity assays. A subset of miRs were mechanically-regulated in ex vivo cartilage explants and in vivo joint cartilage. miR-221, miR-222, miR-21-5p and miR-27a-5p were increased and miR-483 levels decreased with increasing load magnitude. Tissue inhibitor of metalloproteinase 3 (TIMP3) and cytoplasmic polyadenylation element binding protein 3 (CPEB3) were identified as putative downstream targets. Our data confirm miR-221 and -222 mechano-regulation and demonstrates novel mechano-regulation of miR-21-5p and miR-27a-5p in ex vivo and in vivo cartilage loading models. TIMP3 and CPEB3 are putative miR targets in chondrocytes. Identification of specific miRs that are regulated by increasing load magnitude, as well as their potential to impact on tissue homeostasis, has direct relevance to other mechano-sensitive physiological systems and provides a mechanism by which load-induced tissue behaviour is regulated, in both health and pathology.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"143-155"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38587515","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":"Biophysical and morphological changes in inner hair cells and their efferent innervation in the ageing mouse cochlea.","authors":"Jing-Yi Jeng, Adam J Carlton, Stuart L Johnson, Steve D M Brown, Matthew C Holley, Michael R Bowl, Walter Marcotti","doi":"10.1113/JP280256","DOIUrl":"10.1113/JP280256","url":null,"abstract":"<p><strong>Key points: </strong>Age-related hearing loss is a progressive hearing loss involving environmental and genetic factors, leading to a decrease in hearing sensitivity, threshold and speech discrimination. We compared age-related changes in inner hair cells (IHCs) between four mouse strains with different levels of progressive hearing loss. The surface area of apical coil IHCs (9-12 kHz cochlear region) decreases by about 30-40% with age. The number of BK channels progressively decreases with age in the IHCs from most mouse strains, but the basolateral membrane current profile remains unchanged. The mechanoelectrical transducer current is smaller in mice harbouring the hypomorphic Cdh23 allele Cdh23^ahl (C57BL/6J; C57BL/6NTac), but not in Cdh23-repaired mice (C57BL/6NTac^Cdh23+ ), indicating that it could contribute to the different progression of hearing loss among mouse strains. The degree of efferent rewiring onto aged IHCs, most likely coming from the lateral olivocochlea fibres, was correlated with hearing loss in the different mouse strains.</p><p><strong>Abstract: </strong>Inner hair cells (IHCs) are the primary sensory receptors of the mammalian cochlea, transducing acoustic information into electrical signals that are relayed to the afferent neurons. Functional changes in IHCs are a potential cause of age-related hearing loss. Here, we have investigated the functional characteristics of IHCs from early-onset hearing loss mice harbouring the allele Cdh23^ahl (C57BL/6J and C57BL/6NTac), from late-onset hearing loss mice (C3H/HeJ), and from mice corrected for the Cdh23^ahl mutation (C57BL/6NTac^Cdh23+ ) with an intermediate hearing phenotype. There was no significant loss of IHCs in the 9-12 kHz cochlear region up to at least 15 months of age, but their surface area decreased progressively by 30-40% starting from ∼6 months of age. Although the size of the BK current decreased with age, IHCs retained a normal KCNQ4 current and resting membrane potential. These basolateral membrane changes were most severe for C57BL/6J and C57BL/6NTac, less so for C57BL/6NTac^Cdh23+ and minimal or absent in C3H/HeJ mice. We also found that lateral olivocochlear (LOC) efferent fibres re-form functional axon-somatic connections with aged IHCs, but this was seen only sporadically in C3H/HeJ mice. The efferent post-synaptic SK2 channels appear prior to the establishment of the efferent contacts, suggesting that IHCs may play a direct role in re-establishing the LOC-IHC synapses. Finally, we showed that the size of the mechanoelectrical transducer (MET) current from IHCs decreased significantly with age in mice harbouring the Cdh23^ahl allele but not in C57BL/6NTac^Cdh23+ mice, indicating that the MET apparatus directly contributes to the progression of age-related hearing loss.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"269-287"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7612127/pdf/EMS140586.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38593110","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":"Optical measurement of physiological sodium currents in the axon initial segment.","authors":"Luiza Filipis,&nbsp;Marco Canepari","doi":"10.1113/JP280554","DOIUrl":"https://doi.org/10.1113/JP280554","url":null,"abstract":"<p><strong>Key points: </strong>Τhe axonal Na⁺ fluorescence underlying an action potential in the axon initial segment was optically measured at unprecedented temporal resolution. The measurement allowed resolution of the kinetics of the Na⁺ current at different axonal locations. The distinct components of the Na⁺ current were correlated with the kinetics of the action potential. NEURON simulations from a modified published model qualitatively predicted the experimentally measured Na⁺ current. The present method permits the direct investigation of the kinetic behaviour of native Na⁺ channels under physiological and pathological conditions.</p><p><strong>Abstract: </strong>In most neurons of the mammalian central nervous system, the action potential (AP) is generated in the axon initial segment (AIS) by a fast Na⁺ current mediated by voltage-gated Na⁺ channels. While the axonal Na⁺ signal associated with the AP has been measured using fluorescent Na⁺ indicators, the insufficient resolution of these recordings has not allowed tracking the Na⁺ current kinetics underlying this fundamental event. In this article, we report the first optical measurement of Na⁺ currents in the AIS of pyramidal neurons of layer 5 of the somatosensory cortex from brain slices of the mouse. This measurement was obtained by achieving a temporal resolution of 100 μs in the Na⁺ imaging technique, with a pixel resolution of 0.5 μm, and by calculating the time-derivative of the Na⁺ change corrected for longitudinal diffusion. We identified a subthreshold current before the AP, a fast-inactivating current peaking during the rise of the AP and a non-inactivating current during the AP repolarization. We established a correlation between the kinetics of the non-inactivating current at different distances from the soma and the kinetics of the somatic AP. We quantitatively compared the experimentally measured Na⁺ current with the current obtained by computer simulation of published NEURON models, demonstrating how the present approach can lead to the correct estimate of the native behaviour of Na⁺ channels. Finally, we discuss how the present approach can be used to investigate the physiological or pathological function of different channel types during AP initiation and propagation.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"49-66"},"PeriodicalIF":5.5,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1113/JP280554","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38521803","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":"Location location location: muscle glycogen content and endurance exercise.","authors":"Bryan Saunders,&nbsp;Nathan Gobbi","doi":"10.1113/JP280808","DOIUrl":"https://doi.org/10.1113/JP280808","url":null,"abstract":"The percutaneous muscle biopsy technique was developed in Sweden in the 1960s and spawned a decade of revelatory investigations on the interaction between diet, exercise and muscle glycogen. This culminated in the pioneering study that showed the importance of muscle glycogen content for endurance exercise following dietary carbohydrate manipulation (Bergström et al., 1967). These studies have laid the foundations for scientific work in this area, including the use of carbohydrate loading and periodization strategies to enhance muscle glycogen storage capacities. In particular, the muscle biopsy technique has allowed research to elucidate the relationships between muscle glycogen and exercise intensity and duration, individual training status, carbohydrate feeding and carbohydrate restriction (Hearris, et al., 2018). The muscle biopsy is considered a ‘gold standard’ when it comes to biochemical, molecular, histochemical, and histomorphometric muscle analyses. Traditionally, muscle glycogen content has been evaluated using whole-muscle homogenates from muscle biopsies. However, muscle is not a uniform tissue and is composed of multiple fibre types (type I, type IIa, type IIx) which have distinct glycogen contents while it has been known for some time that glycogen is not only differentially located between different muscle fibres but also within subcellular compartments. Whole-muscle quantification, therefore, might not be the most accurate method to elucidate the complex pathways through which muscle glycogen availability may influence exercise performance, and instead, single-fibre and subcellular localisation may further enhance understanding of this topic.","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"19-21"},"PeriodicalIF":5.5,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1113/JP280808","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38436357","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}