Journal of Physiology-London最新文献

{"title":"In vivo human gracilis muscle active force-length relationship is explained by the sliding filament theory","authors":"Zheng Wang,&nbsp;Lomas S. Persad,&nbsp;Benjamin I. Binder-Markey,&nbsp;Ernest M. Hoffman,&nbsp;William J. Litchy,&nbsp;Alexander Y. Shin,&nbsp;Kenton R. Kaufman,&nbsp;Richard L. Lieber","doi":"10.1113/JP288322","DOIUrl":"10.1113/JP288322","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <div>The sliding filament theory explains skeletal muscle fibre force change as a function of length based on the overlap of actin and myosin filaments. Although this length-tension (LT) relationship has been well investigated in animal models, it is not known whether this microscopic sarcomere LT property can be scaled up five orders of magnitude to explain the LT behaviour of a long human muscle such as the gracilis. The goal of this study is to validate the sarcomere LT curve in humans based on human filament length combined with <i>in vivo</i> experimental data. Intraoperative measurements of maximal tetanic force and muscle-tendon unit length at four different joint configurations (JC) were obtained from 19 patients undergoing free functioning muscle transfer surgery. With physiologically measured fibre length and estimated sarcomere shortening resulting from tendon compliance, we show that 79.7% variance in isometric force data is explained by a simple human sarcomere LT model. This study demonstrates that the human whole muscle LT relationship can be modelled by the sliding filament theory given patient-specific fibre length, filament length, tendon compliance and sarcomere shortening.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </div>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Whole human gracilis muscle isometric length-tension relationships were measured in the operating room.</li>\u0000 \u0000 <li>Grouped whole muscle raw length-tension curves showed no obvious form.</li>\u0000 \u0000 <li>The width of each experimental length-tension curve was highly variable across subjects and used to predict fibre length (serial sarcomere number).</li>\u0000 \u0000 <li>After whole muscle length-tension curves were normalized to each patient's serial sarcomere number, the whole human muscle length-tension curve was well predicted by the sliding filament theory.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 10","pages":"3049-3059"},"PeriodicalIF":4.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144051894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"14-3-3 proteins: Regulators of cardiac excitation-contraction coupling and stress responses.","authors":"Heather C Spooner, Rose E Dixon","doi":"10.1113/JP288566","DOIUrl":"https://doi.org/10.1113/JP288566","url":null,"abstract":"<p><p>14-3-3 proteins are highly conserved proteins that regulate numerous cellular processes mostly through phosphorylation-dependent protein-protein interactions. In the heart 14-3-3 proteins play critical roles in cardiac conduction pathways, excitation-contraction (EC) coupling, development and stress responses. This review summarizes the current understanding of cardiac 14-3-3 regulation and function, with particular emphasis on its role in ion channel regulation and β-adrenergic signalling. We discuss how 14-3-3 proteins act through three main mechanisms - masking, clamping, and scaffolding - to regulate target proteins, including Cx43, Ca_V1.2, Na_V1.5, and various potassium channels. The seven mammalian 14-3-3 isoforms display distinct but overlapping functions, with tissue-specific expression patterns and isoform-specific regulation through phosphorylation and dimerization. Recent work has revealed 14-3-3's importance in cardiac development and stress responses, where it generally serves a cardioprotective role. However in some pathological contexts such as ischaemia-reperfusion injury, 14-3-3 can be detrimental. We highlight emerging themes in cardiac 14-3-3 biology, including its role in prolonging β-adrenergic signalling. Understanding the complex regulation of cardiac 14-3-3 and its numerous targets presents both opportunities and challenges for therapeutic development.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144042854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Load and muscle-dependent changes in triceps surae motor unit firing properties in individuals with non-insertional Achilles tendinopathy.","authors":"Ignacio Contreras-Hernandez, Deborah Falla, Michail Arvanitidis, Francesco Negro, David Jimenez-Grande, Eduardo Martinez-Valdes","doi":"10.1113/JP287588","DOIUrl":"https://doi.org/10.1113/JP287588","url":null,"abstract":"<p><p>Non-insertional Achilles tendinopathy (NIAT) induces morpho-mechanical changes to the Achilles tendon (AT). Evidence on how triceps surae motor unit firing properties are influenced by altered tendon mechanics in NIAT is limited. This study investigated motor unit firing properties (mean discharge rate (DR), recruitment and de-recruitment thresholds, and discharge rate variability (COVisi)), motor unit firing-torque relationships (cross-correlation coefficient between cumulative spike train (CST) and torque, and neuromechanical delay (NMD)) and neural drive distribution (connectivity strength and functional networks) of the medial gastrocnemius (MG), lateral gastrocnemius (LG), and soleus (SO) muscles during isometric plantarflexion contractions at 10%, 40%, and 70% maximal voluntary contraction (MVC) using high-density surface electromyography (HD-sEMG) on 26 individuals with NIAT and 25 healthy controls. AT's morpho-mechanical properties (thickness, cross-sectional area, length, and stiffness) were assessed via ultrasonography. Motor unit properties changed in a load and muscle-dependent manner. LG DR increased (p = 0.002) and de-recruitment threshold decreased (p = 0.039) at 70% MVC in the NIAT group compared to controls. The CST-torque cross-correlation coefficient of the LG decreased at 10% MVC (p < 0.0001) and increased at 70% MVC (p = 0.013) in the NIAT group. Connectivity strength for the 0-5 Hz and 5-15 Hz frequency bands decreased (p < 0.01) in the NIAT group at 10% MVC. Furthermore, NIAT individuals showed reduced tendon stiffness and increased thickness (p < 0.01). This study shows that individuals with NIAT exhibit load- and muscle-dependent changes in motor unit firing properties, motor unit-torque relationships, and neural drive distribution to the triceps surae. These alterations may be due to muscle-specific compensations for AT's modified mechanical properties. KEY POINTS: Individuals with non-insertional Achilles tendinopathy (NIAT) have changes in the neural drive to the lateral gastrocnemius (LG) muscle and altered contribution of the LG to the net plantarflexion torque. Individuals with NIAT show a more uneven distribution of neural drive to the triceps surae muscle at low force levels, characterised by reduced intermuscular coherence between the medial and lateral gastrocnemius in the 0-5 Hz and 5-15 Hz bands compared to the control group. Our findings support the idea that the LG may have a central role in the pathophysiology of this condition, possibly affecting the load transmission to the Achilles tendon (AT).</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144045189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Properties of rhythmogenic currents in spinal Shox2 interneurons across postnatal development","authors":"Shayna Singh,&nbsp;Natalia A. Shevtsova,&nbsp;Lihua Yao,&nbsp;Ilya A. Rybak,&nbsp;Kimberly J. Dougherty","doi":"10.1113/JP287752","DOIUrl":"10.1113/JP287752","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;Locomotor behaviours are performed by organisms throughout life, despite developmental changes in cellular properties, neural connectivity and biomechanics. The basic rhythmic activity in the central nervous system underlying locomotion is considered to be generated via a complex interplay between network and intrinsic cellular properties. Within mature mammalian spinal locomotor circuitry, we have yet to determine which properties of spinal interneurons (INs) are critical to rhythmogenesis and how they change during development. Here, we combined whole cell patch clamp recordings, immunohistochemistry and RNAscope targeting lumbar Shox2 INs in mice, which are known to be involved in locomotor rhythm generation. Our goal was to determine the postnatal developmental expression of voltage-sensitive conductances, in addition to respective ion channels, in Shox2 INs. We show that subsets of Shox2 INs display persistent inward currents, M-type potassium currents, slow afterhyperpolarization and T-type calcium currents, which are enhanced with age. By contrast, the hyperpolarization-activated and A-type potassium currents were either found with low prevalence in subsets of neonatal, juvenile, and adult Shox2 INs or did not developmentally change. We show that Shox2 INs become more electrophysiologically diverse by juvenile and adult ages, when locomotor behaviour becomes weight-bearing. Computational modelling was used to simulate and reproduce electrophysiological experiments for representative Shox2 INs to make predictions regarding the interactions between experimentally recorded conductances and persistent inward currents, and bursting behaviour. Our results suggest a developmental shift in the magnitude of rhythmogenic ionic currents and the expression of corresponding ion channels that may be important for mature locomotor behaviour.\u0000\u0000 &lt;figure&gt;\u0000 &lt;div&gt;&lt;picture&gt;\u0000 &lt;source&gt;&lt;/source&gt;&lt;/picture&gt;&lt;p&gt;&lt;/p&gt;\u0000 &lt;/div&gt;\u0000 &lt;/figure&gt;\u0000 &lt;/div&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;The intrinsic and voltage-sensitive properties of locomotor-related neurons contribute to shaping and maintaining activity.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Shox2 interneurons (INs), similar to many other components of locomotor circuitry, are well-characterized in the neonatal mouse.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Electrophysiological recordings reveal that subsets of Shox2 INs express ‘rhythmogenic properties’, including persistent inward currents, M-type potassium currents and slow afterhyperpolarization, as well as corresponding ion channels/RNA.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Hierarchical clustering demonstrates that deve","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 10","pages":"3201-3221"},"PeriodicalIF":4.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144045176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comparative study of lumped heart models for personalized medicine through sensitivity and identifiability analysis.","authors":"Marie Haghebaert, Pavlos Varsos, Roel Meiburg, Irene Vignon-Clementel","doi":"10.1113/JP287929","DOIUrl":"https://doi.org/10.1113/JP287929","url":null,"abstract":"<p><p>Numerical modelling of the cardiovascular system is becoming an increasingly accepted tool for clinical applications, with the ultimate goal of personalized medicine. Lumped parameter models are attractive due to their low computational cost but often do not directly incorporate physical properties, thus requiring calibration to (often sparse) clinical data. Furthermore there exists a trade-off between physiological relevance and model complexity, making the choice of cardiac model non-trivial. For two established cardiac chamber models embedded in a haemodynamics whole circulation model, we perform sensitivity and identifiability analyses to examine the possibility of finding a unique subset of important parameters with varying levels of clinically measurable data, thereby examining their applicability in personalized medicine. To provide a concrete clinical context, the case of treatment planning for a young pulmonary arterial hypertension patient is considered. The methodology is however relevant for other pathophysiologies. The results suggest that the single-fibre model, although a priori more complex than the time-varying elastance model, is more amenable for patient-specific modelling. This was found for representing the patient state from clinical data, defining parameter ranges for sensitivity analysis (SA), and in the results of the identifiability analysis. SA also revealed the most influential parameters, which for the right (respectively left) heart chambers, mostly affect the haemodynamics of these chambers and the pulmonary (respectively systemic) circulation but also the ones of the left (respectively right) side. This highlights the importance of studying the whole circulation, especially in diseases traditionally thought to affect only one side. KEY POINTS: Two established cardiac chamber computational models are compared in the context of pulmonary hypertension, but the methodology holds for other pathophysiologies. Comprehensive patient-specific data, accurate parameter ranges and thorough model validation are essential to enhance parameter identifiability, improve model personalization and eventually lead to better prediction of haemodynamic changes after clinical intervention. Due to its inherent mathematical constraints and physiologically interpretable input parameters, the single-fibre model is easier to make patient-specific and more accurately captures the non-linear dynamics of ventricular pressure-volume loops than the simpler time-varying elastance model, making it more suitable for personalized cardiac simulations. Accurate representation of both the left and right heart chambers in cardiac modelling is important, as our results suggest that parameters of each side impact the haemodynamics of the other circulatory side, making it worthwhile to measure the characteristics of both the right and left chambers, even if the disease emerges from one side.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144047687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ErbB2 as a therapeutic target for post-trauma muscle recovery.","authors":"Nasrin Dabirian, Chunyu Wang","doi":"10.1113/JP288895","DOIUrl":"https://doi.org/10.1113/JP288895","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144006278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Re: JP-TR-2024-286891 'The ageing brain: Cortical overactivation - How does it evolve?'","authors":"Wolfgang Taube, Benedikt Lauber","doi":"10.1113/JP286891","DOIUrl":"https://doi.org/10.1113/JP286891","url":null,"abstract":"<p><p>There is overwhelming evidence for an age-related change in brain activity when performing motor and motor-cognitive tasks (i.e. dual-tasking). In general this research shows increased cortical activity, i.e. cortical overactivation, and, less evident, subcortical deactivation in the healthy brains of older compared to young adults. Furthermore brain network activity becomes less distinct and less segregated. Interestingly from a behavioural point of view some of these adaptations seem helpful, leading to better motor performances than in age-matched seniors, but others are related to inferior performance. Current theories try to explain these findings, therefore, either in favour of compensatory strategies or in terms of non-selective, inefficient (dedifferentiated) brain activation. However the limitation of current theories is that they are 'static', considering only one point in time instead of age-related progression of brain activity over time. In contrast this review article proposes a developmental process, from compensation to negative overcompensation to chronic maladaptive overcompensation, which leads to dedifferentiation and desegregation. In addition this article highlights that elderly subjects utilize motor control strategies, such as increased cortical activity, down-regulation of inhibitory processes and less-segregated and lateralized brain activation patterns, that are also commonly found in healthy young adults when task challenges increase. Thus many findings about differences in brain activation may result from the fact that although 'absolute task difficulty' remains the same, 'relative task difficulty' increases for the older subjects, forcing them to apply the above-mentioned neural activation strategies. This initially compensatory strategy can, however, turn into non-efficient brain activation over time.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144051896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The contribution of age and sex hormones to female neuromuscular function across the adult lifespan.","authors":"Steven J O'Bryan, Annabel Critchlow, Cas J Fuchs, Danielle Hiam, Séverine Lamon","doi":"10.1113/JP287496","DOIUrl":"https://doi.org/10.1113/JP287496","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Neuromuscular ageing is characterized by neural and/or skeletal muscle degeneration that decreases maximal force and power. Female neuromuscular ageing occurs earlier in life compared to males, potentially due to sex hormone changes during the menopausal transition. We quantified neuromuscular function in 88 females represented equally over each decade from 18 to 80 years of age and investigated the role of decreased ovarian hormone concentrations following menopause. Neuromuscular assessment included quadriceps maximal voluntary and evoked isometric torque and surface electromyography measurements, plus one-repetition maximum leg press. Voluntary and evoked torques and one-repetition maximum decreased non-linearly with age, with accelerated reductions starting during the fourth decade. An absence of changes in volitional recruitment of existing quadriceps motor units and Ia afferent facilitation of spinal motoneurons suggests that functional decline was largely mediated by impairment in intrinsic peripheral muscle function and/or neuromuscular transmission. Maximal muscle compound action potential amplitude decreased with increasing age for rectus femoris muscle only, indicating increased vulnerability to neuromuscular degeneration compared to vastus lateralis and medialis. In postmenopausal females, some variance was explained by inter-individual differences in quadriceps tissue composition and lifestyle factors, but changes in total or free concentrations of oestradiol, progesterone and/or testosterone were included in all correlations with age-related decreases in isometric voluntary and evoked torques. We demonstrate an accelerated onset of neuromuscular degeneration of peripheral muscular origin around menopause onset associated with changes in sex hormone concentrations. Interventions aimed at mitigating declines in ovarian hormones and their subsequent effects on neuromuscular function after menopause should be further explored. KEY POINTS: Neuromuscular deterioration with age is associated with poor physical function and quality of life in older adults, but female-specific trajectories and mechanisms remain unclear. This study is the first to map neuromuscular function across each decade of the adult lifespan in 88 females from 18 to 80 years old and to examine the potential role of hormonal changes after menopause. We show an accelerated reduction in neuromuscular function, primarily of peripheral muscular origin, that occurs during the fourth decade and coincides with menopause onset. In postmenopausal females, age-related reductions in neuromuscular function can in part be explained by quadriceps lean and intramuscular fat composition, physical activity and protein intake, and sex hormone concentrations. These findings help us better understand the factors that contribute to the loss of neuromuscular function with age in females, enabling the identification of potential therapeutic interventions to prolong female health span.&lt;/p","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144057158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early adversity and the comorbidity between metabolic disease and psychopathology.","authors":"Ameyalli Gómez-Ilescas, Patricia Pelufo Silveira","doi":"10.1113/JP285927","DOIUrl":"https://doi.org/10.1113/JP285927","url":null,"abstract":"<p><p>Although the co-existence of metabolic and psychiatric disorders in the same individual (comorbidity) is very prevalent, the mechanisms by which these disorders co-occur are poorly understood, but a history of early-life adversity is a common developmental risk factor. Exposure to adverse environments during critical periods of development (e.g. fetal life and infancy) modifies the metabolism and the function of the brain persistently, influencing behaviours that contribute to both metabolic and mental health disarrangements over the life course. We will review molecular and clinical evidence supporting the notion that early adversity is an important risk factor for the comorbidity between metabolic and psychiatric conditions. We will also discuss the possible mechanisms involved: neurometabolic programming, epigenetic alterations and the cumulative effects of altered inflammatory and oxidative pathways linked to early adversity.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143996226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intermittent time-restricted eating may increase autophagic flux in humans: an exploratory analysis","authors":"Julien Bensalem,&nbsp;Xiao Tong Teong,&nbsp;Kathryn J. Hattersley,&nbsp;Leanne K. Hein,&nbsp;Célia Fourrier,&nbsp;Linh V. P. Dang,&nbsp;Sanjna Singh,&nbsp;Kai Liu,&nbsp;Gary A. Wittert,&nbsp;Amy T. Hutchison,&nbsp;Leonie K. Heilbronn,&nbsp;Timothy J. Sargeant","doi":"10.1113/JP287938","DOIUrl":"10.1113/JP287938","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;Autophagy slows age-related pathologies and is stimulated by nutrient restriction in animal studies. However, this has never been shown in humans. We measured autophagy using a physiologically relevant measure of autophagic flux (flux of MAP1LC3B isoform II/LC3B-II in peripheral blood mononuclear cells in the context of whole blood) in 121 humans with obesity who were randomised to standard care (SC, control condition), calorie restriction (CR) or intermittent fasting plus time-restricted eating (iTRE) for 6 months. While the differences in change from baseline between groups was not significant at 2 months, we observed a significant difference in change from baseline between iTRE compared to SC at 6 months (&lt;i&gt;P&lt;/i&gt; = 0.04, &lt;i&gt;post hoc&lt;/i&gt; analysis). This effect may be driven partly by a tendency for autophagy to decrease in the SC group. The difference in change from baseline between CR and SC was not significant. Uncorrected analysis of correlations showed a negative relationship between change in autophagy and change in blood triglycerides. Data on the specificity and performance of the methods used to measure human autophagy are also presented. This shows autophagy may be increased by intermittent nutrient restriction in humans. If so, this is a demonstration that nutrient restriction can be used to improve a primary hallmark of biological ageing and provides a mechanism for how fasting could delay the onset of age-related disease.\u0000\u0000 &lt;figure&gt;\u0000 &lt;div&gt;&lt;picture&gt;\u0000 &lt;source&gt;&lt;/source&gt;&lt;/picture&gt;&lt;p&gt;&lt;/p&gt;\u0000 &lt;/div&gt;\u0000 &lt;/figure&gt;\u0000 &lt;/div&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Autophagy slows biological ageing, and dysfunction of autophagy has been implicated in age-related disease – an effective way of increasing autophagy in cells and animal models is nutrient restriction.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;However, the impact of different types of nutrient restriction on physiological autophagic flux in humans has not been extensively researched.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Here we measure the effect of intermittent time-restricted eating (iTRE) and calorie restriction on physiological autophagic flux in peripheral blood mononuclear cells.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;After 6 months, there was a significant difference in change from baseline between the iTRE and the standard care control group, with flux being higher in the iTRE group at this timepoint.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;However, there was no significant increase from baseline within the iTRE group, showing that although autoph","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"603 10","pages":"3019-3032"},"PeriodicalIF":4.7,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP287938","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144057132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}