Katharina Gers-Barlag, Ana Gómez del Campo, Pablo Hernández-Ortego, Eva Quintero, Félix Viana
Aim
To elucidate the molecular mechanism of cold sensing by visceral sensory endings, a side-by-side characterization of cold-sensitive (CS) neurons in adult mouse trigeminal (TG) and vagal ganglia (VG) was performed.
Methods
A combination of physiological, pharmacological, molecular, and genetic tools was employed on trigeminal and vagal neurons.
Results
CS neurons are more abundant in VG, and the majority co-express TRPA1. Cold-evoked responses are severely blunted in Trpa1 KO mice. In contrast, TRPM8 deletion or pharmacological TRPM8 blockade had little impact on VG cold sensitivity. In Trpm8eYFP reporter mice, VG TRPM8 expression was restricted to the rostral jugular ganglion. In vivo labeling of airway-innervating VG neurons demonstrated their enhanced cold sensitivity and higher TRPA1 expression compared to neurons innervating the stomach wall. In contrast, the majority of CS TG neurons co-express TRPM8 markers, and their cold sensitivity is reduced after TRPM8 deletion or blockade. However, pharmacological or genetic ablation of TRPA1 confirmed its contribution to high-threshold cold sensitivity in TG, suggestive of a role in noxious cold sensing. In both ganglia, a fraction of CS neurons responded to cooling by a mechanism independent of TRPA1 or TRPM8. Blocking potassium channels enhanced cold sensitivity independently of the specific transducer mechanism, suggestive of a common excitability brake mechanism.
Conclusions
The study highlights the differential contribution of TRPM8 and TRPA1 channels to cold sensitivity in somatic and visceral ganglia, establishing a critical role of TRPA1 channels in visceral cold transduction. Finally, cold sensitivity seems fine-tuned to the specific physiological needs of different organs.
{"title":"Transduction Mechanisms for Cold Temperature in Mouse Trigeminal and Vagal Ganglion Neurons Innervating Different Peripheral Organs","authors":"Katharina Gers-Barlag, Ana Gómez del Campo, Pablo Hernández-Ortego, Eva Quintero, Félix Viana","doi":"10.1111/apha.70111","DOIUrl":"10.1111/apha.70111","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>To elucidate the molecular mechanism of cold sensing by visceral sensory endings, a side-by-side characterization of cold-sensitive (CS) neurons in adult mouse trigeminal (TG) and vagal ganglia (VG) was performed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A combination of physiological, pharmacological, molecular, and genetic tools was employed on trigeminal and vagal neurons.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>CS neurons are more abundant in VG, and the majority co-express TRPA1. Cold-evoked responses are severely blunted in <i>Trpa1</i> KO mice. In contrast, TRPM8 deletion or pharmacological TRPM8 blockade had little impact on VG cold sensitivity. In <i>Trpm8</i><sup><i>eYFP</i></sup> reporter mice, VG TRPM8 expression was restricted to the rostral jugular ganglion. In vivo labeling of airway-innervating VG neurons demonstrated their enhanced cold sensitivity and higher TRPA1 expression compared to neurons innervating the stomach wall. In contrast, the majority of CS TG neurons co-express TRPM8 markers, and their cold sensitivity is reduced after TRPM8 deletion or blockade. However, pharmacological or genetic ablation of TRPA1 confirmed its contribution to high-threshold cold sensitivity in TG, suggestive of a role in noxious cold sensing. In both ganglia, a fraction of CS neurons responded to cooling by a mechanism independent of TRPA1 or TRPM8. Blocking potassium channels enhanced cold sensitivity independently of the specific transducer mechanism, suggestive of a common excitability brake mechanism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The study highlights the differential contribution of TRPM8 and TRPA1 channels to cold sensitivity in somatic and visceral ganglia, establishing a critical role of TRPA1 channels in visceral cold transduction. Finally, cold sensitivity seems fine-tuned to the specific physiological needs of different organs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70111","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205073","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}
Yi Yan, Minxing Zheng, Xuanjing Wang, Tingting Fu, Jiahui Qi, Xiaofang Wei, Yaqin Sun, Jiayin Lu, Xiaomao Luo, Ying Wang, Haidong Wang
Aim
In the process of muscle growth and repair, microRNAs (miRNAs) serve as a critical factor in spatiotemporal regulation. Nevertheless, the molecular regulatory mechanisms underlying muscle regeneration remain largely unknown.
Methods
Exosomes from control and miR-126-knockdown BMSCs were isolated via ultracentrifugation. A mouse muscle injury model was established using 1.2% barium chloride in gastrocnemius muscles. Injured tissues received local injections of BMSC exosomes or AAV-miR-126. Gene expression was analyzed by qRT-PCR/Western blot. Tissue morphology and repair were assessed via H&E staining, while regeneration markers were evaluated through immunostaining.
Results
Here, we identified miR-126-5p in BMSC-derived exosomes as a positive regulator of muscle regeneration. These exosomes promoted the proliferation and maturation of myoblasts and facilitated the regeneration of skeletal muscle in male C57BL/6J mice. FBXO32 was confirmed as the downstream target of exosomal miR-126-5p to regulate skeletal muscle regeneration, and it ubiquitinated and degraded myogenic differentiation 1 (MyoD). Notably, miR-126-5p knockdown from BMSC-derived exosomes significantly inhibited proliferation and differentiation of Pax7+ SCs and muscle regeneration, whereas adeno-associated virus (AAV)-mediated overexpression of miR-126-5p accelerated these processes. Specifically, the BMSC-derived exosomes delivered miR-126-5p to skeletal muscle, thus decreasing the expression of FBXO32, in turn increasing MyoD expression, finally significantly promoting satellite cell differentiation and skeletal muscle regeneration.
Conclusions
BMSC-derived exosomes could promote skeletal muscle injury repair through miR-126-5p, and thus miR-126-5p may act as a molecular therapeutic target of skeletal muscle diseases. Elucidating functional mechanisms of exosomes and miRNA is of great significance for developing new biotherapy strategies for skeletal muscle disease.
{"title":"MiR-126-5p Derived From Bone Marrow Mesenchymal Stem Cell Exosomes Promotes Skeletal Muscle Regeneration by Regulating FBXO32/MyoD Signaling","authors":"Yi Yan, Minxing Zheng, Xuanjing Wang, Tingting Fu, Jiahui Qi, Xiaofang Wei, Yaqin Sun, Jiayin Lu, Xiaomao Luo, Ying Wang, Haidong Wang","doi":"10.1111/apha.70114","DOIUrl":"10.1111/apha.70114","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>In the process of muscle growth and repair, microRNAs (miRNAs) serve as a critical factor in spatiotemporal regulation. Nevertheless, the molecular regulatory mechanisms underlying muscle regeneration remain largely unknown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Exosomes from control and miR-126-knockdown BMSCs were isolated via ultracentrifugation. A mouse muscle injury model was established using 1.2% barium chloride in gastrocnemius muscles. Injured tissues received local injections of BMSC exosomes or AAV-miR-126. Gene expression was analyzed by qRT-PCR/Western blot. Tissue morphology and repair were assessed via H&E staining, while regeneration markers were evaluated through immunostaining.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Here, we identified miR-126-5p in BMSC-derived exosomes as a positive regulator of muscle regeneration. These exosomes promoted the proliferation and maturation of myoblasts and facilitated the regeneration of skeletal muscle in male C57BL/6J mice. FBXO32 was confirmed as the downstream target of exosomal miR-126-5p to regulate skeletal muscle regeneration, and it ubiquitinated and degraded myogenic differentiation 1 (MyoD). Notably, miR-126-5p knockdown from BMSC-derived exosomes significantly inhibited proliferation and differentiation of Pax7<sup>+</sup> SCs and muscle regeneration, whereas adeno-associated virus (AAV)-mediated overexpression of miR-126-5p accelerated these processes. Specifically, the BMSC-derived exosomes delivered miR-126-5p to skeletal muscle, thus decreasing the expression of FBXO32, in turn increasing MyoD expression, finally significantly promoting satellite cell differentiation and skeletal muscle regeneration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>BMSC-derived exosomes could promote skeletal muscle injury repair through miR-126-5p, and thus miR-126-5p may act as a molecular therapeutic target of skeletal muscle diseases. Elucidating functional mechanisms of exosomes and miRNA is of great significance for developing new biotherapy strategies for skeletal muscle disease.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190434","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}
Pregnancy is a time of significant maternal physiological change to meet the metabolic demands of the feto-placental unit. In cases of pregnancy complications, mal-adaptive physiological responses may occur, potentially impacting the health of both mother and fetus. Moreover, some maternal changes may persist beyond delivery. Although the clinical symptoms of preeclampsia (PE) and gestational diabetes mellitus (GDM) usually resolve post-partum, growing evidence suggests that these conditions confer a lifelong increased risk of cardiometabolic disease in affected women. This review aimed to summarize epidemiological evidence linking PE and GDM to future maternal cardiometabolic disorders, explore potential underlying mechanisms based on animal and small-scale human studies, and discuss implications for future research and postpartum clinical care.
Methods
Targeted PubMed searches were conducted to search for relevant publications.
Results
Data suggest that pregnancy complications may both reveal an underlying predisposition to cardiometabolic disease and induce lasting physiological changes that contribute to future health risks. Notably, women with a history of PE may have a 3–4-fold increased risk of cardiovascular disease, while those with prior GDM may face up to a 10-fold higher risk of developing type 2 diabetes.
Conclusion
Pregnancy offers a valuable window into a woman's future health, presenting a unique opportunity for preventative medicine for up to half of the world's population.
{"title":"The Impact of Preeclampsia and Gestational Diabetes on Future Maternal Cardiometabolic Health","authors":"Alice M. Barrell, Amanda N. Sferruzzi-Perri","doi":"10.1111/apha.70113","DOIUrl":"10.1111/apha.70113","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Pregnancy is a time of significant maternal physiological change to meet the metabolic demands of the feto-placental unit. In cases of pregnancy complications, mal-adaptive physiological responses may occur, potentially impacting the health of both mother and fetus. Moreover, some maternal changes may persist beyond delivery. Although the clinical symptoms of preeclampsia (PE) and gestational diabetes mellitus (GDM) usually resolve post-partum, growing evidence suggests that these conditions confer a lifelong increased risk of cardiometabolic disease in affected women. This review aimed to summarize epidemiological evidence linking PE and GDM to future maternal cardiometabolic disorders, explore potential underlying mechanisms based on animal and small-scale human studies, and discuss implications for future research and postpartum clinical care.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Targeted PubMed searches were conducted to search for relevant publications.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Data suggest that pregnancy complications may both reveal an underlying predisposition to cardiometabolic disease and induce lasting physiological changes that contribute to future health risks. Notably, women with a history of PE may have a 3–4-fold increased risk of cardiovascular disease, while those with prior GDM may face up to a 10-fold higher risk of developing type 2 diabetes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Pregnancy offers a valuable window into a woman's future health, presenting a unique opportunity for preventative medicine for up to half of the world's population.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184222","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}
In the adult brain, GABA exerts either depolarizing or hyperpolarizing effects on neuronal membranes, depending on neuron type, subcellular location, and neuronal activity. Depolarizing GABA typically inhibits neurons through shunting, which is mediated by increased membrane conductance upon GABAA receptor activation; however, it can also excite neurons by recruiting voltage-dependent conductances. The net influence of these opposing actions of depolarizing GABA on glutamatergic synaptic inputs remains incompletely understood. We aimed to examine the spatiotemporal characteristics of membrane polarization and shunting mediated by GABAA receptors and assess their functional impact on the integration of GABAergic and glutamatergic inputs along dendrites.
Methods
Using whole-cell current-clamp recordings in CA1 pyramidal neurons and dentate gyrus granule cells (GCs) from rat hippocampal slices, we mimicked GABAergic and glutamatergic inputs with local GABA puff and glutamate spot-uncaging, respectively. A mathematical model further quantified the relative effects of local shunting and polarization.
Results
Depolarizing GABAergic postsynaptic responses (GPSRs) exhibited biphasic actions, exerting inhibitory effects at the synapse through shunting, and excitatory effects distally, where depolarization predominated. The excitatory component also persisted longer than the shunting inhibition. In contrast, hyperpolarizing GPSRs remained consistently inhibitory across both spatial and temporal dimensions.
Conclusions
These findings highlight the complex spatiotemporal interplay between shunting and membrane polarization mediated by GABAergic inputs, providing new insights into dendritic computation and neuronal network dynamics.
{"title":"Spatiotemporal Differences of GABAergic Polarization and Shunting During Dendritic Integration","authors":"Yulia Dembitskaya, Artem Kirsanov, Yu-Wei Wu, Alexey Brazhe, Alexey Semyanov","doi":"10.1111/apha.70112","DOIUrl":"https://doi.org/10.1111/apha.70112","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>In the adult brain, GABA exerts either depolarizing or hyperpolarizing effects on neuronal membranes, depending on neuron type, subcellular location, and neuronal activity. Depolarizing GABA typically inhibits neurons through shunting, which is mediated by increased membrane conductance upon GABA<sub>A</sub> receptor activation; however, it can also excite neurons by recruiting voltage-dependent conductances. The net influence of these opposing actions of depolarizing GABA on glutamatergic synaptic inputs remains incompletely understood. We aimed to examine the spatiotemporal characteristics of membrane polarization and shunting mediated by GABA<sub>A</sub> receptors and assess their functional impact on the integration of GABAergic and glutamatergic inputs along dendrites.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using whole-cell current-clamp recordings in CA1 pyramidal neurons and dentate gyrus granule cells (GCs) from rat hippocampal slices, we mimicked GABAergic and glutamatergic inputs with local GABA puff and glutamate spot-uncaging, respectively. A mathematical model further quantified the relative effects of local shunting and polarization.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Depolarizing GABAergic postsynaptic responses (GPSRs) exhibited biphasic actions, exerting inhibitory effects at the synapse through shunting, and excitatory effects distally, where depolarization predominated. The excitatory component also persisted longer than the shunting inhibition. In contrast, hyperpolarizing GPSRs remained consistently inhibitory across both spatial and temporal dimensions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These findings highlight the complex spatiotemporal interplay between shunting and membrane polarization mediated by GABAergic inputs, providing new insights into dendritic computation and neuronal network dynamics.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145146977","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}
<p>Endurance training (ET) effectively enhances aerobic capacity in healthy humans by increasing circulating hemoglobin mass (Hb<sub>mass</sub>) [<span>1</span>]. We and others have observed that improved peak O<sub>2</sub> consumption (VO<sub>2peak</sub>) after ET is reverted to pre-training values following blood withdrawal to negate the ET-induced gain in Hb<sub>mass</sub> [<span>2, 3</span>]. Likewise, increases in Hb<sub>mass</sub> and VO<sub>2peak</sub> are determined by the ET dose [<span>4</span>]. Consequently, we are skeptical of large improvements in VO<sub>2peak</sub> not primarily underlain by hematological adaptations, and expect that lifestyle interventions, including ET as the main stimuli, enhance VO<sub>2peak</sub> along with erythropoiesis.</p><p>Dietary calcium supplementation is highly prevalent in developed countries. Around half of the US population, including 70% of older women, supplement their diets with calcium. Calcium supplementation is also used as a placebo in pharmacological trials, assuming its negligible effects on hematological and cardiovascular systems [<span>5</span>]. However, in the past century, animal studies demonstrated large alterations in hemoglobin (Hb) concentration with calcium supplementation [<span>6, 7</span>]. Recently, a study implementing 8 weeks of ET combined with calcium supplementation as a placebo did not increase Hb<sub>mass</sub> but substantially enhanced VO<sub>2peak</sub> (9% to 17%) in healthy women and men [<span>5</span>]. In that study, the modality of ET did not comprise typical (upright) exercises such as cycling or running, but rowing, which may entail central hemodynamic alterations negatively interacting with the endocrine regulation of erythropoiesis [<span>8</span>]. In fact, the rowing intervention induced isolated left atrial enlargement, commonly reflecting chronic pressure overload [<span>8</span>]. Therefore, the question remains whether typical ET combined with calcium supplementation (ET-Ca) increases VO<sub>2peak</sub> without eliciting hematological adaptations. Here, we tested the hypothesis that 8 weeks of upright cycling ET-Ca enhances VO<sub>2peak</sub> without concomitant increases in Hb<sub>mass</sub> in healthy women and men. A control intervention for ET alone was not implemented since previous ET interventions in our laboratory, applying similar exercise stimuli for 6–8 weeks, resulted in proportional gains in Hb<sub>mass</sub> and VO<sub>2peak</sub> [<span>4, 9</span>].</p><p>Healthy men and women (<i>n</i> = 30, 43% ♀) matched by sex, age (38.5 ± 16.5 vs. 43.6 ± 14.5 years, <i>p</i> = 0.378), body mass index (BMI) (22.3 ± 3.2 vs. 21.7 ± 2.8 kg m<sup>−2</sup>, <i>p</i> = 0.302) and moderate-to-vigorous physical activity (5.2 ± 2.5 vs. 4.9 ± 3.7 h week<sup>−1</sup>, <i>p</i> = 0.811) were recruited via printed/online advertisements in the city of Hong Kong. All individuals were non-obese (body mass index (BMI) < 30), normotensive, and non-smokers. Inc
耐力训练（ET）通过增加循环血红蛋白量（Hbmass）来有效地提高健康人的有氧能力。我们和其他人观察到，ET后改善的峰值耗氧量（vo2峰值）在取血后恢复到训练前的值，以抵消ET引起的Hbmass增加[2,3]。同样，Hbmass和vo2峰值的增加是由ET剂量决定的。因此，我们对vo2峰值的大幅改善持怀疑态度，而不是血液学适应的主要基础，并期望生活方式干预，包括ET作为主要刺激，提高vo2峰值和红细胞生成。在发达国家，膳食补钙非常普遍。大约一半的美国人，包括70%的老年妇女，在饮食中补充钙。在药理学试验中，钙补充剂也被用作安慰剂，假设其对血液系统和心血管系统的影响可以忽略不计。然而，在过去的一个世纪里，动物研究表明，补钙后血红蛋白（Hb）浓度发生了很大的变化[6,7]。最近，一项研究实施了8周的ET联合补钙作为安慰剂，并没有增加健康女性和男性的Hbmass，但显著提高了vo2峰值（9%至17%）。在该研究中，ET的方式不包括典型的（直立）运动，如骑自行车或跑步，而是划船，这可能导致中枢血流动力学改变，与红细胞生成[8]的内分泌调节负相互作用。事实上，划船干预引起孤立性左心房扩大，通常反映慢性压力过载。因此，问题仍然是典型的ET联合钙补充（ET- ca）是否在不引起血液学适应的情况下增加了VO2peak。在这里，我们检验了一个假设，即8周的直立骑行ET-Ca可以提高vo2峰值，而不会同时增加健康女性和男性的Hbmass。由于我们实验室之前的ET干预，应用类似的运动刺激6-8周，导致Hbmass和vo2峰值成比例增加，因此没有单独实施ET的对照干预[4,9]。通过印刷/网络广告在香港招募健康男性和女性（n = 30, 43%♀），性别，年龄（38.5±16.5对43.6±14.5岁，p = 0.378），体重指数（BMI）（22.3±3.2对21.7±2.8 kg m - 2, p = 0.302）和中等至高强度体力活动（5.2±2.5对4.9±3.7 h, p = 0.811）匹配。所有受试者均为非肥胖（身体质量指数（BMI） < 30）、血压正常且不吸烟。纳入标准包括根据临床问卷和静息超声心动图/心电图筛查得出的健康状况，无当前医学症状和药物，无慢性疾病史。这项研究已获香港大学/医院管理局西联网院校检讨委员会（uw22 -025）批准。参与者被分配到8周的ET-Ca。ET项目包括28次垂直骑行几何运动（每周3-4次，每隔一天）。所有ET的平均强度固定为峰值心率（HRpeak）的75%，持续50分钟。补钙包括口服碳酸钙片（500毫克，山东御旺药业）。药片在每次ET前4小时摄入。血液学变量(Hbmass, red blood cell volume (RBCV), plasma volume (PV), blood volume （BV)， erythropo生成素（EPO））和有氧能力的测量遵循我们实验室建立的方案，最近有详细报道[10,11]。统计分析（SPSS 26.0， IBM）包括双向方差分析，重复测量性别和时间（前，后）作为受试者之间和受试者内部因素，以及它们的相互作用。ET-Ca未改变男性（865±194比868±237 g， p = 0.878； 2657±589比2665±524 mL， p = 0.894）和女性（550±75比569±103 g， p = 0.414； 1691±230比1752±317 mL， p = 0.407）的Hbmass和RBCV。女性PV随ET-Ca升高（3163±380 vs 3430±574 mL, p = 0.027），而男性PV无升高（4065±681 vs 4187±774 mL, p = 0.224）。ET-Ca未增加男性BV（6722±1176 vs. 6852±1427 mL, p = 0.395）和女性BV（4854±542 vs. 5182±842 mL, p = 0.083）。男性（20.1±5.6 vs. 22.3±10.7 mlU mL - 1, p = 0.316）和女性（17.7±5.2 vs. 20.9±4.9 mlU mL - 1, p = 0.075）的循环EPO未随ET-Ca升高。性别和时间之间没有相互作用（p≥0.190）。图1显示了ET-Ca对有氧运动能力的影响。ET-Ca增加了男性（p < 0.001）和女性（p < 0.001）的vo2峰值和峰值功率输出（Wpeak）。性别和时间之间没有相互作用（p≥0.127）。结果证实了经过测试的假设，但提出了钙补充如何损害et诱导的红细胞生成的问题。 四分之三世纪前，在小鼠身上进行的实验表明，补钙后Hb浓度显著下降（高达46%），20世纪90年代在大鼠身上也得到了类似的结果。铁的补充和钙的补充在一定程度上阻止了血液携氧能力的降低。尽管如此，钙诱导的（部分）铁吸收阻滞似乎是短暂的，不能完全解释人类血红蛋白在数周内的红细胞生成减少。另外，增加血钙浓度的药物（高钙血症）会引起循环EPO的急剧下降。在这方面，我们没有观察到循环EPO的减少。因此，潜在的机制仍然难以捉摸。尽管如此，我们的研究揭示了一种有趣的可能性，即广泛使用的提高成绩的药物，即糖皮质激素，可以降低血液中钙的浓度，可能会加速红细胞生成。如果耐力运动的剂量足够高，ET毫无例外地提高了健康人的有氧运动能力。在我们的研究中，vo2峰值的增加与健康个体中中等剂量ET的预期效果一致[0]。vo2峰值的增加也与先前在健康女性和男性中实施ET和补钙的研究相匹配[0]。同样，在两项研究中，ET-Ca诱导PV轻度升高，这在女性中具有重要意义。然而，我们之前确定，孤立的PV扩张不会提高健康女性和男性的vo2峰值。因此，补钙不会减弱ET对vo2峰值的影响，但必须改变其主要的潜在机制，使其朝着非血液学的方向发展，目前尚不清楚。综上所述，ET联合补钙不会增强女性和男性有氧运动能力的血液学决定因素。然而，ET-Ca可以提高两性的有氧运动能力。因此，增加循环Hbmass和BV扩张对于适度改善健康成人的vo2峰值并不是必不可少的。钙在运动诱导红细胞生成的调节中的潜在作用为临床和提高成绩的目标开辟了新的研究路线。作者声明无利益冲突。
{"title":"Does Calcium Supplementation Negate Erythropoiesis With Endurance Training?","authors":"Meihan Guo, David Montero","doi":"10.1111/apha.70108","DOIUrl":"https://doi.org/10.1111/apha.70108","url":null,"abstract":"<p>Endurance training (ET) effectively enhances aerobic capacity in healthy humans by increasing circulating hemoglobin mass (Hb<sub>mass</sub>) [<span>1</span>]. We and others have observed that improved peak O<sub>2</sub> consumption (VO<sub>2peak</sub>) after ET is reverted to pre-training values following blood withdrawal to negate the ET-induced gain in Hb<sub>mass</sub> [<span>2, 3</span>]. Likewise, increases in Hb<sub>mass</sub> and VO<sub>2peak</sub> are determined by the ET dose [<span>4</span>]. Consequently, we are skeptical of large improvements in VO<sub>2peak</sub> not primarily underlain by hematological adaptations, and expect that lifestyle interventions, including ET as the main stimuli, enhance VO<sub>2peak</sub> along with erythropoiesis.</p><p>Dietary calcium supplementation is highly prevalent in developed countries. Around half of the US population, including 70% of older women, supplement their diets with calcium. Calcium supplementation is also used as a placebo in pharmacological trials, assuming its negligible effects on hematological and cardiovascular systems [<span>5</span>]. However, in the past century, animal studies demonstrated large alterations in hemoglobin (Hb) concentration with calcium supplementation [<span>6, 7</span>]. Recently, a study implementing 8 weeks of ET combined with calcium supplementation as a placebo did not increase Hb<sub>mass</sub> but substantially enhanced VO<sub>2peak</sub> (9% to 17%) in healthy women and men [<span>5</span>]. In that study, the modality of ET did not comprise typical (upright) exercises such as cycling or running, but rowing, which may entail central hemodynamic alterations negatively interacting with the endocrine regulation of erythropoiesis [<span>8</span>]. In fact, the rowing intervention induced isolated left atrial enlargement, commonly reflecting chronic pressure overload [<span>8</span>]. Therefore, the question remains whether typical ET combined with calcium supplementation (ET-Ca) increases VO<sub>2peak</sub> without eliciting hematological adaptations. Here, we tested the hypothesis that 8 weeks of upright cycling ET-Ca enhances VO<sub>2peak</sub> without concomitant increases in Hb<sub>mass</sub> in healthy women and men. A control intervention for ET alone was not implemented since previous ET interventions in our laboratory, applying similar exercise stimuli for 6–8 weeks, resulted in proportional gains in Hb<sub>mass</sub> and VO<sub>2peak</sub> [<span>4, 9</span>].</p><p>Healthy men and women (<i>n</i> = 30, 43% ♀) matched by sex, age (38.5 ± 16.5 vs. 43.6 ± 14.5 years, <i>p</i> = 0.378), body mass index (BMI) (22.3 ± 3.2 vs. 21.7 ± 2.8 kg m<sup>−2</sup>, <i>p</i> = 0.302) and moderate-to-vigorous physical activity (5.2 ± 2.5 vs. 4.9 ± 3.7 h week<sup>−1</sup>, <i>p</i> = 0.811) were recruited via printed/online advertisements in the city of Hong Kong. All individuals were non-obese (body mass index (BMI) < 30), normotensive, and non-smokers. Inc","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70108","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145135701","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}
Michael J. Gaudry, Amanda Bundgaard, Maria Kutschke, Klaudia Ostatek, Margeoux A. S. Dela Rosa, Paul G. Crichton, Jane Reznick, Martin Jastroch
Aim
Uncoupling protein 1 (UCP1) is the crucial protein for non-shivering thermogenesis in placental mammals, but the molecular mechanism of thermogenic proton transport is still unknown. Its histidine pair motif (H145 and H147) has been claimed as a critical element for proton translocation, leading to the paradigmatic “cofactor model” of the UCP1 thermogenic mechanism. The histidine pair motif is mutated (H145Q) in the naked mole-rat (NMR, Heterocephalus glaber) UCP1, suggesting disrupted thermogenic function in line with NMR's poor thermoregulatory abilities. Here, we investigated the functionality NMR versus mouse UCP1 to scrutinized the importance of the histidine pair motif.
Methods
Respiratory analyses for UCP1 function were performed in isolated brown adipose tissue mitochondria from NMR and mouse. The histidine pair motif of NMR UCP1 was manipulated through mutations, ectopically overexpressed in HEK293 cells and subjected to plate-based respirometry for functional comparison.
Results
Isolated BAT mitochondria of NMRs display guanosine diphosphate-sensitive respiration, indicative of thermogenically competent UCP1. Overexpressed wildtype NMR UCP1 demonstrates proton leak activity comparable to mouse UCP1. Neither restoration of the histidine pair motif nor full ablation of the motif through a double mutation affects UCP1-dependent respiration.
Conclusions
The UCP1 variant of the NMR, a warm-adapted fossorial species, excludes the histidine pair motif as crucial for UCP1 thermogenic function. Collectively, we show that functional investigation into natural sequence variation of UCP1 not only casts new light on the thermophysiology of NMRs but also represents a powerful tool to delineate structure-function relationships underlying the enigmatic thermogenic proton transport of UCP1.
目的：解偶联蛋白1 （Uncoupling protein 1, UCP1）是胎盘哺乳动物非寒战产热的关键蛋白，但其产热质子转运的分子机制尚不清楚。它的组氨酸对基序（H145和H147）被认为是质子易位的关键因素，导致UCP1产热机制的典型“辅因子模型”。裸鼹鼠（NMR, Heterocephalus glaber） UCP1的组氨酸对基序（H145Q）发生突变，表明其产热功能受到破坏，这与NMR较差的热调节能力有关。在这里，我们研究了功能性核磁共振与小鼠UCP1，以仔细检查组氨酸对基序的重要性。方法：对核磁共振和小鼠分离的棕色脂肪组织线粒体进行UCP1功能的呼吸分析。通过突变操纵NMR UCP1的组氨酸对基序，在HEK293细胞中异位过表达，并进行基于板的呼吸测量进行功能比较。结果：NMRs分离的BAT线粒体显示鸟苷二磷酸敏感呼吸，表明UCP1具有产热能力。过表达的野生型NMR UCP1显示出与小鼠UCP1相当的质子泄漏活性。组氨酸对基序的恢复和基序的完全消融都不会通过双突变影响ucp1依赖的呼吸。结论：UCP1的NMR变体是一种适应温暖的穴居物种，它排除了组氨酸对基序，而组氨酸对基序对于UCP1的产热功能至关重要。总之，我们表明，对UCP1自然序列变化的功能研究不仅为nmr的热生理学提供了新的视角，而且还代表了描述UCP1神秘的热质子传输背后的结构-功能关系的有力工具。
{"title":"Natural Mutation in Naked Mole-Rat UCP1 Refutes Importance of the Histidine Pair Motif for Proton Conductance and Thermogenesis","authors":"Michael J. Gaudry, Amanda Bundgaard, Maria Kutschke, Klaudia Ostatek, Margeoux A. S. Dela Rosa, Paul G. Crichton, Jane Reznick, Martin Jastroch","doi":"10.1111/apha.70109","DOIUrl":"10.1111/apha.70109","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Uncoupling protein 1 (UCP1) is the crucial protein for non-shivering thermogenesis in placental mammals, but the molecular mechanism of thermogenic proton transport is still unknown. Its histidine pair motif (H145 and H147) has been claimed as a critical element for proton translocation, leading to the paradigmatic “cofactor model” of the UCP1 thermogenic mechanism. The histidine pair motif is mutated (H145Q) in the naked mole-rat (NMR, <i>Heterocephalus glaber</i>) UCP1, suggesting disrupted thermogenic function in line with NMR's poor thermoregulatory abilities. Here, we investigated the functionality NMR versus mouse UCP1 to scrutinized the importance of the histidine pair motif.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Respiratory analyses for UCP1 function were performed in isolated brown adipose tissue mitochondria from NMR and mouse. The histidine pair motif of NMR UCP1 was manipulated through mutations, ectopically overexpressed in HEK293 cells and subjected to plate-based respirometry for functional comparison.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Isolated BAT mitochondria of NMRs display guanosine diphosphate-sensitive respiration, indicative of thermogenically competent UCP1. Overexpressed wildtype NMR UCP1 demonstrates proton leak activity comparable to mouse UCP1. Neither restoration of the histidine pair motif nor full ablation of the motif through a double mutation affects UCP1-dependent respiration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The UCP1 variant of the NMR, a warm-adapted fossorial species, excludes the histidine pair motif as crucial for UCP1 thermogenic function. Collectively, we show that functional investigation into natural sequence variation of UCP1 not only casts new light on the thermophysiology of NMRs but also represents a powerful tool to delineate structure-function relationships underlying the enigmatic thermogenic proton transport of UCP1.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 10","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70109","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129640","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}
In the present issue of Acta Physiologica [1], an international consortium of investigators reports that the iron-transporter glycoprotein lipocalin-2 (LCN2), originally identified in neutrophils and named neutrophil gelatinase-associated lipocalin, abbreviated NGAL or 24p3, may protect the kidneys from ischemia–reperfusion injury. The findings suggest that LCN2 protects the kidneys by restoring the sensitivity of soluble guanylate cyclase (sGC) to drug activators in afferent glomerular arterioles through a receptor-mediated mechanism. LCN2 is produced and released by several tissues including adipose tissue, liver, kidneys, and neutrophils. It is categorized as an acute-phase protein that is upregulated during inflammatory states. LCN2 is widely used in clinical and experimental settings as an early biomarker in acute kidney injury and for the staging of chronic kidney disease.
The study by Zhao et al. [1] is an elegant follow-up study on a series of independent observations dating 10–20 years back, which include a study by authors from 2016 [2]. A consistent kidney-protective effect of exogenous LCN2 was found in preclinical kidney ischemia-injury models, including a kidney transplantation model. The study in Acta shows ex vivo with murine, isolated kidney microvessels, that LCN2 mitigates excessive microvascular resistance through restoring vascular smooth sGC sensitivity towards activator drugs. The sensitivity is typically lost by more severe prolonged hypoxia. Soluble GCs can be oxidized to the heme-free form, apo-sGC, and the authors confirm that apo-sGC cannot be activated by the endogenous agonist nitric oxide (NO). The class of sGC activator drugs is unique and different from sGC stimulators since they can overcome this state and activate apo-sGC independently of NO to increase target cell cyclic guanosine monophosphate (cGMP) production even under detrimental oxidative stress. Zhao et al. [1] show that LCN2 restores sensitivity of the kidney afferent arterioles towards sGC activators dependent on iron. The effect is found in arterioles subjected to hypoxia ex vivo after isolation and in arterioles subjected to hypoxia “in situ” in transplanted kidneys before microdissection and testing. The conclusion is that by delivering ferric iron bound to LCN2 (holo-LCN2) to arterioles, this oxidizes sGC, which restores sensitivity to activator drugs. The study corroborates that LCN2 may be a direct, extracellular, signaling molecule that indirectly protects vascular smooth muscle suffering from prolonged ischemic insults in the kidneys (Figure 1).
What is the mechanism? LCN2 binds hydrophobic microbial siderophores, which are small molecules that bacteria produce to sequester iron from their environment. The acute phase reactant LCN2 is thereby bacteriostatic since iron is a vital nutrient for many microbes. Deletion of LCN2 increases susceptibility to Esch
{"title":"Beyond Being a Biomarker: Lipocalin-2/NGAL as a Facilitator for Protective Drug Action in Hypoxic Kidney Injury","authors":"Boye L. Jensen","doi":"10.1111/apha.70110","DOIUrl":"10.1111/apha.70110","url":null,"abstract":"<p>In the present issue of <i>Acta Physiologica</i> [<span>1</span>], an international consortium of investigators reports that the iron-transporter glycoprotein lipocalin-2 (LCN2), originally identified in neutrophils and named <i>neutrophil gelatinase-associated lipocalin</i>, abbreviated NGAL or 24p3, may protect the kidneys from ischemia–reperfusion injury. The findings suggest that LCN2 protects the kidneys by restoring the sensitivity of soluble guanylate cyclase (sGC) to drug activators in afferent glomerular arterioles through a receptor-mediated mechanism. LCN2 is produced and released by several tissues including adipose tissue, liver, kidneys, and neutrophils. It is categorized as an acute-phase protein that is upregulated during inflammatory states. LCN2 is widely used in clinical and experimental settings as an early biomarker in acute kidney injury and for the staging of chronic kidney disease.</p><p>The study by Zhao et al. [<span>1</span>] is an elegant follow-up study on a series of independent observations dating 10–20 years back, which include a study by authors from 2016 [<span>2</span>]. A consistent kidney-protective effect of exogenous LCN2 was found in preclinical kidney ischemia-injury models, including a kidney transplantation model. The study in <i>Acta</i> shows ex vivo with murine, isolated kidney microvessels, that LCN2 mitigates excessive microvascular resistance through restoring vascular smooth sGC sensitivity towards activator drugs. The sensitivity is typically lost by more severe prolonged hypoxia. Soluble GCs can be oxidized to the heme-free form, apo-sGC, and the authors confirm that apo-sGC cannot be activated by the endogenous agonist nitric oxide (NO). The class of sGC activator drugs is unique and different from sGC stimulators since they can overcome this state and activate apo-sGC independently of NO to increase target cell cyclic guanosine monophosphate (cGMP) production even under detrimental oxidative stress. Zhao et al. [<span>1</span>] show that LCN2 restores sensitivity of the kidney afferent arterioles towards sGC activators dependent on iron. The effect is found in arterioles subjected to hypoxia ex vivo after isolation and in arterioles subjected to hypoxia “in situ” in transplanted kidneys before microdissection and testing. The conclusion is that by delivering ferric iron bound to LCN2 (holo-LCN2) to arterioles, this oxidizes sGC, which restores sensitivity to activator drugs. The study corroborates that LCN2 may be a direct, extracellular, signaling molecule that indirectly protects vascular smooth muscle suffering from prolonged ischemic insults in the kidneys (Figure 1).</p><p>What is the mechanism? LCN2 binds hydrophobic microbial siderophores, which are small molecules that bacteria produce to sequester iron from their environment. The acute phase reactant LCN2 is thereby bacteriostatic since iron is a vital nutrient for many microbes. Deletion of LCN2 increases susceptibility to <i>Esch","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 10","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70110","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123858","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}
The cerebral circulation is continuously challenged by intravascular micrometer-sized particles that become trapped microvascular-emboli. These particles may include micro-thrombi, stiffened erythrocytes, and leukocytes, while also fat particles, air, and microplastics may cause microvascular embolism.
Review Scope
In this narrative review, we discuss these embolization processes and their acute and chronic consequences. These relate to the local flow interruption as well as the direct interaction with the endothelium. In addition, we address the clearing processes, including local thrombolysis and extravasation, or angiophagy, of the emboli.
Conclusion
A continuous balance exists between embolic events and their resolution under normal conditions. Increased micro-embolic rates, as occur in e.g., atrial fibrillation, or decreased clearing, possibly related to endothelial cell dysfunction, disturb this balance. This could lead to continuing loss of capillaries, micro-infarcts, and cognitive decline.
{"title":"Micro-Embolic Events and Their Clearing in the Brain. A Narrative Review","authors":"Kevin Mol, Inge A. Mulder, Ed van Bavel","doi":"10.1111/apha.70098","DOIUrl":"https://doi.org/10.1111/apha.70098","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The cerebral circulation is continuously challenged by intravascular micrometer-sized particles that become trapped microvascular-emboli. These particles may include micro-thrombi, stiffened erythrocytes, and leukocytes, while also fat particles, air, and microplastics may cause microvascular embolism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Review Scope</h3>\u0000 \u0000 <p>In this narrative review, we discuss these embolization processes and their acute and chronic consequences. These relate to the local flow interruption as well as the direct interaction with the endothelium. In addition, we address the clearing processes, including local thrombolysis and extravasation, or angiophagy, of the emboli.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>A continuous balance exists between embolic events and their resolution under normal conditions. Increased micro-embolic rates, as occur in e.g., atrial fibrillation, or decreased clearing, possibly related to endothelial cell dysfunction, disturb this balance. This could lead to continuing loss of capillaries, micro-infarcts, and cognitive decline.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 10","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70098","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145021990","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}
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