Acta Physiologica最新文献_第3页

The Absence of Collagen VI Reduces Systolic Function but Paradoxically Increases Ca2+ Release in the Rat Heart 缺乏胶原VI降低收缩功能，但矛盾的是增加Ca2+释放在大鼠心脏。

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2025-12-22 DOI: 10.1111/apha.70144

A. Krstic, H. Moammer, S. Hassan, J. Bai, P. Kallingappa, Y. Hou, M. Annandale, A. Taberner, J.-C. Han, K. Mellor, M. L. Ward, C. J. Barrett, D. J. Crossman

Aim

Collagen VI has recently been strongly linked to poor outcomes in heart failure through increased endotrophin, a collagen VI-derived signaling molecule linked to fibrotic remodeling in cardiovascular disease. The mutation of collagen VI can result in Ullrich congenital muscular dystrophy and Bethlem myopathy, pointing to a critical function in muscle physiology. However, the functional role of collagen VI in the heart is poorly understood. In human heart failure with reduced ejection fraction, collagen VI is increased within the remodeled T-tubules, suggesting a possible role in tubular structure and Ca²⁺ dynamics.

Methods

To investigate this hypothesis, a global knockout of the collagen VI alpha 1 gene (Col6a1^−/−) was generated in the rat.

Results

T-tubule structure and ryanodine receptor cluster organization were unchanged, but echocardiography demonstrated reduced systolic function. Consistent with this, isolated trabeculae from Col6a1^−/− hearts generated significantly less peak stress, confirming impaired contractile force at the tissue level. Paradoxically, isolated cardiomyocytes from the Col6a1^−/− rat had increased Ca²⁺ transient amplitude and increased sarcoplasmic reticulum Ca²⁺ load that would be expected to increase force. β-adrenergic stimulation further increased Ca²⁺ transient amplitude and was associated with diastolic Ca²⁺ release events in Col6a1^−/− cardiomyocytes. Furthermore, β-adrenergic stimulation of Col6a1^−/− trabeculae exhibited spontaneous contractions, indicating an increased susceptibility to arrhythmic activity.

Conclusion

Together, these results indicate collagen VI has a role in both force transduction and Ca²⁺ cycling in the heart.

目的：胶原VI通过增加内营养蛋白（一种胶原VI衍生的信号分子，与心血管疾病的纤维化重塑相关）与心力衰竭的不良结局密切相关。胶原VI突变可导致乌尔里希先天性肌营养不良和贝氏肌病，提示其在肌肉生理中具有重要功能。然而，胶原VI在心脏中的功能作用尚不清楚。在射血分数降低的心力衰竭患者中，胶原VI在重塑的t小管内增加，提示其可能在管状结构和Ca2+动力学中起作用。方法：为了验证这一假设，在大鼠体内产生了胶原VI α 1基因（Col6a1-/-）的全局敲除。结果：t小管结构和ryanodine受体簇组织没有变化，但超声心动图显示收缩功能降低。与此一致的是，Col6a1-/-心脏的分离小梁产生的峰值应力显著减少，证实了组织水平的收缩力受损。矛盾的是，从Col6a1-/-大鼠分离的心肌细胞增加了Ca2+瞬态振幅和增加的肌浆网Ca2+负荷，预计会增加力。β-肾上腺素能刺激进一步增加Ca2+瞬态振幅，并与Col6a1-/-心肌细胞舒张期Ca2+释放事件相关。此外，β-肾上腺素能刺激Col6a1-/-小梁表现出自发收缩，表明对心律失常活动的易感性增加。结论：综上所述，这些结果表明胶原VI在心脏的力传导和Ca2+循环中都有作用。

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引用次数: 0

DDR1 Regulates Femoral Arterial Calcification in Lower-Extremity Artery Disease Through NF-Kappa B Activation DDR1通过nf - κ B激活调节下肢动脉疾病的股动脉钙化。

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2025-12-16 DOI: 10.1111/apha.70146

Manovriti Thakur, Thibaut Quillard, Nico Angliker, Mark Siegrist, Yvonne Jansen, Yi Yan, Julia Wollenhaupt, Claudia Goettsch, Lars Maegdefessel, Nadia Sachs, Marc Schindewolf, Drosos Kotelis, Heidi Noels, Yvonne Döring

Aim

Lower-extremity arterial disease (LEAD) is a manifestation of atherosclerotic cardiovascular disease, affecting 230 million people worldwide with increasing prevalence. Medial arterial calcification (MAC) is common in LEAD patients and contributes to disease-related mortality. However, therapeutic strategies targeting femoral MAC are lacking, and its underlying mechanisms remain unclear. This study aimed to identify molecular drivers of femoral MAC in LEAD.

Methods & Results

Calcium deposits and pro-calcifying markers were analyzed in human patient samples using von Kossa staining, immunofluorescence, and gene expression analysis. Femorals showed significantly more calcification and pro-calcifying gene expression than carotids. Given MAC abundance in LEAD, we assessed medial calcification in Apoe−/− mice fed a WD for 4/21 weeks. Digital PCR revealed upregulation of Ddr1 and Bmp2 in femoral versus carotid arteries after 21 weeks of WD. DDR1 expression positively correlated with calcification in human femoral samples. In vitro experiments with mouse femoral vs. carotid vascular smooth muscle cells (VSMCs) confirmed a significantly higher prevalence of calcifying proteins (DDR1, BMP2, and RUNX2) in femoral VSMCs. Additionally, calcification analyses in murine and human VSMCs showed that DDR1 inhibition reduced, while DDR1 activation increased, calcium deposition. Transcriptomic analysis revealed elevated NF-κB expression in human femoral arteries, matching data in femoral VSMCs. DDR1 stimulation activated NF-κB, and its inhibition blocked DDR1-induced calcification.

Conclusion

This study identifies DDR1 as a key driver of calcification in LEAD, operating through NF-κB activation and the expression of calcifying proteins. Targeting DDR1 may offer a novel therapeutic approach to prevent MAC in LEAD.

目的：下肢动脉疾病（LEAD）是动脉粥样硬化性心血管疾病的一种表现形式，影响全球2.3亿人，且患病率不断上升。内侧动脉钙化（MAC）在铅患者中很常见，并导致疾病相关的死亡率。然而，针对股骨MAC的治疗策略缺乏，其潜在机制仍不清楚。本研究旨在确定铅致股骨MAC的分子驱动因素。方法与结果：采用von Kossa染色法、免疫荧光法和基因表达法分析患者标本中的钙沉积和促钙化标志物。股骨的钙化和促钙化基因表达明显高于颈动脉。考虑到铅中MAC的丰度，我们评估了Apoe-/-小鼠喂养WD 4/21周后的内侧钙化情况。数字PCR显示，WD 21周后，股骨动脉和颈动脉中Ddr1和Bmp2表达上调。DDR1表达与人股骨钙化呈正相关。小鼠股骨和颈动脉血管平滑肌细胞（VSMCs）的体外实验证实，在股骨血管平滑肌细胞中，钙化蛋白（DDR1、BMP2和RUNX2）的发生率明显更高。此外，小鼠和人VSMCs的钙化分析显示，DDR1抑制降低，而DDR1激活增加，钙沉积。转录组学分析显示，人股动脉中NF-κB表达升高，与股VSMCs中的数据相符。DDR1刺激可激活NF-κB，其抑制可阻断DDR1诱导的钙化。结论：本研究确定DDR1通过NF-κB激活和钙化蛋白的表达，是铅细胞钙化的关键驱动因素。靶向DDR1可能提供一种新的治疗方法来预防LEAD中的MAC。

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引用次数: 0

Succinate Modulation as a Biochemical Correlate of Metabolic and Neurobehavioral Changes Associated With Intermittent Fasting in Obesity 琥珀酸调节作为与间歇性禁食肥胖相关的代谢和神经行为变化的生化相关。

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2025-12-15 DOI: 10.1111/apha.70143

Andrea Tognozzi, Fabrizia Carli, Sherif Abdelkarim, Sara Cornuti, Francesca Damiani, Maria Grazia Giuliano, Alice Miniati, Martina Nasisi, Lia De Benedictis, Kousha Changizi Ashtiani, Gaia Scabia, Margherita Maffei, Pierre Baldi, Amalia Gastaldelli, Paola Tognini

Aim

Obesity significantly impacts the central nervous system (CNS), increasing the risks of neuropsychiatric disorders and dementia. Intermittent fasting (IF) shows promise for improving peripheral and CNS health, but its mechanisms are unclear.

Methods

Using a diet-induced obesity mouse model [10 weeks high fat diet (HFD), then 4 weeks intervention], we compared HFD, HFD-IF, ad libitum control chow (CC), and CC-IF groups.

Results

Switching to CC or IF reduced body weight, fat mass, and improved glucose tolerance. Notably, CC-IF uniquely enhanced exploration and reduced anxiety-like behavior. Transcriptomics revealed HFD-induced hippocampal neuroinflammation, whereas metabolomics identified a specific succinate signature in CC-IF mice: plasma concentration decreased, whereas liver and brown adipose tissue (BAT) levels increased. Succinate supplementation mimicked CC-IF metabolic and behavioral benefits and reduced hippocampal inflammation.

Conclusion

These findings suggest that regulating plasma succinate and its metabolism in liver and BAT may represent a novel biochemical correlate underlying the metabolic, neuroinflammatory, and behavioral improvements induced by IF.

目的：肥胖显著影响中枢神经系统（CNS），增加神经精神疾病和痴呆的风险。间歇性禁食（IF）显示出改善外周和中枢神经系统健康的希望，但其机制尚不清楚。方法：采用饮食性肥胖小鼠模型[高脂饮食（HFD） 10周，然后干预4周]，比较HFD组、HFD- if组、任意对照饲料（CC）组和CC- if组。结果：切换到CC或IF降低体重，脂肪量，并改善葡萄糖耐量。值得注意的是，CC-IF独特地增强了探索和减少了焦虑样行为。转录组学揭示了hfd诱导的海马神经炎症，而代谢组学在CC-IF小鼠中发现了特定的琥珀酸盐特征：血浆浓度降低，而肝脏和棕色脂肪组织（BAT）水平升高。琥珀酸盐的补充模拟了CC-IF的代谢和行为益处，并减少了海马炎症。结论：这些研究结果表明，调节血浆琥珀酸盐及其在肝脏和BAT中的代谢可能是IF诱导的代谢、神经炎症和行为改善的一种新的生化关联。

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引用次数: 0

Body Temperature Regulation in the Rat by Muscle Tone 肌肉张力对大鼠体温的调节。

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2025-12-15 DOI: 10.1111/apha.70148

Arild Njå, Terje Lømo

Aim

We have previously described an important role of skeletal muscle tone in body temperature regulation, muscle tone defined as the tonic motor unit activity recorded between movements. Here, we study muscle tone in an extensive sample of new muscles outside (external muscles) and inside (internal muscles) the body core.

Methods

Skeletal muscles of adult, male Wistar rats were chronically implanted with EMG electrodes, and EMG was recorded during exposures to changes in ambient temperatures between 30°C and 5°C. Every consecutive period between movements (M) was identified as one of rest (R), whether the rat was awake or asleep. The amount of tonic motor unit impulse activity, or muscle tone, within (R) was then measured by root mean square analysis of the raw EMG.

Results

Muscle tone in external muscles depended strictly on ambient temperature, rising and falling with falling and rising ambient temperatures. In contrast, muscle tone in internal iliacus and psoas muscles showed no relation to ambient temperature but increased markedly during recovery from hypothermia caused by general anesthesia. Mean tonic motor unit firing rates varied between 10 and 75 Hz.

Conclusion

All examined muscles, except iliopsoas, participated in moment-to-moment regulation of body temperature by heat-producing muscle tone during rest. Iliopsoas appeared to have an emergency function coming into play when the body temperature fell below some critical value, as during anesthesia. The wide range of tonic firing rates indicated that not only slow but also fast, fatigue-resistant motor units contributed to heat-producing muscle tone during rest.

目的：我们之前已经描述了骨骼肌张力在体温调节中的重要作用，肌肉张力被定义为运动之间记录的紧张性运动单位活动。在这里，我们在身体核心外（外部肌肉）和内（内部肌肉）的大量新肌肉样本中研究肌肉张力。方法：将成年雄性Wistar大鼠骨骼肌长期植入肌电图电极，在30℃~ 5℃的环境温度变化下记录肌电图。无论大鼠是醒着还是睡着，每个连续的运动间隔时间(M)都被识别为休息时间(R)。(R)内的强直运动单位脉冲活动量或肌肉张力，然后通过原始肌电图的均方根分析来测量。结果：外肌张力与环境温度密切相关，随环境温度的升高而升高和下降。相比之下，髂内肌和腰肌的肌张力与环境温度无关，但在全身麻醉引起的低体温恢复期间显着增加。强直运动单元的平均放电频率在10至75赫兹之间变化。结论：除髂腰肌外，所有被测肌肉均在休息时通过产热肌张力参与体温的时刻调节。当体温低于某个临界值时，髂腰肌似乎具有紧急功能，如在麻醉期间。宽范围的强直性放电率表明，在休息时，不仅是缓慢的，而且是快速的，抗疲劳的运动单元有助于产生热量的肌肉张力。

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引用次数: 0

Upregulated Calcium Sensing Receptor Mediates Pulmonary Venous Remodeling in Pulmonary Hypertension 钙敏感受体上调介导肺动脉高压患者肺静脉重构。

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2025-12-12 DOI: 10.1111/apha.70142

Qiudi Mo, Xing Wen, Luyao Wang, Weitao Cao, Jieping Liang, Shaoxing Li, Zhenli Fu, Xiaohua Gao, Yan Xue, Hong Yuan, Zhenbo Xu, Wei Hong, Yumin Zhou, Gongyong Peng

Aim

The mechanism of pulmonary venous remodeling (PVR) remains unclear. We tested the role of the calcium sensing receptor (CaSR) in PVR in pulmonary hypertension (PH).

Methods

PVR was investigated in two PH models, monocrotaline (MCT)-induced PH (MCT-PH) and hypoxia-induced PH (HPH). Human pulmonary venous smooth muscle cells (PVSMCs) were subjected to hypoxia. We examined whether CaSR is involved in the enhanced Ca²⁺ influx and proliferation in PVSMCs and whether CaSR mediates PVR.

Results

PVR presented in distal pulmonary veins (PV) in MCT-PH and HPH rats, accompanied by upregulated CaSR expression in PVSMCs from PH rats. Hypoxia promoted human PVSMCs proliferation with increased CaSR and HIF-1α expression in hypoxic cells. Extracellular Ca²⁺ restoration induced a huge increase in [Ca²⁺]_i in MCT-PH PVSMCs and human hypoxic PVSMCs, which was significantly higher than that in normal cells. Both the basal [Ca²⁺]_i and proliferate rate in MCT-PH PVSMCs and human hypoxic PVSMCs were higher than in normal PVSMCs. Spermine or R568 enhanced, whereas both NPS2143 or NPS2390 and siCaSR attenuated the extracellular Ca²⁺-induced [Ca²⁺]_i increase in rat MCT-PH PVSMCs and human hypoxic PVSMCs and hypoxia-induced human PVSMCs proliferation. Blockade of CaSR with NPS2143 attenuated the increases in basal [Ca²⁺]_i in PVSMCs, right ventricular systolic pressure, and Fulton index in PH rats and prevented PVR and PH development in rats injected with MCT or exposed to hypoxia.

Conclusions

Upregulated CaSR mediating excessive PVSMCs proliferation through enhanced CaSR function and increased intracellular Ca²⁺ signaling is an important pathogenic mechanism underlying the development of PVR in PH.

目的：肺静脉重构（PVR）的机制尚不清楚。我们检测了钙敏感受体（CaSR）在肺动脉高压（PH）患者PVR中的作用。方法：采用单苦杏仁碱（MCT）诱导的PH （MCT-PH）和缺氧诱导的PH （HPH）两种PH模型研究PVR。人肺静脉平滑肌细胞（PVSMCs）缺氧。我们研究了CaSR是否参与PVSMCs中Ca2+内流和增殖的增强，以及CaSR是否介导PVR。结果：MCT-PH和HPH大鼠远端肺静脉（PV）中出现PVR， PH大鼠PVSMCs中CaSR表达上调。缺氧促进人PVSMCs增殖，缺氧细胞中CaSR和HIF-1α表达增加。细胞外Ca2+恢复诱导MCT-PH PVSMCs和人缺氧PVSMCs中[Ca2+]i的大量增加，明显高于正常细胞。MCT-PH PVSMCs和人缺氧PVSMCs的基础[Ca2+]i和增殖率均高于正常PVSMCs。精胺或R568增强，而NPS2143或NPS2390和siCaSR均减弱细胞外Ca2+诱导的大鼠MCT-PH PVSMCs和人缺氧PVSMCs的[Ca2+]i增加以及缺氧诱导的人PVSMCs增殖。NPS2143阻断CaSR可降低PVSMCs中基础[Ca2+]i的升高、PH大鼠右心室收缩压和Fulton指数，并可阻止MCT注射或缺氧大鼠PVR和PH的发展。结论：CaSR上调通过增强CaSR功能和增加细胞内Ca2+信号传导介导PVSMCs过度增殖是PH中PVR发生的重要致病机制。

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引用次数: 0

Effect of Weight-Neutral Treatment With Semaglutide or Tirzepatide on β-Cell Identity in db/db Mice 西马鲁肽或替西帕肽对db/db小鼠β细胞特性的影响。

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2025-12-07 DOI: 10.1111/apha.70141

Zhaobin Deng, Dongxu Zheng, Jinsook Son, Wen Du, Wendy M. McKimpson, Qingli Liu, Domenico Accili

Aim

Insulin resistance and pancreatic β-cell failure are key characteristics of type 2 diabetes (T2D). Impaired β-cell function is associated with loss of β-cell identity, resulting in β-cell dedifferentiation or trans-differentiation to other endocrine cells. We have shown that β-cell dedifferentiation can be reversed, restoring insulin secretion. The aim of this study was to investigate whether semaglutide or tirzepatide treatment can reverse early stages of β-cell dedifferentiation in db/db mice independent of their effect on body weight.

Methods

After 4 weeks of treatment, 12-week-old db/db mice were assessed by oral glucose tolerance test and immunofluorescence to evaluate glucose clearance capacity and effects on pancreatic β-cell. Body weight, fasting blood glucose, and plasma insulin levels were monitored weekly. Bulk RNA sequencing from islets was performed to identify potential targets.

Results

At the doses employed, tirzepatide stabilized, whereas semaglutide was unable to reverse the weight gain of db/db mice. After a 4-week course, both groups showed comparable glucose lowering and increased insulin levels. However, both treatments failed to reverse pancreatic β-cell dedifferentiation, as assessed by either the percentage of cells expressing the dedifferentiation marker ALDH1A3⁺ or FOXO1 translocation. Furthermore, the number of β-cells expressing low levels of PDX1 was higher in both treatment groups than in controls. Gene expression analyses showed a muted transcriptional response in overlapping patterns in islets treated with either compound but no obvious candidate target genes.

Conclusion

The findings highlight that the early glucose-lowering effects of semaglutide and tirzepatide in db/db mice occur independently of changes to β-cell identity.

目的：胰岛素抵抗和胰腺β细胞衰竭是2型糖尿病（T2D）的关键特征。β细胞功能受损与β细胞身份丧失相关，导致β细胞去分化或向其他内分泌细胞反分化。我们已经证明β细胞去分化可以逆转，恢复胰岛素分泌。本研究的目的是研究西马鲁肽或替西帕肽治疗是否可以逆转db/db小鼠早期β细胞去分化，而不依赖于它们对体重的影响。方法：治疗4周后，采用口服糖耐量试验和免疫荧光法评价12周龄db/db小鼠的葡萄糖清除能力及对胰腺β细胞的影响。每周监测体重、空腹血糖和血浆胰岛素水平。从胰岛进行大量RNA测序以确定潜在的靶点。结果：在使用的剂量下，替西帕肽稳定，而西马鲁肽无法逆转db/db小鼠的体重增加。在4周的疗程后，两组患者的血糖水平下降，胰岛素水平升高。然而，通过表达去分化标志物ALDH1A3+或fox01易位的细胞百分比来评估，两种治疗都未能逆转胰腺β细胞的去分化。此外，两个治疗组中表达低水平PDX1的β-细胞数量均高于对照组。基因表达分析显示，两种化合物处理的胰岛重叠模式的转录反应减弱，但没有明显的候选靶基因。结论：研究结果表明，在db/db小鼠中，西马鲁肽和替西帕肽的早期降糖作用独立于β细胞特性的改变。

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引用次数: 0

Suprachiasmatic Nuclei Possess Glucocorticoid Receptors That Activate Downstream Signaling Pathways but Do Not Entrain Their Circadian Clock 视交叉上核拥有糖皮质激素受体，可激活下游信号通路，但不干扰其生物钟

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2025-11-28 DOI: 10.1111/apha.70138

Martin Sládek, Vendula Lužná, Pavel Houdek, Alena Sumová

Aim

The circadian clock in the suprachiasmatic nuclei of the hypothalamus (SCN) is resistant to glucocorticoids (GC) in adults but responds to dexamethasone (DEX) during the fetal stage. Previously, this resistance of the adult SCN clock was attributed to a developmental loss of the glucocorticoid receptor (GR). The aim of our study was to re-examine the mechanism underlying SCN clock resistance.

Methods

We detected GR in the adult SCN at the mRNA level (Nr3c1) using RT-qPCR and at the protein level by immunohistochemistry, and examined the effects of DEX on the SCN clock of mPer2^Luc mice ex vivo at embryonic day E17, postnatal days P1–2, P3, P5, P10, and adulthood.

Results

Surprisingly, we found that Nr3c1 expression gradually increases from the fetal stage to postnatal day (P)28. In the adult SCN, GR immunoreactivity is present in both neurons and glia. The effect of DEX on the SCN clock disappears shortly after birth. Although DEX does not entrain the adult SCN clock, it acutely increases the expression of Gilz and Sgk1, indicating that GRs in the adult SCN can activate downstream signaling pathways. Inhibition of glial metabolism by fluorocitrate had no effect on resistance to DEX, but treatment with tetrodotoxin sensitized the clock to DEX and induced phase shifts similar to those observed at the fetal stage.

Conclusion

These results indicate that the adult SCN possesses GRs capable of activating GC-signaling pathways, but the clock is resistant to GC in part due to coupling between individual cellular oscillators.

目的：成人下丘脑视交叉上核（SCN）的生物钟对糖皮质激素（GC）有抗性，但在胎儿期对地塞米松（DEX）有应答。以前，成人SCN时钟的这种抗性归因于糖皮质激素受体（GR）的发育缺失。我们研究的目的是重新检查SCN时钟抗性的机制。方法采用RT-qPCR和免疫组化方法分别在mRNA水平（Nr3c1）和蛋白水平检测成体SCN中的GR，并检测DEX对mPer2Luc小鼠胚胎期E17、出生后P1-2、P3、P5、P10和成体SCN时钟的影响。结果令人惊讶的是，我们发现Nr3c1的表达从胎儿期到出生后逐渐增加(P)28。在成人SCN中，GR免疫反应性存在于神经元和胶质细胞中。DEX对SCN时钟的影响在出生后不久就消失了。虽然DEX不携带成人SCN时钟，但它会急剧增加Gilz和Sgk1的表达，这表明成人SCN中的GRs可以激活下游信号通路。氟柠檬酸抑制神经胶质代谢对DEX的耐药性没有影响，但河豚毒素治疗使时钟对DEX敏感，并诱导与胎儿期观察到的相移相似。这些结果表明，成年SCN具有能够激活GC信号通路的GRs，但由于单个细胞振荡器之间的耦合，时钟对GC具有抗性。

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引用次数: 0

Acute Normobaric Hypoxia Reveals Blunted Chemoreflex and Autonomic Dysfunction in Asymptomatic Post-COVID-19 Patients 急性常压缺氧显示无症状covid -19后患者化疗反射迟钝和自主神经功能障碍

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2025-11-25 DOI: 10.1111/apha.70136

Elissa Silva de Farias Mello, André Luiz Musmanno Branco Oliveira, Pedro Paulo da Silva Soares, Gabriel Dias Rodrigues

引用次数: 0

Differential pH Regulation in Cardiomyocytes 心肌细胞的差异pH调节。

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2025-11-18 DOI: 10.1111/apha.70134

Rudolf Schubert

<p>The recent study by Espejo and colleagues published in <i>Acta Physiologica</i> [<span>1</span>] caught my attention because it addresses a theme of particular interest to me, as well as a mechanism for which there is growing evidence: The differential expression and function of transporter molecules. In particular, this study focused on transporter molecules beyond the well-known ion channels and transporters responsible for the action potential and primary calcium handling [<span>2, 3</span>] in atrial and ventricular cardiomyocytes. On the one hand, this complicates the understanding of the functional role of these molecules (although it makes the life of a researcher more interesting). On the other hand, it opens up possibilities for more targeted interventions and therapeutic approaches.</p><p>The concept of differential expression and function of transporter molecules was previously addressed at the structural level [<span>4</span>] by the group that authored the study by Espejo and colleagues published in <i>Acta Physiologica</i> [<span>1</span>]. In this earlier study, the promoter activity of the electroneutral Na<sup>+</sup>, HCO<sub>3</sub><sup>−</sup> cotransporter NBCn1 (encoding gene Slc4a7) was observed in atrial, but not ventricular cardiomyocytes [<span>4</span>], and the differential expression of NBCn1 suggested a differential function of NBCn1 in atria and ventricles.</p><p>Notably, the authors remained curious about the functional consequences of the differential expression of NBCn1 in cardiomyocytes. Thus, when a specific tool for functionally exploring this question, namely an appropriate transgenic mouse, became available, Espejo and colleagues could address this issue [<span>1</span>]. The merit of their study lies in investigating the functional consequences of differential expression of NBCn1 with a clear and well-founded hypothesis at multiple levels: That NBCn1 influences structure, contractile function, and electrophysiological properties of the heart. The hypothesis was tested using a mouse model with global elimination of NBCn1. This model may have limitations, such as the possible development of compensatory mechanisms. However, for the present study, it was adequate as it simulates the effects of loss-of-function genetic variants or systemic therapeutic interventions.</p><p>What novel, additional insight was obtained by Espejo and colleagues in the <i>Acta Physiologica</i> publication [<span>1</span>] (see Figure 1)? It was shown that NBCn1 mRNA and protein expression are stronger in the atria compared to the ventricles. The knockdown of NBCn1 reduced acid transport function in the atria by more than 50%; alterations in net acid extrusion in the ventricles were not observed. These effects were accompanied by increased blood pressure and cardiac hypertrophy with slower ventricular relaxation, whilst detailed analysis of the ECG did not reveal alterations in electrophysiological properties. Further insight, howe

Espejo及其同事最近发表在《生理学学报》上的研究引起了我的注意，因为它提出了一个我特别感兴趣的主题，以及一个越来越多证据表明的机制：转运体分子的差异表达和功能。本研究特别关注了众所周知的离子通道之外的转运蛋白分子，以及心房和心室心肌细胞中负责动作电位和初级钙处理的转运蛋白[2,3]。一方面，这使对这些分子的功能作用的理解变得复杂（尽管这使研究人员的生活更有趣）。另一方面，它开辟了更有针对性的干预和治疗方法的可能性。Espejo及其同事发表在《生理学报》（Acta physi）上的研究报告的作者小组先前在结构水平上阐述了转运蛋白分子的差异表达和功能的概念。在这项早期的研究中，电中性Na+， HCO3−共转运体NBCn1（编码基因Slc4a7）的启动子活性在心房心肌细胞中被观察到，而在心室心肌细胞[4]中未被观察到，NBCn1的差异表达表明NBCn1在心房和心室中的不同功能。值得注意的是，作者仍然对心肌细胞中NBCn1差异表达的功能后果感到好奇。因此，当一种特定的工具，即一种合适的转基因小鼠，在功能上探索这个问题时，Espejo和他的同事就可以解决这个问题了。他们的研究的优点在于研究NBCn1差异表达的功能后果，并在多个层面上提出了一个明确且有充分根据的假设：NBCn1影响心脏的结构、收缩功能和电生理特性。这一假设通过一种NBCn1完全消除的小鼠模型进行了验证。这种模式可能有局限性，例如可能发展代偿机制。然而，对于目前的研究来说，它是足够的，因为它模拟了功能丧失基因变异或系统治疗干预的影响。Espejo和他的同事在《生理学学报》发表的b[1]（见图1）中获得了哪些新颖的、额外的见解？结果表明，NBCn1 mRNA和蛋白在心房的表达强于心室。NBCn1基因敲低可使心房酸转运功能降低50%以上；未观察到心室净酸挤压的改变。这些影响伴随着血压升高和心脏肥厚，心室舒张减慢，而心电图的详细分析并未显示电生理特性的改变。然而，通过对心房动作电位的进一步分析，可能会获得进一步的见解。总的来说，新发现强调了NBCn1在心房细胞内pH调节中的重要性，而不是在心室（至少在实验条件下研究）。此外，他们指出了一种间接效应，即心室肥厚伴舒张受损，这很可能是由于先前在该模型中报道的基于内皮功能障碍的血压升高[5,6]。这些作用的确切机制应该在心肌细胞特异性敲除模型中进行研究。总之，Espejo和他的同事[1]值得赞扬，他们证明了在启动子水平（在早期的研究中）检测到的NBCn1的差异表达具有功能影响。因此，他们的研究进一步提出了离子转运蛋白的不同功能，而不仅仅是众所周知的离子通道和转运蛋白，它们负责心肌细胞的动作电位和初级钙处理。此外，NBCn1基因全局性敲除引起的心功能相当温和的变化使作者认为NBCn1是一个相对安全的药物干预靶点。虽然转运蛋白分子在心肌细胞中的差异表达/功能最初引起了我的主要兴趣，但我想解决另一个重要方面。这与NBCn1蛋白在心室中的表达低于心房的观察结果有关，但NBCn1蛋白仍以相当高的水平表达。然而，在NBCn1基因敲除后，脑室的净酸分泌没有变化。这一观察证实并扩展了越来越多的证据，即心脏离子转运体，如钠/钙交换器和钠/钾atp酶的表达，无论是在mRNA水平还是在蛋白质水平上确定，都不一定反映在它们的功能影响中。事实上，这并不奇怪，因为功能活性不仅取决于表达，还取决于许多不反映在纯表达水平上的因素，如翻译后修饰，与其他激活或抑制分子的分子相互作用，与影响同一靶标的转运蛋白的功能相互作用，区隔化，参与亚细胞，局部调节过程，功能角色仅限于特定的（极端或病理生理）条件。然而，在对时髦的分子生物学技术的热情中，这一点经常被忽视，关于功能甚至潜在治疗后果的结论往往只根据表达数据得出。因此，表达式数据的解释应该更多地由数据驱动。或者，甚至更好的是，应该使用尽可能接近真实生理条件的模型进行功能实验。这是Espejo和他的同事在《生理学学报》上发表的研究成果，作者应该受到赞扬。作者声明无利益冲突。数据共享不适用于本文，因为在本研究中没有生成或分析数据集。

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引用次数: 0

Physiology of K+ Homeostasis in Cerebrospinal Fluid: The Fine-Tuning Role of the Choroid Plexus Kir7.1 Channel 脑脊液钾离子稳态的生理机制：脉络膜丛Kir7.1通道的微调作用。

IF 5.6 2区医学 Q1 PHYSIOLOGY

Acta Physiologica

Pub Date : 2025-11-17 DOI: 10.1111/apha.70137

Peng Long, Gelei Xiao

<p>Cerebrospinal fluid homeostasis typically refers to the dynamic equilibrium in the secretion, circulation, absorption, and physicochemical properties of cerebrospinal fluid (CSF). It is crucial for maintaining normal intracranial pressure, the stability of the intracranial internal environment, and normal cellular functions. In the November issue of <i>Acta Physiologica</i>, Henao et al. conducted further research on K<sup>+</sup> homeostasis in the CSF and published their findings in the article “Role of the choroid plexus Kir7.1 channel in the regulation of mouse cerebrospinal fluid K<sup>+</sup> concentration.” Using genome editing technology to establish models and observing the electrophysiological characteristics of mouse choroid plexus epithelial cells (CPE) and related K<sup>+</sup> transport pathways, they revealed a novel mechanism regulating K<sup>+</sup> concentration in the CSF and drew an important conclusion: Kir7.1 plays a critical role in the formation of the membrane potential in CPE and the regulation of [K<sup>+</sup>]<sub>CSF</sub> [<span>1</span>].</p><p>The choroid plexus, located in parts of the cerebral ventricles, is a key structure for CSF secretion. The apical and basolateral membranes of the CPE contain numerous ion transport pathways, including Na<sup>+</sup>-K<sup>+</sup>-ATPase, NKCC1, and Kir7.1 [<span>2</span>]. Kir (inward rectifying K<sup>+</sup> channels) are a class of K<sup>+</sup> channels with inward rectification properties. <i>Acta Physiologica</i> reported in 2017 on the important role of Kir4.1/Kir5.1 potassium channels in the renal distal tubules [<span>3</span>], suggesting that different Kir subtypes have distinct distributions and functions within the body. The gene name for Kir7.1 is KCNJ13. Unlike other “strong” rectifying channels, Kir7.1 exhibits weak inward rectification characteristics, very low single-channel conductance [<span>4</span>], and is highly sensitive to intra- and extracellular signals. NKCC1 stands for Na<sup>+</sup>-K<sup>+</sup>-2Cl<sup>−</sup> cotransporter 1. Its primary function is to mediate the coupled transport of Na<sup>+</sup>, K<sup>+</sup>, and CI<sup>−</sup> by utilizing the Na<sup>+</sup> and Cl<sup>−</sup> electrochemical gradients [<span>2</span>]. In summary, these three ion pathways interact and function cooperatively in K<sup>+</sup> transport.</p><p>Compared to the K<sup>+</sup> concentration in plasma (approximately 5.0 mmol/L), the K<sup>+</sup> level in the CSF is consistently maintained at a lower value of 2.5–3.0 mmol/L. Regarding this, MacAulay et al. conceptualized the “CPE-CSF K<sup>+</sup> cycle”, attributing the physiological recycling of K<sup>+</sup> in the CSF to the action of NKCC1 [<span>5</span>]. However, new research has found that Na<sup>+</sup>-K<sup>+</sup>-ATPase, NKCC1, and Kir7.1 are confirmed to co-localize and be highly expressed on the apical membrane of the CPE [<span>6</span>]. Specifically, Na<sup>+</sup>-K<sup>+</sup>-ATPase

脑脊液稳态通常是指脑脊液的分泌、循环、吸收和理化性质的动态平衡。它对于维持正常的颅内压、颅内内环境的稳定和正常的细胞功能至关重要。在《生理学报》11月刊上，Henao等人进一步研究了脑脊液中K+的稳态，并发表了“脉络丛Kir7.1通道在小鼠脑脊液K+浓度调节中的作用”一文。他们利用基因组编辑技术建立模型，观察小鼠脉络丛上皮细胞（CPE）电生理特征及相关K+转运途径，揭示了一种调节脑脊液中K+浓度的新机制，并得出重要结论：Kir7.1在CPE膜电位形成及[K+]脑脊液[1]调控中起关键作用。脉络膜丛位于脑室的部分区域，是脑脊液分泌的关键结构。CPE的顶膜和基底膜包含许多离子转运途径，包括Na+-K+- atp酶、NKCC1和Kir7.1[2]。Kir（向内整流K+通道）是一类具有向内整流特性的K+通道。2017年《生理学报》报道了Kir4.1/Kir5.1钾通道在肾远端小管[3]中的重要作用，表明不同的Kir亚型在体内具有不同的分布和功能。Kir7.1的基因名称是KCNJ13。与其他“强”整流通道不同，Kir7.1表现出弱的内向整流特性，非常低的单通道电导[4]，并且对细胞内和细胞外信号高度敏感。NKCC1代表Na+-K+-2Cl−共转运体1。其主要功能是利用Na+和Cl -电化学梯度[2]介导Na+、K+和CI -的耦合输运。综上所述，这三种离子途径在K+输运中相互作用并协同起作用。与血浆中K+浓度（约5.0 mmol/L）相比，脑脊液中的K+水平始终维持在2.5-3.0 mmol/L的较低水平。对此，MacAulay等人提出了“CPE-CSF K+循环”的概念，认为脑脊液中K+的生理循环是通过NKCC1[5]的作用实现的。然而，新的研究发现Na+-K+- atp酶、NKCC1和Kir7.1被证实在CPE[6]的顶膜上共定位并高表达。具体来说，Na+-K+- atp酶将K+从脑脊液转运到CPE细胞，同时在脑脊液中建立高Na+梯度。随后，NKCC1利用这种梯度将Na+、K+和CI -共运输到细胞中。两者的共同作用维持了脑脊液中的低K+环境。然而，为了防止脑脊液中K+水平过低，将CPE吸收的K+再循环回脑脊液的机制至关重要。Kir7.1由于其独特的生理特性和共表达谱，在K+循环过程中起着关键作用。Kir7.1具有独特的[K+]o不依赖性甚至负相关性，这意味着它将K+转运出细胞的过程可以在各种[K+]o条件下发生，差异很小[7]。正因为如此，Kir7.1在CPE-CSF K+循环中的具体调控机制具有重要的研究意义。Henao等在Acta physiology上的文章详细介绍了Kir7.1的作用机制。作者发现，Kir7.1在任何[K+]o条件下都表现出适度的内向整流特性，这与它对CPE总电流的主要贡献是一致的。然而，当Kir7.1表达不足时，CPE内电流轨迹由内向整流转向向外整流，逆转电位（Erev）呈现正偏移。这表明Kir7.1向内整流受损，K+外排功能受损，因此[K+]CSF减少。体内的基尔通常起稳定膜电位的微小变化或膜上离子浓度的微小波动的作用。因此，尽管Kir7.1是一个向内的整流通道，但其在顶膜上的主要作用实际上是K+外排，即介导和控制K+的再循环，K+通过Na+-K+- atp酶和NKCC1途径转运到CPE，再回到CSF（图1）。结果表明，Kir7.1是K+恢复到脑脊液的重要途径。当Kir7.1的[K+]o独立性被破坏时，随着[K+]CSF的升高，K+恢复到脑脊液的速率增加。作者进一步研究了Kir7.1在脑脊液稳态中的调节作用。Kir7.1确实对NKCC1的活性有显著的调控作用。NKCC1介导的离子转运方向一直存在争议。在这里，作者将NKCC1的功能定义为促进K+和水从CSF转运到CPE。尽管Kir7.1表达缺失并未改变脑脊液分泌量（可能是由于膜电位变化引发的其他电压门控离子通道的代偿机制），但Kir7.1的缺失极大地影响了NKCC1的活性。作者发现了一个高度非典型的特征：Kir7.1的功能缺失并不影响NKCC1的转运活性，但其结构缺失会显著损害NKCC1的活性，从而影响K+和水的转运（图1）。当使用高效特异性阻滞剂ML418急性抑制Kir7.1活性时，NKCC1共转运体的功能不受影响。然而，在Kir7.1条件敲除模型小鼠中，Kir7.1的结构缺失伴随着NKCC1共转运蛋白功能的显著抑制。虽然NKCC1的表达水平没有明显变化，但其磷酸化水平升高。虽然NKCC1表达和磷酸化的解耦需要进一步研究，但上述结果强烈表明，仅仅存在Kir7.1蛋白本身就足以维持正常的NKCC1功能。Kir7.1对[K+]脑脊液的调控充分说明了脑正常生理功能的复杂性。正因为如此，深入探索CPE和CSF稳态的调控已成为当前脑研究的一个重要热点。尽管脑脊液-脑屏障存在，但脑脊液稳态与脑实质之间一定存在潜在且高度复杂的相互作用。正如作者在他们的文章中指出的那样：脑脊液和脑间质液（ISF）中离子的变化是否相互影响仍然是一个值得探索的话题。彭龙：写作——原稿。肖戈雷：写作-评论和编辑。作者声明无利益冲突。作者没有什么可报告的。

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