Journal of General Physiology最新文献

Exploring a peripheral PIP2-binding site and its role in the alternative regulation of the TRP channel superfamily. 探索外周pip2结合位点及其在TRP通道超家族的替代调节中的作用。

IF 2.9 2区医学

Journal of General Physiology Pub Date : 2025-11-03 Epub Date: 2025-08-22 DOI: 10.1085/jgp.202413574

L Gonzalo Espinoza-Arcos, Mariela González-Avendaño, Matías Zuñiga-Bustos, Ricardo A Zamora, Ariela Vergara-Jaque, Horacio Poblete

{"title":"Exploring a peripheral PIP2-binding site and its role in the alternative regulation of the TRP channel superfamily.","authors":"L Gonzalo Espinoza-Arcos, Mariela González-Avendaño, Matías Zuñiga-Bustos, Ricardo A Zamora, Ariela Vergara-Jaque, Horacio Poblete","doi":"10.1085/jgp.202413574","DOIUrl":"https://doi.org/10.1085/jgp.202413574","url":null,"abstract":"Phosphatidylinositol 4,5-bisphosphate (PIP2) is recognized as an essential modulator of transient receptor potential (TRP) channels. Specifically, it influences the vanilloid receptor I (TRPV1), a pain receptor activated by a wide range of stimuli, including the binding of phospholipids, such as PIP2. The primary PIP2-binding site in TRPV1 has been identified through advanced techniques, revealing that the PIP2 binds to a specific pocket composed of positively charged residues located predominantly within the proximal C-terminus region. Additionally, a conserved segment with positively charged amino acids, K431 and R432, situated at the beginning of TRPV1's S1 transmembrane domain, has attracted considerable attention from the TRP research community. To date, our knowledge of this site's function and the subsequent effects following PIP2 binding is still emerging. In this work, MD simulations were conducted using coarse-grained models to investigate the binding dynamics of PIP2 on both WT and various mutated forms of TRPV1 channels. Our findings indicate that the K431A and R432A mutations significantly reduce the frequency of PIP2 contacts, suggesting that these mutated residues are part of a \"peripheral binding pocket.\" This pocket seems to play a crucial role in facilitating the entry of PIP2 to the TRPV1 channel's primary binding site. Furthermore, our research has shown that these highly conserved residues within the TRPV subfamily are also structurally conserved across other TRP subfamilies, such as TRPM and TRPC, a detail not evident from sequence alignment alone. Consequently, we propose the existence of a structurally conserved peripheral PIP2-binding site shared among the diverse members of the TRP family, which can be categorized into distinct subfamilies.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 6","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144979395","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}

引用次数: 0

PIP2-driven cytoplasmic domain motions are coupled to Kir2 channel gating. pip2驱动的细胞质结构域运动与Kir2通道门控相耦合。

IF 2.9 2区医学

Journal of General Physiology Pub Date : 2025-11-03 Epub Date: 2025-10-03 DOI: 10.1085/jgp.202513864

Eva-Maria Zangerl-Plessl, Anna Stary-Weinzinger, Colin G Nichols, Sun-Joo Lee

{"title":"PIP2-driven cytoplasmic domain motions are coupled to Kir2 channel gating.","authors":"Eva-Maria Zangerl-Plessl, Anna Stary-Weinzinger, Colin G Nichols, Sun-Joo Lee","doi":"10.1085/jgp.202513864","DOIUrl":"10.1085/jgp.202513864","url":null,"abstract":"Inwardly rectifying potassium (Kir) channel activity is important in the control of membrane potentials in both excitable and non-excitable cells and is regulated through various ligands, including specific membrane lipids. Phosphatidyl-4,5-bisphosphate (PIP2) is required for activity of all Kir channels, binding to the cytoplasmic domain in a compact conformation tightly tethered to the transmembrane domain. Most Kir2 channel structures determined in complex with PIP2 molecules are nevertheless in a closed state, requiring additional conformational changes for channel opening. We have carried out full atomistic MD simulations, which indicate PIP2-dependent conformational changes that are coupled to opening and closing of the channel. In the presence of bound PIP2, the cytoplasmic domain performs clockwise twisting motions, with a pivot residing near the C-linker in each subunit. These motions are reduced when PIP2 is removed, leading to narrowing of the critical gate at the M2 helix bundle crossing (HBC), but expansion at the region G-loop, as well as reduced overall fourfold symmetry, in turn coupled to cessation of ion permeation.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 6","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12493300/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214542","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}

引用次数: 0

Investigating the role of the I-II linker in Nav1.5 channel function. 研究I-II连接体在Nav1.5通道功能中的作用。

IF 2.9 2区医学

Journal of General Physiology Pub Date : 2025-11-03 Epub Date: 2025-09-04 DOI: 10.1085/jgp.202413692

Emily Wagner, Martina Marras, Shashi Kumar, Jacob Kelley, Kiersten Ruff, Jonathan Silva

{"title":"Investigating the role of the I-II linker in Nav1.5 channel function.","authors":"Emily Wagner, Martina Marras, Shashi Kumar, Jacob Kelley, Kiersten Ruff, Jonathan Silva","doi":"10.1085/jgp.202413692","DOIUrl":"https://doi.org/10.1085/jgp.202413692","url":null,"abstract":"The cardiac voltage-gated sodium channel, Nav1.5, initiates the cardiac action potential. Its dysfunction can lead to dangerous arrhythmias, sudden cardiac arrest, and death. The functional Nav1.5 core consists of four homologous repeats (I, II, III, and IV), each formed from a voltage sensing and a pore domain. The channel also contains three cytoplasmic linkers (I-II, II-III, and III-IV). While Nav1.5 structures have been published, the I-II and II-III linkers have remained absent, are predicted to be disordered, and their functional role is not well understood. We divided the I-II linker into eight regions ranging in size from 32 to 52 residues, chosen based on their distinct properties. Since these regions had unique sequence properties, we hypothesized that they may have distinct effects on channel function. We tested this hypothesis with experiments with individual Nav1.5 constructs with each region deleted. These deletions had small effects on channel gating, though two (430-457del and 556-607del) reduced peak current. Phylogenetic analysis of the I-II linker revealed five prolines (P627, P628, P637, P640, and P648) that were conserved in mammals but absent from the Xenopus sequence. We created mutant channels, where these were replaced with their Xenopus counterparts. The only mutation that had a significant effect on channel gating was P627S, which depolarized channel activation (10.13 ± 2.28 mV). Neither a phosphosilent (P627A) nor a phosphomimetic (P627E) mutation had a significant effect, suggesting that either phosphorylation or another specific serine property is required. Since deletion of large regions had little effect on channel gating while a point mutation had a conspicuous impact, the I-II linker role may be to facilitate interactions with other proteins. Variants may have a larger impact if they create or disrupt these interactions, which may be key in evaluating the pathogenicity of variants.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 6","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144994424","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}

引用次数: 0

SUMOylation and an ATS1 variant converge to disrupt PIP2-dependent gating of Kir2.1. SUMOylation和ATS1变体汇聚破坏Kir2.1的pip2依赖性门控。

IF 2.9 2区医学

Journal of General Physiology Pub Date : 2025-11-03 Epub Date: 2025-10-14 DOI: 10.1085/jgp.202513837

Aishwarya Chandrashekar, Yu Xu, Xinyi Ma, Anne K Yauch, Elizabeth Scholl, Yuchen Yang, Kirin D Gada, Takeharu Kawano, Meng Cui, Leigh D Plant

{"title":"SUMOylation and an ATS1 variant converge to disrupt PIP2-dependent gating of Kir2.1.","authors":"Aishwarya Chandrashekar, Yu Xu, Xinyi Ma, Anne K Yauch, Elizabeth Scholl, Yuchen Yang, Kirin D Gada, Takeharu Kawano, Meng Cui, Leigh D Plant","doi":"10.1085/jgp.202513837","DOIUrl":"https://doi.org/10.1085/jgp.202513837","url":null,"abstract":"Precise control of Kir2.1 channel gating is essential for maintaining membrane potential and enabling repolarization in excitable cells. Disruption of Kir2.1 function can cause Andersen-Tawil syndrome type 1 (ATS1), a multisystem channelopathy that predisposes patients to ventricular dysrhythmias and increases the risk of sudden cardiac death. Kir2.1 activity depends on interactions with the membrane phospholipid PIP2, and these interactions can be weakened by genetic mutations or posttranslational modifications. Here, we identify a shared mechanism by which hypoxia-induced SUMOylation and a heterozygous ATS1-linked variant, R67Q, independently and cooperatively suppress Kir2.1 function. We found that SUMOylation reduces Kir2.1 current in a stoichiometric manner, with up to two SUMO proteins per channel tetramer diminishing current by ∼24% each. Channels containing heterozygous R67Q subunits are disproportionately sensitive to hypoxic suppression. Inhibiting the SUMO pathway with TAK-981 prevents this suppression and enhances current in both WT and R67Q-containing channels. Further analysis revealed that both SUMOylation and the R67Q mutation reduce the stability of Kir2.1-PIP2 interactions, indicating a convergent gating defect. These findings support a two-hit model of channel dysfunction, in which a genetic variant and an environmental stressor act through a common structural mechanism to impair Kir2.1 gating. By identifying PIP2 destabilization as the point of convergence, this work provides new insight into how stress-sensitive channelopathies arise and suggests that SUMO pathway inhibition may offer a strategy to restore function under adverse physiological conditions.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 6","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145287718","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}

引用次数: 0

Resolving zone-specific regulation of cardiac myosin. 解决心肌肌球蛋白的区域特异性调控。

IF 2.9 2区医学

Journal of General Physiology Pub Date : 2025-11-03 Epub Date: 2025-08-28 DOI: 10.1085/jgp.202513838

Shane R Nelson

{"title":"Resolving zone-specific regulation of cardiac myosin.","authors":"Shane R Nelson","doi":"10.1085/jgp.202513838","DOIUrl":"https://doi.org/10.1085/jgp.202513838","url":null,"abstract":"Cardiac contractility is driven by shortening of ∼2-μm-long, macromolecular assemblies known as sarcomeres. During contraction, the motor protein myosin binds to, and exerts force upon actin filaments, utilizing energy from the hydrolysis of ATP. When not actively contracting, myosin partition into two subpopulations, distinguished by their basal rates of ATP hydrolysis, known as the \"Disordered Relaxed\" (DRX) and \"Super Relaxed\" (SRX) states. Additionally, the slower hydrolyzing SRX state has been proposed as a sequestered or \"reserve pool\" of myosin that do not contribute to contraction but can be recruited for enhanced contractility in response to external stimuli. Thus, the fraction of myosin in the SRX state is thought to reflect the overall regulatory state of the myosin population. In this volume of the Journal of General Physiology, a study by Pilagov et al. explores how the SRX state is regulated by phosphorylation or haploinsufficiency of a key regulatory protein, Myosin Binding Protein-C (MyBP-C). Surprisingly, they found that perturbations of MyBP-C led to a negligible change in the overall abundance of SRX. Instead, they found a rearrangement of SRX myosin throughout the sarcomere - specifically a decrease in SRX in regions of the sarcomere that contain MyBP-C and a compensatory increase in SRX in regions lacking MyBP-C. Their findings suggest that the influence of MyBP-C extends beyond its immediate vicinity and can simultaneously exert both positive and negative effects in a location-specific manner.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 6","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144979416","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}

引用次数: 0

Cortical spreading depression dynamics are altered by topical D2 receptor ligands. 局部D2受体配体改变了皮质扩张抑制动力学。

IF 2.9 2区医学

Journal of General Physiology Pub Date : 2025-11-03 Epub Date: 2025-10-07 DOI: 10.1085/jgp.202513843

Sonia Carolina Guerrero Prieto, Michael Cabrera Baez, Rubem Carlos Araújo Guedes

{"title":"Cortical spreading depression dynamics are altered by topical D2 receptor ligands.","authors":"Sonia Carolina Guerrero Prieto, Michael Cabrera Baez, Rubem Carlos Araújo Guedes","doi":"10.1085/jgp.202513843","DOIUrl":"https://doi.org/10.1085/jgp.202513843","url":null,"abstract":"Cortical spreading depression (CSD) is a transient wave of neuronal and glial depolarization that propagates slowly through the cerebral cortex and is implicated in neurological events such as migraine aura. While glutamate, GABA, and serotonin have established roles in CSD modulation, the contribution of dopaminergic signaling, particularly via D2 receptors (D2Rs), remains unclear. In this study, we examined whether topical cortical application of D2R-targeting agents alters CSD propagation and neuronal activation in vivo. Using a KCl-induced CSD model in anesthetized male Wistar rats, we applied metoclopramide (MCP), raclopride (RCP), and quinpirole (QNP) directly onto the cortex. MCP completely blocked CSD propagation at all time points. RCP and QNP produced opposing, time-dependent effects: RCP initially reduced CSD speed, followed by an increase after prolonged exposure, whereas QNP transiently accelerated propagation at 5 min but suppressed it with longer exposure. These changes were accompanied by alterations in waveform morphology, particularly in the secondary negative deflection. c-Fos immunoreactivity revealed reduced neuronal activation in MCP- and QNP-treated animals, mainly in superficial cortical layers, while RCP showed no significant effect. To support these findings, a reaction-diffusion computational model incorporating drug diffusion, receptor binding kinetics, and excitability parameters successfully reproduced the experimental CSD propagation profiles. Together, these results demonstrate that cortical D2R ligands modulate CSD dynamics and neuronal activation in a ligand-specific and time-dependent manner. This study provides mechanistic insight into how dopaminergic signaling influences cortical excitability and CSD propagation, advancing our understanding of dopamine's role in fundamental neurophysiological processes.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 6","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240361","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}

引用次数: 0

Muscle fatigue arising intrinsically from SUR2- but not Kir6.1-dependent gain-of-function in Cantu syndrome mice. Cantu综合征小鼠中由SUR2而非kir6.1依赖的功能获得引起的肌肉疲劳。

IF 2.9 2区医学

Journal of General Physiology Pub Date : 2025-11-03 Epub Date: 2025-10-07 DOI: 10.1085/jgp.202513781

Rosa Scala, Maya Mukadam, Yuezhou Chen, Courtney Frazier, Nathaniel W York, Robert C Tryon, Gretchen A Meyer, Colin G Nichols

{"title":"Muscle fatigue arising intrinsically from SUR2- but not Kir6.1-dependent gain-of-function in Cantu syndrome mice.","authors":"Rosa Scala, Maya Mukadam, Yuezhou Chen, Courtney Frazier, Nathaniel W York, Robert C Tryon, Gretchen A Meyer, Colin G Nichols","doi":"10.1085/jgp.202513781","DOIUrl":"https://doi.org/10.1085/jgp.202513781","url":null,"abstract":"Cantu syndrome (CS) is a rare disease caused by gain-of-function (GOF) mutations of Kir6.1 or SUR2 subunits of ATP-sensitive potassium (KATP) channels. CS patients with SUR2 and Kir6.1 variants display a similar constellation of symptoms, including muscle weakness and fatigue. The effects of CS mutations on skeletal muscle KATP channels, and any consequent direct effects on contractility, are currently unclear. Here, we used two knock-in mouse models of CS, respectively, carrying GOF mutations Kir6.1[V65M] or SUR2[A478V], to assess KATP channel properties and contractility in isolated fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus (SOL) muscles. Electrophysiological recordings in isolated myofibers showed normal resting potentials, and excised patch-clamp recordings showed normal KATP channel density in both genotypes, but enhanced Mg-nucleotide activation only in SUR2[A478V] fibers, consistent with muscle KATP channels being formed predominantly as complexes of SUR2A and Kir6.2 subunits. Ex vivo testing of isolated SUR2[A478V], but not Kir6.1[V65M], muscles showed an earlier onset of fatigue and a marked intra-tetanic decline of force compared with littermate controls. Importantly, normal contractile behavior was restored ex vivo and in vivo in SUR2[A478V] muscles in the presence of the FDA-approved KATP channel inhibitor glibenclamide, indicating that the increased fatigue of isolated muscles is a direct consequence of overactive sarcolemmal KATP channels. These results shed light on the pathophysiologic relevance of SUR2-dependent KATP channel subunits in skeletal muscle and highlight their role in fatiguing conditions, as well as identifying potential therapeutic benefit of skeletal muscle KATP inhibition in CS.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 6","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240403","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}

引用次数: 0

Voltage-gated sodium channels: Mechanisms, disease, and a growing research community. 电压门控钠通道：机制、疾病和日益增长的研究群体。

IF 2.9 2区医学

Journal of General Physiology Pub Date : 2025-11-03 Epub Date: 2025-10-10 DOI: 10.1085/jgp.202513878

Hugues Abriel, Angelika Lampert

引用次数: 0

NALCN/Cch1 channelosome subunits originated in early eukaryotes. NALCN/Cch1通道体亚基起源于早期真核生物。

IF 2.9 2区医学

Journal of General Physiology Pub Date : 2025-11-03 Epub Date: 2025-09-05 DOI: 10.1085/jgp.202413636

Adriano Senatore, Tatiana D Mayorova, Luis A Yañez-Guerra, Wassim Elkhatib, Brian Bejoy, Philippe Lory, Arnaud Monteil

{"title":"NALCN/Cch1 channelosome subunits originated in early eukaryotes.","authors":"Adriano Senatore, Tatiana D Mayorova, Luis A Yañez-Guerra, Wassim Elkhatib, Brian Bejoy, Philippe Lory, Arnaud Monteil","doi":"10.1085/jgp.202413636","DOIUrl":"10.1085/jgp.202413636","url":null,"abstract":"The sodium leak channel NALCN, a key regulator of neuronal excitability, associates with three ancillary subunits that are critical for its function: a subunit called FAM155, which interacts with the extracellular regions of the channel, and two cytoplasmic subunits called UNC79 and UNC80. Interestingly, NALCN and FAM155 have orthologous phylogenetic relationships with the fungal calcium channel Cch1 and its subunit Mid1; however, UNC79 and UNC80 have not been reported outside of animals. In this study, we leveraged expanded gene sequence data available for eukaryotes to reexamine the evolutionary origins of NALCN and Cch1 channel subunits. Our analysis corroborates the direct phylogenetic relationship between NALCN and Cch1 and identifies a larger clade of related channels in additional eukaryotic taxa. We also identify homologues of FAM155/Mid1 in Cryptista algae and UNC79 and UNC80 homologues in numerous non-metazoan eukaryotes, including basidiomycete and mucoromycete fungi and the microbial eukaryotic taxa Apusomonadida, Malawimonadida, and Discoba. Furthermore, we find that most major animal lineages, except ctenophores, possess a full complement of NALCN subunits. Comparing structural predictions with the solved structure of the human NALCN complex supports orthologous relationships between metazoan and non-metazoan FAM155/Mid1, UNC79, and UNC80 homologues. Together, our analyses reveal unexpected diversity and ancient eukaryotic origins of NALCN/Cch1 channelosome subunits and raise interesting questions about the functional nature of this channel complex within a broad, eukaryotic context.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 6","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12412391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145001957","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}

引用次数: 0

Stretch activation combats force loss from fatigue in fast-contracting mouse skeletal muscle fibers. 拉伸激活对抗快速收缩小鼠骨骼肌纤维疲劳造成的力损失。

IF 2.9 2区医学

Journal of General Physiology Pub Date : 2025-09-01 Epub Date: 2025-08-11 DOI: 10.1085/jgp.202413679

Philip C Woods, Douglas M Swank, Mark S Miller

{"title":"Stretch activation combats force loss from fatigue in fast-contracting mouse skeletal muscle fibers.","authors":"Philip C Woods, Douglas M Swank, Mark S Miller","doi":"10.1085/jgp.202413679","DOIUrl":"10.1085/jgp.202413679","url":null,"abstract":"Stretch activation (SA) is the delayed increase in force following a rapid stretch and improves muscle performance during repetitive cyclical contractions in insect flight and cardiac muscles. Although historically considered too low to be physiologically relevant in skeletal muscle, our recent work showed that higher phosphate concentrations ([Pi]) increased SA in mouse soleus fibers. These results suggest SA has a role combating fatigue, which increases [Pi], lowers pH, and reduces active calcium concentration ([Ca2+]). To test this, we measured SA during Active, High [Ca2+] Fatigue and Low [Ca2+] Fatigue conditions in myosin heavy chain (MHC) I, IIA, IIX, and IIB fibers from mouse soleus and extensor digitorum longus muscles. In the fast-contracting MHC II fibers, calcium-activated isometric tension (F0) decreased from Active to High [Ca2+] Fatigue to Low [Ca2+] Fatigue, as expected. Remarkably, SA tension (FSA) was not decreased but remained unchanged or increased under High and Low [Ca2+] Fatigue, except for a small decrease in MHC IIB fibers in Low [Ca2+] Fatigue compared with Active. This results in SA's percent contribution to total tension production (FSA/[F0 + FSA]) being much greater (58-114%) under fatiguing conditions in fast-contracting MHC II fibers. The SA tension peak for MHC I fibers was not visibly apparent under either fatigue condition, and the peak was about 20% of MHC II fibers' peaks under active conditions. Our results show SA improves force production under fatiguing conditions in MHC II fibers, which could play an important role in increasing endurance for muscles that are lengthened prior to shortening.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 5","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144818345","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}

引用次数: 0