Pflugers Archiv : European journal of physiology最新文献

{"title":"DNase I as a probe for unpolymerized actin: revisiting a classic tool for nuclear actin research.","authors":"Anika Göpel, Laura Bauer, Dörthe M Katschinski, Anke Zieseniss","doi":"10.1007/s00424-026-03158-z","DOIUrl":"10.1007/s00424-026-03158-z","url":null,"abstract":"<p><p>Actin is a key component of the cytoskeleton and also plays diverse roles within the cell nucleus. While polymerized F-actin can be detected using a wide range of probes, reliable methods to identify unpolymerized (“G-”) actin in fixed cells are relatively limited. Fluorescently labeled DNase I has long served as a high-affinity probe for monomeric actin and has recently gained renewed interest in nuclear actin research. Here, we briefly review established methods for visualizing actin in the cytoplasm and nucleus and revisit the history and molecular basis of the DNase I–actin interaction that forms the basis for DNase I staining. We then highlight practical considerations for interpreting DNase I fluorescence signals, such as its binding to filament pointed ends, the influence of divalent cations on its enzymatic activity and DNA binding, and protocol-dependent variations. Notably, fixation conditions significantly influence staining outcomes, affecting the distribution of nuclear versus cytoplasmic signals. Overall, this review aims to provide a concise framework for effectively using DNase I staining to monitor cellular pools of unpolymerized actin in a consistent and interpretable way.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13018090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147513985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting hypertension through natural phenolics: The multifaceted role of cinnamic acid and its derivatives.","authors":"Samuel S P de Araujo, Brenda L B Dos Santos, Waldilleny R A de Moura, Leonardo G Rodrigues, Luiz G S Branco, Helio C Salgado, Renato N Soriano, Marina de T Durand, João Paulo J Sabino","doi":"10.1007/s00424-026-03163-2","DOIUrl":"10.1007/s00424-026-03163-2","url":null,"abstract":"<p><p>Hypertension is a serious global public health problem that significantly increases the risk of cardiovascular diseases. Its etiology involves inflammatory processes, oxidative stress, and imbalances in blood pressure (BP) regulatory systems. In this context, the search for new therapeutic agents remains a major challenge, highlighting natural compounds such as cinnamic acid (CA) and its derivatives, including caffeic acid (CAF) and ferulic acid (FA). This review aimed to investigate the antihypertensive, anti-inflammatory, and antioxidant potential of CA and its derivatives. The phenolic acids analyzed, particularly CA and FA, exhibited greater inhibitory activity on angiotensin-converting enzyme (ACE), whereas CAF showed lower activity. Furthermore, cinnamic acid and its derivatives increased nitric oxide (NO) production, contributing to vasodilation. Regarding the inflammatory response, studies on phenolic acids demonstrated a reduction in the pro-inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α, accompanied by an increase in the anti-inflammatory cytokine IL-10, indicating a relevant anti-inflammatory effect. Similarly, in the antioxidant system, increased levels of superoxide dismutase (SOD) and glutathione (GSH) were observed, along with a reduction in the pro-oxidant marker malondialdehyde (MDA). Additionally, the DPPH and ABTS assays demonstrated greater free radical scavenging activity for CA, CAF, and FA derivatives. Taken together, these findings suggest that phenolic acids are promising candidates for the treatment of hypertension due to their favorable safety profile, with CA standing out as the main compound with hypotensive effects.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13021695/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147514033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nitrergic neurotransmission within the lateral hypothalamus modulates cardiovascular responses to stress in rats.","authors":"Gabriela A Silva, Lilian L Reis-Silva, Lucas Gomes-de-Souza, Lígia R R Tavares, Lucas Barretto-de-Souza, Vinícius Pelarin, Carlos C Crestani","doi":"10.1007/s00424-026-03161-4","DOIUrl":"10.1007/s00424-026-03161-4","url":null,"abstract":"<p><p>The lateral hypothalamus (LH) is a key brain region involved in integrating cardiovascular and autonomic components of the stress response, yet the local neurochemical mechanisms governing these functions remain poorly understood. This study examined the contribution of nitrergic neurotransmission within the LH to cardiovascular adjustments induced by acute restraint stress in rats. To this end, animals received bilateral microinjections into the LH of either the nonselective nitric oxide synthase (NOS) inhibitor L-NAME, the selective neuronal NOS (nNOS) inhibitor N^ω-propyl-L-arginine hydrochloride (NPLA), the selective inducible NOS (iNOS) inhibitor 1400W, or the nitric oxide (NO) donor MAHMA NONOate (NOC-9) prior to the restraint session. Intra-LH administration of L-NAME significantly attenuated both the pressor and tachycardic responses elicited by restraint. In contrast, the selective nNOS inhibitor NPLA selectively enhanced the tachycardic response without altering the pressor effect or sympathetically-mediated cutaneous vasoconstriction. Consistent with the effect observed in NPLA-treated animals, facilitation of local nitrergic neurotransmission through intra-LH injection of the NO donor selectively reduced the heart rate response to restraint. The selective iNOS inhibitor 1400W did not affect any of the cardiovascular parameters measured. Taken together, these findings indicate that nitrergic signaling within the LH plays a critical role in modulating cardiovascular adjustments to acute stress. This regulation appears to involve a complex process involving nNOS and an additional nitrergic mechanism that acts independently of iNOS.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13013230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147514025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low fruit and vegetable intake in children: a dietary stressor raising renal ammonium and adrenal cortisol secretion.","authors":"Thomas Remer, Yifan Hua, Jonas Esche, Lijie Shi, Michaela F Hartmann, Stefan A Wudy","doi":"10.1007/s00424-026-03162-3","DOIUrl":"10.1007/s00424-026-03162-3","url":null,"abstract":"<p><p>Elimination of excess acid loads in metabolic acidosis requires stimulation of ammoniagenesis. Cortisol is critical to increase proximal tubular cells’ ammonia production. We aimed to specifically examine whether children’s low fruit and vegetable (FV) intake, which goes along with an increased dietary acid load, may raise cortisol secretion and whether glucocorticoids relevantly associate with ammonium secretion. Healthy 6–10 years old children (participants of the DONALD study, Dortmund, Germany) with a comparable protein intake and either a low or a high FV-intake were examined in a quasi-experimental design. Urinary 24-h ammonium excretion was analyzed as part of urinary acid-base measurements. Major glucocorticoid metabolites were quantified along with aldosterone precursors in children’s 24-h urine samples by gas chromatography–mass spectrometry to assess adrenal cortisol secretion and aldosterone status. Liquid–chromatography–mass spectrometry was used to quantify urinary free cortisol (UFF) and cortisone. Average FV-intake of children with low compared to high FV-intake was 183 g/d (25th -75th percentile, 129–233 g/d) and 570 g/d (25th -75th percentile, 468–707 g/d), respectively. Both groups’ average protein intake amounted to around 50 g/d. After adjustment for relevant confounders, children with low FV-intake exhibited higher excretion rates of UFF (P = 0.002), cortisone (P = 0.07), potentially bioactive free glucocorticoids (sum of UFF and cortisone) (P = 0.04), 20α-dihydrocortisol (P = 0.02), C21-metabolite sum reflecting cortisol secretion (P = 0.008), and ammonium (P < 0.0001). Concurrently with these children’s lower potassium intake, excretions of the aldosterone precursors tetrahydro-11-dehydrocorticosterone and tetrahydrocorticosterone were reduced (P ≤ 0.02). Urinary ammonium excretion associated closely with UFF (P < 0.0001), cortisone (P < 0.0001), and 20α-dihydrocortisol (P = 0.0003). Our quasi-experimental study indicates the importance of an appropriately high FV-intake in childhood to reduce acid-load-inducible cortisol-increases that are strongly associated with renal ammonium production and may have the potential to adversely affect long-term health.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13006471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147499567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PKC isoform-specific targeting of the phosphorylation site Serine¹⁹¹ in the GIRK4 subunit induces receptor-dependent modulation of GIRK channel activity.","authors":"Leonie Inderwiedenstraße, Marie-Cécile Kienitz","doi":"10.1007/s00424-026-03157-0","DOIUrl":"10.1007/s00424-026-03157-0","url":null,"abstract":"<p><p>G Protein activated inwardly rectifying K+ (GIRK) channels are inhibited during stimulation of Gq Protein-coupled receptors (GqPCRs) by depletion of phosphatidyl-4,5-bisphosphate (PIP2) and/or channel phosphorylation by proteinkinase C (PKC). Receptor-specific effects of Gq signaling pathways on GIRK channel activity comprise the activation of different PKC isoforms that target distinct phosphorylation sites within the GIRK4 subunit. The serine residue S191 in the GIRK4 subunit is an important phosphorylation site for PKC which contributes to GIRK channel inhibition. Until now, the specific PKC isoform that phosphorylates this residue is unknown. Furthermore, the functional impact of S191 for Gq-receptor-specific GIRK channel modulation has not been investigated. To evaluate the contribution of this PKC phosphorylation site to receptor-specific GIRK channel modulation, we monitored the activity of phosphorylation-deficient GIRK4 (S191A) channel mutants during stimulation of adrenergic α1B-receptors (α1B-ARs) or Angiotensin AT1-receptors. GqPCR-dependent modulation of GIRK currents was analyzed in voltage-clamp experiments in rat atrial myocytes and in CHO cells expressing phosphorylation-deficient GIRK channels of various subunit compositions. As a novel finding, we demonstrate that the inhibition of phosphorylation-deficient GIRK4 (S191A) channels is impaired during stimulation of AT1-Rs, indicating that this phosphorylation site is targeted at least by the Angiotensin II-activated PKCε isoform. In contrast, ablation of the S191 phosphorylation site does not attenuate phenylephrine-induced GIRK reduction, suggesting that S191 is not a primary target for the α1B-AR activated PKCα. Our data indicate that the different GqPCR-activated PKC isoforms target distinct phosphorylation sites within the GIRK4 subunit, resulting in receptor-specific regulation of the phosphorylation-deficient GIRK4 (S191A) channel mutant.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12999607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147481313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CO and N₂ are not humane alternatives to CO₂ euthanasia in rats.","authors":"Charlotte Calvet, Philipp Villiger, Francesco Prisco, Tim Buchholz, Felix Gantenbein, Christa Thöne-Reineke, Boris Gourévitch, Carsten A Wagner, Petra Seebeck","doi":"10.1007/s00424-026-03156-1","DOIUrl":"10.1007/s00424-026-03156-1","url":null,"abstract":"<p><p>Carbon dioxide (CO2) is commonly used for rat euthanasia, but its potential negative side effects call for alternatives causing less distress while providing a fast and reliable loss of consciousness (LOC). Euthanasia with CO2 is currently performed in a highly non-standardized manner with different CO2 volume displacement rates/minute (VDRM) ranging from replacing 30 to 70% of the chamber volume with 100% CO2 per minute. Therefore, we evaluated euthanasia with 100% CO2 at 30% and 70% VDRM as well as carbon monoxide (8.6% CO at 70% VDRM), nitrogen (100% N2 at 70% VDRM) and isoflurane anesthesia (6% and 2.1% at 70% VDRM) in female and male rats. We used a multi-modal approach including telemetry for ECG, blood pressure (BP), heart rate measurements, EEG, and plethysmography. Video-recordings were used to track behavior during euthanasia. Stress hormones and lung pathology were assessed post-mortem. A VDRM of 70% CO2 resulted in a rapid LOC compared to 30%, thus, minimizing the time in which distress and eventually pain can be experienced. Nevertheless, the higher amount of distress experienced until LOC potentially outweighs the benefits of a faster LOC. CO and N2 resulted in longer times to LOC, seizures before LOC, increased stress hormone levels, and caused more lung damage. Therefore, CO and N2 are not humane alternatives to CO2 and should not be recommended for euthanasia in rats. </p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12987893/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147459203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural determinants of voltage sensitivity in hyperpolarization-activated ion channels and their persistence in the evolutionary scale.","authors":"Karla G Alvarez-Villagómez, Daniel Balleza","doi":"10.1007/s00424-026-03153-4","DOIUrl":"10.1007/s00424-026-03153-4","url":null,"abstract":"<p><p>HCN channels have a reverse electromechanical coupling mechanism, where hyperpolarized membrane potentials facilitate pore opening through an inward displacement of the S4 segment of the voltage-sensing domain (VSD). This voltage dependence is finely regulated by the binding of cAMP to an intracellular domain (CNBD). Of the four widely studied isoforms of human HCN channels, the HCN3 channel is practically insensitive to cAMP or is even inhibited by it, but the structural determinants underlying this unexpected behavior are still unclear. Here, we evaluated the possible role of flexibility in very specific regions of the VSD that could be determinants for this behavior. Part of the S2-S3L linker is more rigid in HCN3, which correlates with low atomic mobility for this region in proximity to the C-linker subdomain of the opposite subunit. We built structural models using AlphaFold 3 and Swiss-Model and thus reconstructed the disordered regions that connect the transmembrane segments of the VSD and that in some of the structures deposited in the PDB have not been resolved. Besides, in an attempt to reveal the evolutionary trends that this transmembrane domain may have undergone, we conducted a comparative study with phylogenetically distant HCN channels and found an interesting tendency to lose sensitivity to cAMP as VSD flexibility is lost. Our analysis confirms a large body of published experimental findings. Finally, we found that in metazoans, two types of HCN channels clearly diverge: (1) those that are highly sensitive to cAMP with moderate flexibility profiles in protostomes, and (2) those that show less marked sensitivity to this ligand in deuterostomes. We also propose a possible evolutionary scenario for the appearance of cAMP-modulated HCN channels in the last eukaryotic common ancestor (LECA).</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147372976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immature olfactory sensory neurons are intrinsically excitable and show maturation-dependent changes in voltage-gated Na⁺ and K⁺ currents.","authors":"Chiara Ricci, Cesar Adolfo Sánchez Triviño, Uday Rangaswamy, Lorenza Tortella, Remo Sanges, Anna Boccaccio, Anna Menini","doi":"10.1007/s00424-026-03159-y","DOIUrl":"10.1007/s00424-026-03159-y","url":null,"abstract":"<p><p>Olfactory sensory neurons (OSNs) detect odorants and send electrical signals to glomeruli in the olfactory bulb. Unlike most neurons, OSNs are continuously regenerated throughout life and immature neurons contribute to odorant-evoked responses in glomeruli. However, their intrinsic excitability properties are largely unknown. Here, we used acute slices of the olfactory epithelium from neonatal OMP-GFP mice to visually identify mature and immature OSNs and performed patch-clamp recordings to investigate their functional properties. Loose-patch recordings showed that immature OSNs display spontaneous firing at lower frequency than mature neurons. Whole-cell recordings showed that immature OSNs have more depolarized resting potentials, higher input resistance, fire only with phasic patterns, and generate slower action potentials with more depolarized thresholds. Instead, mature OSNs exhibited both phasic and tonic repetitive firing and faster spike kinetics. Voltage-clamp experiments showed that voltage-gated Na⁺ currents in immature OSNs were almost entirely TTX-sensitive, whereas mature OSNs had both TTX-sensitive and TTX-resistant components whose availability depends on membrane potential. Voltage-gated K⁺ currents also differed with maturation: immature OSNs lacked a transient component and had only a sustained K⁺ current, whereas mature OSNs displayed both a transient component and an increased sustained current. Analysis of single-cell transcriptomic data identified upregulation of some Na⁺ and K⁺ channel genes during OSN maturation, consistent with the functional changes. Together, these results provide insights into the intrinsic excitability of immature OSNs and show how intrinsic properties change as OSNs mature, providing a foundation for future studies on the role of immature OSNs in sensory processing. </p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12963238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147366148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preliminary evidence of extrarenal sodium storage in a large mammal: implications for comparative physiology and hypertension research : Running: Sodium storage in cattle.","authors":"Andrew J Abraham, Ethan S Duvall, Callum Leese, Kirstin Abraham, Elizabeth le Roux, Barbara Riond, Sylvia Ortmann, Melissa Terranova, Graham Leese, Matthew A Bailey, Marcus Clauss","doi":"10.1007/s00424-026-03155-2","DOIUrl":"10.1007/s00424-026-03155-2","url":null,"abstract":"<p><p>Under conditions of dietary sodium (Na+) excess, the kidneys may fail to adequately excrete Na+, potentially compromising blood pressure homeostasis. Body tissues, such as skin, can offer sites of short-term extrarenal Na+ storage and previous research has shown that this can help guard against hypertension in small mammals (e.g., rodents). Large mammals have relatively greater Na+ storage potential, but whether extrarenal Na+ storage occurs for this group is unknown. Here, we report preliminary evidence of extrarenal Na+ storage in cattle. We provided a large pulse-dose of NaCl to four cattle (body mass: ~720 kg) and measured excretion of Na+ and potassium (K+) in urine and faeces for a period of 7-days. Following NaCl administration, Na+ excretion spiked in both urine and faeces for ~ 48 h before returning to baseline measurements. After ~ 96 h, however, Na+ excretion increased again; a consistent physiological phenomenon across all individuals studied. We did not observe a pattern in urinary K+ excretion, indicating that the mechanism of Na+ storage does not appear to involve exchange for K+. However, faecal K+ excretion was reciprocal to that of Na+, presumably reflecting exchange of Na+/K+ across the walls of the large intestine. We infer that during the initial period of Na+ stress, short-term extrarenal Na+ storage occurred and the stored Na+ was later released only when the body had returned to Na+ homeostasis. Additional experiments are required to understand how patterns of Na+ regulation changes across body sizes and the specific body compartments involved. Cattle may be a useful model system for examining the impact of high Na+ intake in mammals larger than humans.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12948829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147317975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated effects of altered action potentials and calcium release on skeletal muscle force generation in transgenic Huntington's disease mice.","authors":"Daniel R Miranda, Steven R A Burke, Pooneh Hajmirza Mohammadi Kamalabadi, Julia L Rutherford, John Kamau, Hugo Bibollet, Robert J Talmadge, Gerald M Wilson, Abhyudai Singh, Volker Bahn, Hongmei Ren, Erick Hernández-Ochoa, Andrew A Voss","doi":"10.1007/s00424-026-03151-6","DOIUrl":"10.1007/s00424-026-03151-6","url":null,"abstract":"<p><p>Huntington’s disease (HD) is a movement disorder commonly recognized as being neurodegenerative. An increasing number of studies also show primary HD dysfunction in multiple tissues, consistent with the widespread expression of the mutated huntingtin gene. Studies of HD skeletal muscle have revealed membrane hyperexcitability and prolonged action potentials due to Cl– and K+ channel dysfunction as well as decreased Ca2+ release from the sarcoplasmic reticulum (SR) due to ryanodine receptor dysfunction. However, neither mechanism alone explains HD skeletal muscle function. To address this, we simultaneously recorded action potentials and SR Ca2+ release in model HD muscle and quantitatively linked the concerted mechanism to force generation. We discovered that the reduced SR Ca2+ release does not cause weakness in model HD muscle as expected because of the prolonged SR Ca2+ release (due to wider action potentials) and altered expression of Ca2+-binding proteins. The resulting integrated mechanism helps explains the surprisingly normal specific twitch force in model HD muscle and reveals a precarious balance that we show begins to disintegrate under very mild repetitive stimulation. The interplay of pathways also explains the resistance to myotonia in model HD muscle despite the substantial reduction in Cl− current. By examining a concerted multi-molecular mechanism, we are able to understand tissue-level function in model HD muscle. This detailed study of twitch responses lays the foundation to examine the more complex integration of pathways during repetitive activity in HD muscle as well as in other normal and disease states that would benefit from the multi-molecular approach.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 2","pages":"24"},"PeriodicalIF":3.2,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12916976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146220744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}