American journal of physiology. Cell physiology最新文献

{"title":"Hypoxic eNOS uncoupling as a consequence of DHFR downregulation in various human endothelial cell lines: the crucial role of the BH₄ regeneration pathway.","authors":"Anna Janaszak-Jasiecka, Adrianna Radulska, Anna Siekierzycka, Agata Płoska, Tomasz Borkowski, Iwona T Dobrucki, Rafał Bartoszewski, Leszek Kalinowski","doi":"10.1152/ajpcell.00171.2026","DOIUrl":"10.1152/ajpcell.00171.2026","url":null,"abstract":"<p><p>Tetrahydrobiopterin (BH₄) is an essential cofactor for endothelial nitric oxide synthase (eNOS), which produces nitric oxide (NO) to maintain vascular homeostasis. When BH₄ is deficient, eNOS becomes uncoupled, generating superoxide ([Formula: see text]) instead of NO, contributing to endothelial dysfunction and cardiovascular disease. The cellular BH₄ concentration is determined by its de novo synthesis via GTP cyclohydrolase I (GTPCH), oxidation of BH₄ to BH₂, and the regeneration of BH₄ from BH₂ by dihydrofolate reductase (DHFR). A diminished BH₄/BH₂ ratio, often due to DHFR dysregulation, promotes eNOS uncoupling. This study investigates how hypoxia affects eNOS activity and NO bioavailability in human endothelial cells (ECs) derived from various vascular beds. We show that hypoxia downregulates eNOS and DHFR, impairs BH₄ regeneration, and induces eNOS uncoupling in all human EC types tested. We also demonstrate that human ECs exhibit low basal BH₄ levels, which may result from limited GTPCH expression; consequently, the BH₄/BH₂ ratio appears to depend substantially on DHFR activity. Importantly, we show for the first time that BH₄-dependent regulation of eNOS uncoupling varies between ECs derived from distinct vascular beds. This variability is driven by cell-type-specific differences in the relative levels of eNOS and DHFR under hypoxia. In particular, human aortic endothelial cells (HAECs) display high eNOS expression and low DHFR levels, making them especially prone to hypoxic eNOS uncoupling. These findings suggest that certain vascular beds may be intrinsically more susceptible to hypoxia-induced endothelial dysfunction, driven by greater eNOS uncoupling that depends on DHFR activity, highlighting DHFR as a potential therapeutic target.<b>NEW & NOTEWORTHY</b> This study identifies DHFR-dependent BH₄ regeneration as the key determinant of eNOS coupling in human endothelial cells with intrinsically low BH₄ levels. We show that hypoxia disrupts this pathway, leading to eNOS uncoupling in a vascular bed-specific manner. Notably, human aortic endothelial cells are particularly susceptible due to high eNOS and low DHFR expression, highlighting DHFR as a potential therapeutic target in hypoxia-driven endothelial dysfunction.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C653-C663"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148688369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"β₂-Adrenergic receptor disruption exacerbates cardiac injury and fibroblast activation in a female mouse model of Takotsubo cardiomyopathy.","authors":"Bruno Sanches, Fernanda Tupini, Fernando Espanhol, Pedro Augusto Carvalho Costa, Gabriel Matos Nogueira, Iago Pinheiro, Fernando Souza-Neto, Alexander Birbrair, Pedro Pires Goulart Guimarães, Marina G M Castor, Jop H van Berlo, Silvia Guatimosim","doi":"10.1152/ajpcell.00087.2026","DOIUrl":"10.1152/ajpcell.00087.2026","url":null,"abstract":"<p><p>Takotsubo cardiomyopathy (TTC) is an acute stress-induced cardiac syndrome that predominantly affects women and is driven by surges in catecholamines that excessively activate β-adrenergic receptors (βARs). Although β₁AR signaling mediates much of the injury, β₂ARs have recognized cytoprotective roles in other cardiac settings, yet their contribution to TTC-associated remodeling remains unclear. To address this gap, we induced a TTC-like phenotype in female wild-type (WT) and β₂AR-deficient (β₂AR^-/-) mice with a single high dose of isoproterenol (ISO). After ISO injection, β₂AR^-/- mice exhibited exacerbated myocardial injury, characterized by greater hypertrophy and higher levels of apoptosis and necrosis compared with WT/ISO mice. This heightened injury was accompanied by a more robust inflammatory response, including increased inflammatory score, enhanced CD68⁺ macrophage infiltration, and marked recruitment of CCR2⁺MHC-II^low monocytes. β₂AR^-/-/ISO hearts also displayed more extensive interstitial fibrosis. Because fibrosis is a key driver of long-term functional decline, we isolated cardiac fibroblasts (CFs) and characterized their activation state. CFs from β₂AR^-/-/ISO hearts displayed a significantly higher percentage of α-SMA⁺ cells, increased Collagen 3 and MMP-2 staining, along with upregulation of profibrotic genes (<i>Col1a1</i>, <i>Col3a1</i>, <i>Fap</i>). Functionally, β₂AR^-/-/ISO CFs exhibited an activated molecular signature enriched in cytokines and growth factors, and their conditioned media induced greater hypertrophy in neonatal cardiomyocytes, revealing a potent paracrine contribution to the remodeling process. These findings demonstrate that the female heart relies on β₂AR signaling to limit acute catecholamine-induced injury, underscoring the potential of β₂AR-targeted interventions as therapeutic strategies in a Takotsubo-like setting.<b>NEW & NOTEWORTHY</b> Takotsubo cardiomyopathy (TTC) disproportionately affects women and is driven by excessive β-adrenergic receptor (βAR) activation. We show that loss of β₂AR signaling exacerbates myocardial injury, creating a proinflammatory and profibrotic milieu that amplifies fibroblast activation and reshapes their paracrine profile. These activated cardiac fibroblasts (CFs) further sustain cardiomyocyte hypertrophy, perpetuating the injury loop in β₂AR-deficient hearts. These findings establish β₂AR as a determinant of cardiac resilience and support β₂AR-directed strategies as interventions in the acute phase of TTC.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C747-C758"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148262703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolomics-guided isolation of myogenic progenitor cells for improved transplantation.","authors":"Lauren K McKay, Christopher G Vann, James R Bain, Shihuan Kuang, Christopher B Newgard, James P White, David E Lee","doi":"10.1152/ajpcell.00337.2026","DOIUrl":"10.1152/ajpcell.00337.2026","url":null,"abstract":"<p><p>Skeletal muscle maintains considerable capacity for regeneration following injury, but successful regeneration is limited in instances of volumetric muscle loss, advanced aging, or muscular dystrophies. Considerable research has been done on muscle stem cell (MuSC) transplantation; however, proliferative exhaustion and donor cell dose requirements have slowed progress. Due to the paramount role of cellular metabolism in regenerative function of stem cells, the clinical potential for MuSC therapy may be improved by minimizing the isolation-induced metabolic perturbations experienced by MuSCs. This study uses a model of simulated cell sorting combined with untargeted, small-molecule metabolomic profiling to outline sorting-induced metabolic perturbations in C2C12 myoblasts. We expand upon this by performing a time course of metabolomic profiling on myoblasts recovering from either fluorescence-activated cell sorting or magnetic-bead-activated cell sorting-based isolation procedures to determine the method and recovery timing for optimal redox and energetic status. Using this metabolism-informed method, we then performed primary MuSC transplantation studies in mice to demonstrate the generalizability from the in vitro system to in vivo MuSC transplantation during regeneration from barium chloride-induced injury. Our findings demonstrate metabolically favorable strategies to isolate MuSC for analysis of the quiescent-to-activated metabolic transition or enhance transplantation efficacy.<b>NEW & NOTEWORTHY</b> Due to the paramount role of cellular metabolism in regenerative function of stem cells, the clinical potential for muscle stem cell (MuSC) therapy may be improved by minimizing isolation-induced metabolic perturbations. This study uses a model of simulated cell sorting combined with untargeted, small-molecule metabolomic profiling to outline sorting-induced metabolic perturbations in myoblasts. Our findings demonstrate metabolically favorable strategies to isolate MuSC for analysis of the quiescent-to-activated metabolic transition or enhance transplantation efficacy.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C736-C746"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148683115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic cardiac hyperplasia and hypertrophy in Burmese pythons.","authors":"Yuxiao Tan, Thomas G Martin, Angela K Peter, Christopher D Ozeroff, Christopher C Ebmeier, Ryan Doptis, Brooke Harrison, Leslie A Leinwand","doi":"10.1152/ajpcell.00139.2026","DOIUrl":"10.1152/ajpcell.00139.2026","url":null,"abstract":"<p><p>Cardiomyocyte hyperplasia is the primary form of fetal heart growth, whereas this proliferative capacity is largely lost in adults across most mammalian species. The limited ability of adult cardiomyocytes to re-enter the cell cycle is a major cause of cardiac injury-induced morbidity and mortality. Here, we report that postprandial Burmese python cardiomyocytes activate cell cycle re-entry to promote persistent cardiac growth. Burmese pythons normally eat large meals infrequently, resulting in reversible cardiomyocyte hypertrophy. We found that frequent feeding of large meals amplifies the modest postprandial cardiac proliferation identified in an infrequent feeding interval. By activating <i>E2F</i> and Forkhead Box M1 (<i>FOXM1</i>) pro-proliferation transcriptional networks, frequently fed Burmese pythons potentiate cardiomyocyte proliferation in addition to transient cardiac myocyte hypertrophy. These findings identify hyperplasia as a natural means of sustained cardiac growth in Burmese pythons and demonstrate the use of pythons as a model for investigating noninjury-induced proliferative cardiac remodeling.<b>NEW & NOTEWORTHY</b> This study shows that adult Burmese pythons can not only undergo reversible cardiomyocyte hypertrophy after feeding but can also activate cardiomyocyte cell-cycle re-entry and achieve hyperplasia, especially with frequent large meal consumption. Frequent feeding amplifies proliferation by engaging <i>E2F</i> and <i>FOXM1</i> pro-proliferative signaling, resulting in sustained heart growth through hyperplasia in adult python hearts. These findings establish Burmese pythons as a new model for proliferative cardiac remodeling with potential insights into adult heart regenerative biology.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C641-C652"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13480925/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148443829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia induces microtubule rearrangement in intestinal epithelial cells.","authors":"Darragh Flood, Sarah J Kierans, Emily DeMichele, Ethan T Dehantschutter, Eugene T Dillon, Carlos Matellan, Cormac T Taylor","doi":"10.1152/ajpcell.00238.2026","DOIUrl":"10.1152/ajpcell.00238.2026","url":null,"abstract":"<p><p>Microtubules are integral components of the highly regulated and dynamic cytoskeleton, which is vital for cell function and the maintenance of homeostasis. Microtubule disruption is associated with multiple disease states including colorectal cancer and neurodegenerative disorders. Although much is known about the mechanisms by which microtubules are regulated under physiologic conditions, the effect of pathological stimuli and how this contributes to disease progression is less clear. Hypoxia is a prominent microenvironmental feature of a range of pathological states including inflammation, ischemia, neurodegenerative disease, and cancer. However, our knowledge on the effect of hypoxia on microtubules and whether this impacts disease progression remains limited. Understanding the impact of hypoxia on microtubules is therefore of fundamental importance to understanding disease progression mediated by cytoskeletal changes and may identify new therapeutic targets. In this study, we found that hypoxia decreases intestinal epithelial cell migration. This is associated with a rapid and reversible change in microtubule structure. This cytoskeletal rearrangement occurs independently of changes in α-tubulin protein expression or free-to-polymerized α-tubulin ratio and is also independent of the hypoxia-inducible factor 1α (HIF-1α) pathway. Mechanistically, we found that it is hypoxia-induced changes in glycolytic metabolism that mediate the structural rearrangement of α-tubulin. We hypothesize that these data identify a potential opportunity to utilize drugs targeting glycolytic metabolism to sensitize drug-resistant colorectal epithelial cancer cells to microtubule-based chemotherapies.<b>NEW & NOTEWORTHY</b> We found that in response to hypoxia, epithelial cells reorganize their microtubular structure into intense, punctate clusters with no change in polymerization. Furthermore, while this structural rearrangement is rapidly inducible, reversible, and oxygen-dependent, it is mediated in a HIF-1α-independent manner. We noted that PGAM1, a key glycolytic enzyme, facilitates this structural reorganization of the microtubules via association with α-tubulin and its metabolic activity, in response to hypoxia or other forms of glycolytic stress.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C677-C690"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148700417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulated iron metabolism in remodeling of aging asthmatic human airways.","authors":"Maunick Lefin Koloko Ngassie, Yamillie Ortiz, Preetham Ravi, Daniel A Pfeffer-Kleemann, Samantha K Hamrick, Michael A Thompson, Yun Hua Fang, Christina M Pabelick, Y S Prakash","doi":"10.1152/ajpcell.00897.2025","DOIUrl":"10.1152/ajpcell.00897.2025","url":null,"abstract":"<p><p>Iron is essential for cellular function, and lung cells are no exception. Previous studies have demonstrated an association between increased level of iron in the lung and aging and age-related lung diseases, including pulmonary fibrosis and asthma in the elderly (AIE). However, the mechanisms underlying the accumulation of iron with aging or AIE, or the cell types involved, remain understudied. In the context of asthma, airway smooth muscle is a key cell type contributing to contractility as well as airway remodeling (proliferation, fibrosis). In this study, we characterized iron levels and regulation in human airway smooth muscle cells (hASMs) from young (<45 yr), old (≥65 yr), and AIE (≥65 yr) male/female patients, and investigated the contribution of iron overload in hASM to airway remodeling. Cells were treated with ferric ammonium citrate (FAC; 100 μM; 72 h) or iron chelator deferoxamine (DFO; 100 µM; 72 h). Basal levels of intracellular ferrous iron (Fe²⁺) were determined using the fluorescent dye FerroOrange. Cell lysates were analyzed for iron accumulation, antioxidant, lipid peroxidation, and extracellular matrix (ECM) markers, and cell proliferation was assessed. We found that iron accumulates with aging, but surprisingly decreases with AIE. hASM from AIE patients showed activated antioxidant pathways and lipid peroxidation, whereas FAC exposure impaired iron metabolism and enhanced ECM deposition. Iron depletion mitigated the antioxidant response, lipid peroxidation, cell proliferation, and ECM production. These findings suggest that iron metabolism in hASM contributes to cell hyperplasia and ECM remodeling, whereas in aging and particularly AIE, counter-regulatory changes in iron metabolism and antioxidant pathways occur, overall promoting airway remodeling.<b>NEW & NOTEWORTHY</b> Iron is an essential element for cellular homeostasis and functionality. Increased iron in the lung is associated with aging and asthma in the elderly (AIE). Using human airway smooth muscle cells from young versus elderly versus AIE patients, we found that dysregulated iron metabolism (more than iron accumulation), resulting in activation of antioxidant systems and increased susceptibility to ferroptosis, occurs in AIE, contributing to cell hyperplasia and matrix remodeling of aging and AIE.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C558-C572"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13505837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational modeling of substrate-dependent lung mitochondrial respiration and bioenergetics in rats with different susceptibility to hyperoxia-induced ARDS.","authors":"Pardis Taheri, Devanshi D Dave, Anne V Clough, Ranjan K Dash, Said H Audi","doi":"10.1152/ajpcell.00023.2026","DOIUrl":"10.1152/ajpcell.00023.2026","url":null,"abstract":"<p><p>Prolonged exposure to high oxygen levels (hyperoxia) is unavoidable in managing severe acute respiratory distress syndrome (ARDS), but can itself worsen lung injury and increase mortality. Rats conditioned to be hyperoxia-tolerant (H-T) or hyperoxia-susceptible (H-S) provide a system for assessing the contribution of mitochondrial bioenergetics to the differential susceptibility to hyperoxia-induced ARDS and for identifying potential therapeutic targets. Due to the system's complexity, interpreting lung mitochondrial bioenergetics data from these rat models requires a computational model to define which processes are altered and how changes influence overall lung tissue bioenergetics. We developed a thermodynamically constrained computational model of lung mitochondrial bioenergetics that extends prior models by incorporating regulation by ions (Ca²⁺, H⁺, etc.) and metabolites. The model was parameterized using experimental respirometry data from isolated lung mitochondria of conditioned (H-T and H-S) and control rats with different substrates and ADP concentrations. Model parameterization showed distinct bioenergetic changes. H-S mitochondria had reduced activity in adenine nucleotide translocase (ANT), cytochrome c oxidase (CIV), complex I (CI), and glutamate-oxaloacetate transaminase (GOT). Conversely, H-T mitochondria showed increased activity of ANT and CIV. This supports greater metabolic flexibility in H-T mitochondria compared with H-S. Simulations of ARDS-related changes predicted divergent outcomes. H-S mitochondria underwent rapid failure, with redox collapse, loss of membrane potential, and ATP depletion. H-T mitochondria maintained bioenergetic homeostasis by enhancing electron supply via CI and complex II, with higher CIV activity. This comprehensive computational model provides a framework for identifying critical mitochondrial processes and therapeutic strategies to mitigate mitochondrial dysfunction in ARDS.<b>NEW & NOTEWORTHY</b> We developed a comprehensive computational model of lung mitochondrial bioenergetics that integrates key regulatory mechanisms. The model, parameterized using respirometry data from lung mitochondria of hyperoxia-tolerant and -susceptible rats, identified adenine nucleotide translocase, cytochrome c oxidase, and proton leak as critical determinants of lung mitochondrial bioenergetic homeostasis. Model simulations predict that deficits in these processes drive rapid bioenergetic failure in the lungs of hyperoxia-susceptible rats.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C759-C782"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13521039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148663302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipin1 restores nNOS sarcolemmal localization and improves fatigue resistance in Duchenne muscular dystrophy.","authors":"Ayat Azzam, Abdulrahman Jama, John Karanja Kamau, Lixin Dong, Brooklyn Morris, Pooneh Hajmirza Mohammadi Kamalabadi, Denish Maharjan, Abdullah A Alshudukhi, Hongmei Ren","doi":"10.1152/ajpcell.00547.2025","DOIUrl":"10.1152/ajpcell.00547.2025","url":null,"abstract":"<p><p>In Duchenne muscular dystrophy (DMD), neuronal nitric oxide synthase (nNOS) is mislocalized from the sarcolemmal membrane and exhibits reduced expression and activity, impairing vasomodulation and contributing to increased muscle fatigue. Identification of upstream regulators that restore nNOS localization and function may provide therapeutic strategies to improve muscle performance in dystrophic muscle. In this study, we investigated the role of lipin1 in regulating nNOS expression, sarcolemmal localization, and nitric oxide synthase (NOS) activity in skeletal muscle. Lipin1 deficiency significantly reduced nNOS expression and total NOS enzymatic activity, whereas lipin1 overexpression enhanced these parameters. Skeletal muscle-specific lipin1 knockout mice (lipin1^Myf5cKO) exhibited increased muscle fatigue, consistent with impaired nNOS-dependent muscle function. In contrast, transgenic lipin1 restoration in dystrophic muscle (<i>mdx:lipin1</i>^Tg/0) restored nNOS expression and sarcolemmal localization and improved fatigue resistance. Our findings suggest that lipin1 promotes nNOS sarcolemmal localization, potentially through stabilization of membrane-associated protein complexes, and enhances nNOS expression through a lipin1/diacylglycerol/protein kinase D/cAMP response element-binding protein signaling axis. Collectively, these findings identify lipin1 as an important regulator of nNOS expression and localization in skeletal muscle and support lipin1 restoration as a potential therapeutic strategy for DMD.<b>NEW & NOTEWORTHY</b> In Duchenne muscular dystrophy (DMD) mislocalization and reduced expression of neuronal nitric oxide synthase (nNOS) impair nitric oxide signaling and contribute to muscle dysfunction. This study demonstrates that lipin1 restoration increases nNOS expression, promotes sarcolemmal nNOS localization, enhances NOS activity, and improves fatigue resistance in dystrophic muscle. These findings identify a previously unrecognized role for lipin1 in regulating nNOS and support lipin1 restoration as a potential therapeutic strategy for DMD.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C814-C824"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13531045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148760852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced monocyte influx to the injured heart during the dark phase exacerbates cardiac hypertrophy in a mouse model of Takotsubo cardiomyopathy.","authors":"Bruno Sanches, Fernando Souza-Neto, Giovane L C Pires, Henrique Abramo, Marcos Eliezeck, Sérgio A Scalzo, Nikolas Santos Silva, Flávio Almeida Amaral, Jop H van Berlo, Silvia Guatimosim, Cibele Rocha-Resende","doi":"10.1152/ajpcell.00734.2025","DOIUrl":"10.1152/ajpcell.00734.2025","url":null,"abstract":"<p><p>Although circadian rhythms are critical regulators of cardiovascular physiopathology, their role in Takotsubo syndrome (TTS) remains poorly understood. This study aimed to investigate the influence of time of day on cardiac hypertrophy and inflammation in a mouse model of TTS induced by isoproterenol (ISO) administration. Female mice were injected with saline (Sal) or ISO at the beginning of the light (ZT0) or dark phase (ZT12). Our data show that mice treated with ISO at ZT12 developed more prominent cardiac hypertrophy and exhibited worse cardiomyocyte calcium handling. This was accompanied by an enhanced accumulation of leukocytes in the hearts of ISO/ZT12 compared with ISO/ZT0 mice. Flow cytometry analysis revealed an exacerbation in the number CD64^hi/intLy6C^hi/loCCR2⁺ monocytes/macrophages at ZT12, indicating a time of day influence on the inflammatory response following ISO administration. Of note, these differences were not secondary to differences in initial tissue injury as assessed by Evans Blue uptake by necrotic cells. However, cardiac expression of <i>Ccl2/7</i> was significantly higher in the hearts of ISO/ZT12 than in the hearts of ISO/ZT0, suggesting the involvement of the CCL2/CCR2 signaling axis in the enhanced recruitment of monocytes. Finally, pharmacological and genetic strategies used to prevent CCR2-dependent recruitment of monocytes ameliorated the cardiac hypertrophy induced by ISO at ZT12, indicating that the CCL2/CCR2 signaling axis is crucial to the temporal-dependent effects of ISO. Taken together, our data show a previously unrecognized role of the time of day on cardiac inflammation following adrenergic overload.<b>NEW & NOTEWORTHY</b> Using a mouse model of stress-inducible cardiomyopathy, our study reveals that enhanced monocyte influx to the injured heart during the dark phase exacerbates cardiac hypertrophy through activation of the CCL2/CCR2 axis. These findings extend current knowledge on the mechanisms underlying Takotsubo cardiomyopathy and highlight the potential for time of day-based therapeutic strategies.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C664-C676"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148648071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insulin-regulated actin dynamics is disrupted in a human keratinocyte model of Hailey-Hailey disease.","authors":"Ruby Gupta, Akash Chinchole, Ngozi P Paul, Mrinal K Sarkar, Johann E Gudjonsson, Ajay Verma, Rajini Rao","doi":"10.1152/ajpcell.00372.2026","DOIUrl":"10.1152/ajpcell.00372.2026","url":null,"abstract":"<p><p>The secretory pathway Ca²⁺-ATPase, SPCA1 (gene name <i>ATP2C1</i>), is a Golgi-localized calcium pump defective in the autosomal dominant cutaneous disorder known as Hailey-Hailey disease (HHD). Although clinically well characterized by suprabasal acantholysis and intertriginous blistering of the skin, the mechanistic underpinnings of the disease are still unclear. Here we use CRISPR/Cas9-mediated single- and biallelic <i>ATP2C1</i> knockouts in immortalized human N/TERT keratinocytes to show that SPCA1 is required for dynamic reorganization of actin cytoskeleton in keratinocyte spreading, which is the primary mechanism driving skin reepithelialization. We identify an insulin-activated PI3K-AKT-Rac1 signaling pathway required for lamellipodia formation and keratinocyte spreading, defective in SPCA1 knockout cell lines. Our findings may explain the poor wound healing and impaired keratinocyte migration observed in HHD and may be relevant to the observed effect of insulin on wound healing, including diabetic wounds and burns, reported for nearly a century. Transgenic expression of hSPCA1 or treatment with CDN1163, a small molecule Ca²⁺-ATPase agonist, restored defective phenotypes in the HHD model, paving the way for future therapeutic approaches to treat this disorder.<b>NEW & NOTEWORTHY</b> Keratinocytes spread and change shape dynamically to maintain skin integrity and facilitate the rapid repair of the skin barrier after injury. Defects in these processes are characteristic of Hailey-Hailey disease (HHD), an ulcerative skin disorder caused by mutations in the Golgi Ca²⁺-ATPase SPCA1. By developing new keratinocyte HHD models, we uncover a role for SPCA1 in an insulin-activated signaling pathway that drives lamellipodia formation and keratinocyte spreading, linking Ca²⁺ regulation to actin cytoskeleton reorganization.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C797-C813"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148762306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}