American journal of physiology. Cell physiology最新文献

{"title":"High-fat diet and obesity each increase tumor cell proliferation and muscle wasting in experimental cancer cachexia.","authors":"Brittany R Counts, Andrea Bonetto, Ho Lam Chan, Ernie D Au, Yanlin Jiang, Marion E Couch, Denis C Guttridge, Michael C Ostrowski, Leonidas G Koniaris, Teresa A Zimmers","doi":"10.1152/ajpcell.00545.2025","DOIUrl":"10.1152/ajpcell.00545.2025","url":null,"abstract":"<p><p>High-fat diet (HFD) and associated obesity are suggested to predispose to cancer development, complicate cancer treatment, and accelerate mortality. Paradoxically, obese patients with lung cancer are reported to live longer, suggesting that high body mass is protective. Given that cachexia-tumor-induced weight loss with adipose and muscle wasting-is prevalent in lung cancer, we speculated that patients with obesity might survive longer due to the protective effect of larger tissue reservoirs, slowing time to fatal wasting. Thus, we modeled this condition using lean and high-fat diet (HFD)-induced obese mice with Lewis lung carcinoma (LLC) tumors versus nontumor-bearing controls. We also assessed the effects of feeding HFD to lean mice with and without LLC tumors. HFD and obese-HFD mice without tumors gained weight over the study, with obese-HFD mice exhibiting low muscle mass with obesity at endpoint. Low-fat diet (LFD)-fed lean mice with LLC tumors (LFD-LLC) showed no change in total body weight, but exhibited reduced skeletal muscle, heart, and fat pad mass along with hepatosplenomegaly at endpoint. HFD and pre-existing obesity both modified the response to Lewis lung carcinoma (LLC) tumors. HFD did not affect tumor-induced weight loss, fat loss, or tumor burden, but worsened loss of gastrocnemius, tibialis anterior, and heart muscle, prevented hepatosplenomegaly, and enhanced tumor cell proliferation and expression of the cachexia-inducing cytokine, interleukin-6 (IL-6). Obese-HFD mice showed greater tumor burden versus LFD and the worst cachexia phenotypes, including greater weight loss and muscle loss than HFD or LFD. This worsened cachexia was associated with increased blood-borne inflammatory cytokines, increased phosphorylated STAT3 in muscle, and increased IL-6 expression in muscle, spleen, and tumor. Obese-HFD was associated with the highest rate of tumor cell proliferation in vivo, and serum from obese HFD mice increased LLC cell proliferation in vitro. Thus, HFD and pre-existing obesity each separately enhance inflammation, cachexia, and tumor growth. These distinct contributions of HFD and chronic adiposity are potential therapeutic targets to slow cachexia and tumor growth in cancer.<b>NEW & NOTEWORTHY</b> High-fat diet and obesity are linked to increased cancer risk, but the impact on cachexia development remains unclear. Using mouse models, this study demonstrates high-fat diet and obesity each exacerbate muscle wasting, tumor growth, and tumor and muscle IL-6 expression. Our study reveals distinct, overlapping effects with implications for cancer and cachexia interception.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C727-C740"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13053052/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146776098","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":"New insights into immunoporosis: the impact of ovariectomy on immune cell population in lymph nodes and spleen.","authors":"Nicole Gabriele Sommer, Katharina Jandl, Begüm Okutan, Uwe Yacine Schwarze, Jan Eike Freudenthal-Siefkes, Valentin Herber, Annelie-Martina Weinberg","doi":"10.1152/ajpcell.00638.2025","DOIUrl":"10.1152/ajpcell.00638.2025","url":null,"abstract":"<p><p>It is increasingly appreciated that the immune cells and inflammatory mediators contribute to the impaired osteogenic potential under osteoporotic conditions. Previous studies in experimental animals focused on immune cells isolated from blood or bone marrow. Here we highlight the importance of unraveling the interactions between peripheral tissues, such as spleen and lymph nodes, and bone morphologic markers. Ovariectomized (OVX) animals underwent bilateral ovariectomy at the age of 9 mo. Four, 8, and 12 wk after ovariectomy, osteoporotic parameters and the immunoprofile were investigated by flow cytometric analysis of blood, lymph node, and spleen paired with immunohistochemistry. Ex vivo high-resolution micro-computed tomography (micro-CT) and hard tissue histology were performed on the excised tibiae. We observed trabecular bone loss, with corresponding decreases in bone volume to tissue volume (BV/TV), trabecular number (Tb.N), and connectivity density (Conn.D), as well as an increase in trabecular separation (Tb.Sp) in the OVX rats after 12 wk. Quantitative FACS analysis revealed significantly decreased percentage of granulocytes in lymph nodes at 12 wk in OVX. Correlation of distinct immune cell populations to bone morphologic markers showed that the percentage of granulocytes positively correlated with the Tb.N and Conn.Dn and negatively with the Tb.Sp both in the lymph nodes and in the spleen at 8 wk. At 12 wk after ovariectomy, however, the percentage of granulocytes correlated negatively with BV/TV, Tb.Th, and Tb. N. There was no correlation between distinct immune cells in the blood and bone morphologic markers. Hence, the presented data highlight the unmet need to investigate other compartments rather than blood and bone marrow.<b>NEW & NOTEWORTHY</b> There is supporting immunological evidence in the development of osteoporosis highlighted by bone alterations. Measurements of immune cells in the blood and bone marrow do not always reflect the multifactorial, pathologic situation linked to osteoporosis. Here, we pinpoint to distinct immune cell populations in peripheral tissues, especially in lymph nodes, which are affected during the onset of osteoporosis.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1031-C1043"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147353405","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":"A novel cell indirect calorimetry method unveils the metabolic fluxomic signatures of human monocyte-derived M(LPS + IFN-γ) and M(IL-4) macrophages.","authors":"Gloria Cinquegrani, Valentina Spigoni, Federica Fantuzzi, Anna D'Antuono, Francesca Bagnaresi, Elisabetta Giordano, Alberto Burato, Alessandra Dei Cas, Riccardo C Bonadonna","doi":"10.1152/ajpcell.00635.2025","DOIUrl":"10.1152/ajpcell.00635.2025","url":null,"abstract":"<p><p>Macrophages (MΦ) display distinct immunometabolic phenotypes upon polarization. While transcriptomic analyses have suggested divergent metabolic programs in human M(LPS + IFN-γ) and M(IL-4) MΦ, a comprehensive assessment of their metabolic fluxes is lacking. The aim of this study is to <i>1</i>) develop and validate a novel indirect microcalorimetry method for quantifying cellular metabolic fluxes, and <i>2</i>) exploit it to characterize fluxomic signatures of polarized human monocyte-derived macrophages. MΦ from healthy donors were differentiated into unstimulated macrophages (M0), M(LPS + IFN-γ), and M(IL-4) phenotypes and studied in four defined media: substrate-free, glucose, glycyl-glutamine, and glucose + glycyl-glutamine. A steady-state fluxomic model was constructed by integrating four independent measures, oxygen consumption and proton production (Seahorse XFp) and lactate and ammonia release (microfluorimetry), into stoichiometric equations of metabolism (SAAM II software). Fluxes revealed that macrophages rely on glucose to sustain glycolysis, contributing ∼30% of citrate synthase flux, and predominantly on lipids for net citrate synthesis (first step of TCA cycle). Upon polarization, M(LPS + IFN-γ) macrophages showed increased anaerobic glycolysis versus M0 and M(IL-4), with similar TCA fluxes to M0. In contrast, M(IL-4) macrophages exhibited higher TCA and malic enzyme fluxes, especially with glucose and glycyl-glutamine, and a trend toward enhanced lipid oxidation. This novel method enables precise quantification of bioenergetic fluxes. In human MΦ, it reveals that M(LPS + IFN-γ) and M(IL-4) subsets exhibit distinct metabolic phenotypes, consistent with their immunological roles. These results resolve transcriptomic-metabolic discrepancies and provide a robust framework for assessing immunometabolism in primary human cells.<b>NEW & NOTEWORTHY</b> We present a novel microcalorimetry-based approach for quantifying metabolic fluxes in human cells. Applied to primary monocyte-derived human macrophages, this method reveals that M(LPS + IFN-γ) and M(IL-4) subsets exhibit distinct fluxomic profiles: the former favors glycolysis, whereas the latter shows enhanced TCA cycle activity and lipid oxidation. These findings resolve previous discrepancies between transcriptomic and functional data and provide a robust framework for investigating immunometabolism in primary human cells.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C954-C973"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147324431","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 insights into cellular mechanics and membrane undulations in vascular smooth muscle cells.","authors":"Nisha Khatiwada, Hanna J Sanyour, Iyad A Hammam, Zhuofan Li, James McLean, Abena Dwamena, Alexander Perez, Glen Ebenezer See, Hongmin Wang, Minliang Liu, Zhongkui Hong","doi":"10.1152/ajpcell.00771.2025","DOIUrl":"10.1152/ajpcell.00771.2025","url":null,"abstract":"<p><p>Dynamic oscillations in cell mechanics are fundamental yet poorly understood features of living cells. In vascular smooth muscle cells (VSMCs), such oscillations may play important roles in regulating contractility, mechanosensitivity, and vascular function. Here, real-time atomic force microscopy (AFM), advanced signal processing, biochemical analysis, and machine learning-based image quantification were combined to investigate the spatiotemporal coupling between cellular mechanics, membrane undulation, cytoskeletal organization, and actomyosin signaling in VSMCs. Continuous AFM force and height mapping revealed intrinsic, low-frequency oscillations in both elastic modulus and membrane roughness, with dominant modes at ∼0.55, ∼1.6, and ∼3.5 mHz, that were absent in passive material controls. Pharmacological modulation of the actin cytoskeleton demonstrated frequency-dependent regulation of these oscillations: stabilization of F-actin with jasplakinolide increased cellular stiffness and selectively enhanced low-frequency mechanical oscillations while suppressing membrane roughness fluctuations, whereas actin depolymerization with latrunculin A reduced stiffness and mechanical oscillations but markedly amplified membrane undulations. Confocal imaging and deep learning-based analysis confirmed corresponding changes in actin fiber density and organization. Moreover, inhibition of myosin light chain kinase (MLCK) signaling reduced cell stiffness and preferentially attenuated higher-frequency oscillatory modes, whereas biochemical analysis revealed differential regulation of MLCK phosphorylation following actin perturbation. Together, our findings suggest that changes in actin organization and MLCK-driven contractility control different patterns of mechanical oscillation and membrane behavior in VSMCs. This helps us better understand how smooth muscle mechanics are regulated across different scales and why disruptions in these processes could influence vascular function and disease.<b>NEW & NOTEWORTHY</b> In this study, we observed previously unrecognized mechanical oscillations in vascular smooth muscle cells that occur at specific frequencies and remain synchronized across the cell, alongside coordinated membrane movements. By combining real-time atomic force microscopy with targeted perturbations of the cytoskeleton and myosin light chain kinase activity, we found that different oscillatory behaviors depend on actin organization and contractile signaling. These results outline a multiscale framework for understanding how smooth muscle mechanics are dynamically controlled.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C877-C890"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13105306/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147300701","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":"Forgotten Foundations: Basement Membranes in Lung Function and Cancer.","authors":"Dasol Yoo, Thomas R Cox, Amelia L Parker","doi":"10.1152/ajpcell.00599.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00599.2025","url":null,"abstract":"<p><p>The basement membrane is a specialised extracellular matrix network that orchestrates fundamental cellular processes in many organs. In the lung, this dynamic scaffold provides compositionally encoded instructions that direct epithelial differentiation, regulate injury responses, and modulate disease progression. Despite its fundamental importance, the basement membrane remains an understudied aspect of lung biology, with its precise composition, spatial organisation and biomechanical properties in health and disease poorly defined. This review synthesises current understanding of lung epithelial basement membrane composition and function with emphasis on how this matrix layer supports lung development, injury repair, and cancer progression. We highlight evidence that basement membrane components are not merely structural supports but active regulators of cellular phenotype and discuss how this conceptual shift opens new therapeutic strategies in lung cancer.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147580101","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":"SK Channels as Anti-Arrhythmic Targets for Atrial Fibrillation: Structural and Pharmacological Perspectives.","authors":"Megan K McKie, Emma H Meibom, Andreina Gil Ramirez, Luca Soattin, Bo Hjorth Bentzen","doi":"10.1152/ajpcell.00921.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00921.2025","url":null,"abstract":"<p><p>Small-conductance Ca²⁺-activated K⁺ (SK) channels have emerged as promising atrial-selective targets for rhythm control in atrial fibrillation (AF). Genetic association studies, functional experiments, and early clinical trials collectively support a role for SK channels in atrial repolarization and AF maintenance. Recent breakthroughs in single-particle cryo-electron microscopy have provided high-resolution structures of the SK2 channel, revealing unique architectural features that underlie its low conductance, and susceptibility to pharmacological modulation. Numerous studies have shown alterations in SK transcript abundance in AF in both humans and animal models. However, recent functional studies have demonstrated dynamic regulation of SK channel gating and membrane trafficking in AF, highlighting context-dependent pro- and anti-arrhythmic effects. This mini review summarizes the recent structural and functional advances in our understanding of SK channels, and emerging therapeutic implications for AF.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479455","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":"The role of osteomimicry factors in prostate cancer progression and metastasis.","authors":"Said M Elshafae, Payton H Utzman, Maha A Moussa, Ahmed Fotouh, Selvarangan Ponnazhagan, Blake E Hildreth","doi":"10.1152/ajpcell.00845.2025","DOIUrl":"10.1152/ajpcell.00845.2025","url":null,"abstract":"<p><p>Prostate cancer progression and metastasis are complex steps that are controlled by various molecular and cellular mechanisms. Here, the process of osteomimicry has a vital role in the context of bone metastasis. Osteomimicry phenomenon refers to the ability of cancer cells to acquire bone-like properties, thus enabling them to adapt to and survive in their bone microenvironment. This phenomenon promotes cancer cell and bone microenvironment interactions and contributes directly to tumor survival, growth, and the development of bone metastatic lesions. In this review, we discuss the role of different osteomimicry factors in prostate cancer progression and metastasis, highlighting their involvement in each stage of the metastatic cascade. Key factors involved in osteomimicry-such as bone matrix proteins, signaling pathways, and transcriptional regulators-play important roles throughout the various stages of cancer progression. These include the initial development of the tumor, its local invasion into surrounding tissues, entry into the bloodstream (intravasation), spread to other more distant areas (extravasation), and ultimately, colonization and growth in the bone. Gaining a better understanding of how these factors are regulated, interact, and function can shed light on new treatment strategies aimed at targeting osteomimicry to slow down or prevent the progression of prostate cancer and its spread to the bones.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C605-C618"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145964996","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":"STL1267 inhibits myofibroblast differentiation in a TGFβ1-driven human lung fibroblast model.","authors":"Chandrashekhar Prasad, Steven K Huang, Thomas P Burris, Isaac Kirubakaran Sundar","doi":"10.1152/ajpcell.00561.2025","DOIUrl":"10.1152/ajpcell.00561.2025","url":null,"abstract":"<p><p>Pulmonary fibrosis is a progressive interstitial lung disease characterized by excessive fibroblast-to-myofibroblast transition (FMT) and extracellular matrix (ECM) deposition, largely driven by transforming growth factor-beta 1 (TGFβ1). Existing therapies offer limited efficacy, particularly in advanced disease. Circadian rhythms have recently emerged as key modulators of lung inflammation and fibrosis. In this study, we developed an in vitro model of chronic fibrotic signaling using adenovirus-mediated TGFβ1 overexpression (Ad-TGFβ1) or human recombinant protein TGFβ1 in primary normal human lung fibroblasts. Using this model, we investigated the antifibrotic potential of STL1267, a next-generation REV-ERBα agonist with improved potency, specificity, and pharmacokinetic properties. RNA sequencing and pathway analysis revealed that STL1267 significantly reversed Ad-TGFβ1-induced expression of genes associated with ECM remodeling, collagen biosynthesis, and immune suppression. STL1267 also upregulated pathways related to IL-10, IL-4, and IL-13 signaling, which are known to counteract fibrotic responses. Quantitative PCR and immunoblotting confirmed STL1267's ability to downregulate key profibrotic markers, including COL1A1, αSMA, FN1, and FAP, at both gene and protein levels. Comparative studies with other Rev-erbα agonists (GSK4112, SR9009), saracatinib, and Food and Drug Administration (FDA)-approved antifibrotic drugs (pirfenidone, nintedanib) demonstrated superior efficacy of STL1267 in inhibiting both preventive and postfibrotic induction models. Moreover, lentiviral overexpression of Rev-erbα suppressed TGFβ1-induced αSMA expression, supporting a direct antifibrotic role. These findings highlight Rev-erbα as a key regulator of myofibroblast differentiation and support both STL1267 and GSK4112 as promising candidates for circadian-based antifibrotic therapy. Future in vivo studies are warranted to evaluate its translational potential in idiopathic pulmonary fibrosis.<b>NEW & NOTEWORTHY</b> This study introduces a novel in vitro adenovirus-based model of persistent TGFβ1 signaling in normal human lung fibroblasts to mimic chronic fibrosis. Using this model, we show that the next-generation REV-ERBα agonist STL1267 robustly inhibits myofibroblast differentiation and ECM gene expression. STL1267 outperforms Food and Drug Administration-approved antifibrotic drugs and modulates immune and circadian signaling pathways, supporting its potential as a promising circadian-based therapeutic strategy for pulmonary fibrosis.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C571-C589"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13008274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145942053","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":"ADAM17-induced shedding of glypican-1 as a mechanism of impaired endothelial shear stress mechanotransduction.","authors":"Marc A Augenreich, Larissa Ferreira-Santos, Gavin Power, Francisco I Ramirez-Perez, Juan D Gonzalez-Vallejo, Morgan B Williams, Natnicha Imkaew, Min Jeong Cho, Andrew A Wheeler, Camila Manrique-Acevedo, Luis A Martinez-Lemus, Jaume Padilla","doi":"10.1152/ajpcell.00794.2025","DOIUrl":"10.1152/ajpcell.00794.2025","url":null,"abstract":"<p><p>Endothelial dysfunction occurs early in the pathogenesis of type 2 diabetes (T2D)-associated cardiovascular disease. Previous work has revealed that endothelial glycocalyx mechanosensing structures are degraded in T2D, likely contributing to impaired shear stress mechanotransduction and consequent blunted vasodilation. Evidence from proteomic analysis suggests that glypican-1, a well-known mechanosensor, is a substrate of the proinflammatory enzyme ADAM17. A critical step in ADAM17 activation is externalization of phosphatidylserine (PS) to the outer leaflet of the plasmalemma, which can be enacted by the Ca²⁺-activated phospholipid scramblase anoctamin-6 (ANO6). However, whether ANO6-mediated activation of ADAM17 leads to glypican-1 shedding in endothelial cells remains unknown. Also, unknown are the mechanisms by which this pathway becomes overactive in T2D. We recently reported that the activity of neuraminidase, a soluble enzyme that cleaves sialic acid, is elevated in the plasma of individuals with T2D and that this occurs in concert with increased ADAM17 activity. Here, in an extended cohort of males and females with T2D, we report that this association is also coupled with reduced flow-mediated dilation (FMD). Furthermore, we report that subjecting endothelial cells to neuraminidase increases intracellular Ca²⁺, which provokes ANO6-mediated PS externalization, leading to ADAM17-dependent reductions of glypican-1. In isolated arteries, intraluminal exposure to neuraminidase impairs FMD, which can be prevented by ANO6 or ADAM17 inhibition. Lastly, isolated arteries from endothelial cell-specific ADAM17 knockout mice fed a Western diet exhibit greater FMD than genetic controls. Collectively, this work identifies the neuraminidase-ANO6-ADAM17 axis as a potential novel mechanism underlying impaired endothelial shear stress mechanotransduction in T2D.<b>NEW & NOTEWORTHY</b> We provide evidence that neuraminidase, which is elevated in plasma from males and females with type 2 diabetes (T2D), is involved in the activation of endothelial ADAM17 and shedding of the mechanosensor glypican-1. We also provide evidence that neuraminidase-induced ADAM17 activation and consequent glypican-1 shedding are mediated by ANO6 scramblase externalization of phosphatidylserine. Together, this work suggests the neuraminidase-ANO6-ADAM17 axis may be a mechanism underlying impaired endothelial shear stress mechanotransduction in T2D.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C631-C642"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12905800/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987609","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":"Adamts5 deletion exacerbates inflammation and fibrosis resulting in compromised skeletal muscle regeneration.","authors":"John Dulos, Richard Sun, Valentina Jovanovska, Fabrice Kolb, Nicole Stupka","doi":"10.1152/ajpcell.00443.2025","DOIUrl":"10.1152/ajpcell.00443.2025","url":null,"abstract":"<p><p>The extracellular matrix (ECM) protease Adamts5 and its ECM substrates are critical regulators of inflammation and fibrosis, whether Adamts5 also regulates muscle regeneration is not known. Right tibialis anterior (TA) muscles from adult <i>Adamts5</i>^-/- or wild-type mice were injected with glycerol to induce injury. In uninjured muscles and at 7 and 14 days after injury, TA contractile function was determined in situ, followed by an assessment of pathology using histology and immunohistochemistry. Immunoblotting was performed for the versikine fragment, which is generated when Adamts5 cleaves its substrate versican. Versikine protein, which correlates with Adamts5 proteolytic activity, was lower in uninjured and injured TA muscles from <i>Adamts5</i>^-/- versus wild-type mice. In uninjured TA muscles, Adamts5 deletion of the catalytic and ancillary domains decreased the absolute (P_o) and normalized to muscle size (sP_o) force output, with no significant effect on muscle mass and myofiber size. Adamts5 deletion compromised regeneration with greater impairment evident at the later timepoint. Force output (P_o and sP_o) was lower in <i>Adamts5</i>^-/- mice at 7 and 14 days after injury. TA mass and myofiber size were only decreased at 14 days after injury, whereas embryonic myosin heavy chain expression did not significantly differ between genotypes. Degeneration, mononuclear infiltrates, and ECM deposition including fibronectin protein were greater in injured TA muscles from <i>Adamts5</i>^-/- mice. Resolution of inflammation was also delayed in <i>Adamts5</i>^-/- mice, with more infiltrating macrophages observed at 14 days after injury. In conclusion, Adamts5 regulates the balance between muscle regeneration, fibrosis, and inflammation following glycerol injury.<b>NEW & NOTEWORTHY</b> Glycerol injury to mouse hindlimb muscles results in inefficient regeneration and fibrosis. Adamts5 is a secreted protease, which degrades extracellular matrix (ECM) proteins and has an emerging role in inflammation, fibrosis, and muscle development. In Adamts5-deficient mice, muscle degeneration, inflammation, and fibrosis were increased, and contractile function was impaired for up to 14 days after glycerol injury when compared with wild-type mice. These findings demonstrate the significant role of Adamts5 in muscle regeneration.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C651-C668"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146058561","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}