American journal of physiology. Cell physiology最新文献

{"title":"The fibrocystin C-terminal domain inhibits Src/STAT3 signal-induced cystogenesis of kidney epithelial cells.","authors":"Fatima Hassan, Susanne T Hahnenstein, Andre Kraus, Bjoern Buchholz, Markus Mukenhirn, Alf Honigmann, Claudia Dafinger, Max C Liebau, Thomas Pokrant, Jan Faix, Andrea Grund, Dieter Haffner, Wolfgang H Ziegler","doi":"10.1152/ajpcell.00086.2026","DOIUrl":"10.1152/ajpcell.00086.2026","url":null,"abstract":"<p><p>Autosomal recessive polycystic kidney disease (ARPKD) is caused by impaired function of fibrocystin/polyductin (FPC) in collecting duct epithelia, resulting in cyst formation. We hypothesized that the membrane-bound C-terminal FPC domain (FPCct) is necessary to suppress cystogenesis and facilitate epithelial homeostasis. In ARPKD, cystic kidney epithelia are characterized by a secretory phenotype associated with high intracellular cAMP levels and enhanced STAT3-dependent transcription. Moreover, impaired FPC function may lead to enhanced activation of Src tyrosine kinase, thereby activating STAT3 signaling and its downstream transcriptional activity. To investigate the effects of FPC loss on the cystic epithelial cell phenotype, we used an established principal-like MDCK cell line (pl-MDCK) and studied monolayers in both two- and three-dimensional culture. In this in vitro model of collecting duct epithelia, FPC-deficient cells showed twofold elevated basal cAMP levels and enhanced apical secretion leading to threefold higher luminal pressure. Forskolin-stimulated elevation of cAMP levels triggered enhanced Src-dependent activation of STAT3, resulting in a pronounced cystic phenotype. Notably, expression of wild-type FPCct reduced both STAT3-dependent transcription and the secretory phenotype in knockout epithelial cells. Our data suggest that FPCct interacts with Src kinase at the plasma membrane, thereby reducing Src-mediated STAT3 phosphorylation and limiting STAT3-dependent transcription. Thus, FPCct appears to act like a physiological suppressor of cystogenic signaling, as found in healthy kidney epithelia, which is essential for maintaining epithelial homeostasis. Protein constructs that restore FPC C-terminal function may offer a therapeutic lead to mitigate epithelial dysfunction and slow disease progression in ARPKD.<b>NEW & NOTEWORTHY</b> ARPKD is caused by impaired function of fibrocystin. We hypothesized that its C-terminal domain, FPCct, can suppress cystogenesis and uphold homeostasis. In epithelial spheroids of principal-like MDCK cells, high cAMP levels triggered Src-dependent activation of STAT3 inducing cystic phenotype. FPCct expressed in knockout epithelia, reduced both STAT3-dependent transcription and cystic phenotype, acting like a physiological suppressor of cystogenic signaling. FPCct may offer a therapeutic lead to mitigate epithelial dysfunction and slow disease progression in ARPKD.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C934-C946"},"PeriodicalIF":5.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148838906","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":"Correction for Xiao et al., volume 292, 2007, p. C342-C352.","authors":"","doi":"10.1152/ajpcell.00341.2006_COR","DOIUrl":"https://doi.org/10.1152/ajpcell.00341.2006_COR","url":null,"abstract":"","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"331 4","pages":"C1075"},"PeriodicalIF":5.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149102569","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":"Effect of glabridin on ion transport across primary human bronchial epithelial cells.","authors":"Aaron Kolski-Andreaco, John Sembrat, Michael B Butterworth, Daniel C Devor","doi":"10.1152/ajpcell.00216.2026","DOIUrl":"10.1152/ajpcell.00216.2026","url":null,"abstract":"<p><p><i>Glycyrrhiza glabra</i> is 1 of 30 species of licorice, which has been prescribed for centuries for a wide range of ailments and conditions. In particular, licorice root extract, as well as its main isoflavonoid constituent, glabridin, has been used to treat a variety of respiratory diseases, ranging from infection to asthma. As glabridin has been shown to modulate the activity of ion channels in other tissues, we determined the effect of glabridin on K⁺ and Cl^- secretion across primary human bronchial epithelial cells (HBEs), as these may represent therapeutic targets. Glabridin stimulated BK_Ca-dependent transepithelial potassium secretion across HBEs. In contrast, the glabridin derivative, vutiglabridin, failed to stimulate K⁺ secretion and inhibited the glabridin-dependent K⁺ secretory current. Whole cell patch-clamp studies on HEK cells expressing BK_Ca demonstrate that glabridin activates, whereas vutiglabridin inhibits, BK_Ca. We further demonstrate glabridin inhibits forskolin-mediated transepithelial Cl^- secretion across HBEs, whereas vutiglabridin has little effect. Using Fisher rat thyroid (FRT) cells stably expressing either wild-type (FRT-WT) or F508del CFTR (FRT-F508del), we demonstrate glabridin neither potentiates WT CFTR nor corrects F508del CFTR. In contrast, whole cell patch-clamp studies demonstrate glabridin inhibits KCa3.1 stably expressed in HEK cells. We previously demonstrated a role for KCa3.1 in forskolin-mediated Cl^- secretion across HBEs, likely explaining the inhibition of Cl^- secretion observed. In summary, we show that glabridin both stimulates BK_Ca-dependent K⁺ secretion and inhibits cAMP-mediated Cl^- secretion across HBEs. These findings support a role for BK_Ca in the therapeutic effects of glabridin in airway.<b>NEW & NOTEWORTHY</b> We demonstrate for the first time that the natural isoflavone, glabridin, stimulates transepithelial K⁺ secretion and inhibits forskolin-mediated Cl^- secretion across primary human bronchial epithelial cells (HBEs). We demonstrate that these effects are due to the activation of BK_Ca and inhibition of KCa3.1, respectively. Furthermore, glabridin does not potentiate wild-type (WT) or correct F508del CFTR. In contrast, the glabridin derivative, vutiglabridin, inhibits BK_Ca and is antagonistic to the action of glabridin in HBEs.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1037-C1046"},"PeriodicalIF":5.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13595419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879039","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":"Exogenous lactate ameliorates Aβ-induced energy deficit and neurotoxicity with increased mitochondrial TCA cycle carbon flux in SH-SY5Y cells.","authors":"Yewon Chang, Hee-Joo Kim, Yeongmin Kim, Aron Park, Seungyoon Nam, Deveena R Banerjee, Clinton M Hasenour, Jamey D Young, George A Brooks, Robert R Wolfe, Il-Young Kim","doi":"10.1152/ajpcell.00268.2026","DOIUrl":"10.1152/ajpcell.00268.2026","url":null,"abstract":"<p><p>A growing body of evidence has demonstrated the existence of metabolic dysfunction in neurodegenerative diseases, including Alzheimer's disease (AD), suggesting that deprivation of energy substrates impairs cellular dynamics. As glucose utilization declines in patients with AD, the need for alternative energy sources becomes crucial to sustain neuronal activities and prevent cell death induced by neurotoxic proteins, such as amyloid beta (Aβ) aggregates. In this context, lactate has been investigated as a potential alternative brain energy substrate in several studies, yet its impact on neuronal cells under Aβ-induced toxicity remains unclear. We confirmed significant suppression of energy production-related biological pathways by analyzing brain transcriptomic data of patients with AD. In subsequent in vitro studies, exogenous lactate treatment ameliorated neuron-like cell death caused by Aβ aggregates. Using a ¹³C stable isotope tracer, we verified cellular lactate uptake and its incorporation into tricarboxylic acid (TCA) cycle in neurons under the neurotoxic condition. ¹³C metabolic flux analysis further supported these findings by revealing that lactate treatment restored Aβ-suppressed mitochondrial TCA cycle fluxes. These metabolic improvements were accompanied by increased expression of mitochondrial proteins. These findings support lactate shuttling as a mechanism for supplying lactate-derived carbon to mitochondrial energy metabolism, which may improve neuronal resilience under Aβ-induced metabolic stress.<b>NEW & NOTEWORTHY</b> This study shows that lactate treatment attenuates Aβ-induced cell death in neuron-like cells and supports mitochondrial carbon metabolism. Glycolytic hypometabolism was observed in human AD brain transcriptome and Aβ-treated neuron-like cells. We confirmed that lactate replenished mitochondrial energetics, making neurons more resilient to neurotoxicity. Using ¹³C tracing and metabolic flux analysis, we found that lactate-derived carbon was incorporated into the TCA cycle and that lactate treatment was associated with restoration of Aβ-suppressed mitochondrial fluxes.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C888-C900"},"PeriodicalIF":5.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787228","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":"Physiological functions of MCT1 and MCT4 in intramuscular lactate shuttle, exercise performance, and glucose disposal.","authors":"Zinan Wang, Shixuan Zhuo, Chenchen Li, Jing Zhu, Shuying Wang, Yan Chen","doi":"10.1152/ajpcell.00414.2026","DOIUrl":"10.1152/ajpcell.00414.2026","url":null,"abstract":"<p><p>Lactate shuttling between glycolytic and oxidative muscle fibers via monocarboxylate transporters MCT1 and MCT4 is fundamental to muscle energy homeostasis, yet the physiological necessity of these two transporters remained obscured by functional redundancy. To investigate the significance of these two transporters in intermuscular lactate shuttle, we generated and characterized skeletal muscle-specific MCT1/4 double-knockout (MCT1/4-mKO) mice alongside with MCT4 single-knockout mice (MCT4-mKO). Although MCT4-mKO mice had minimal metabolic disturbances, MCT1/4-mKO mice exhibited markedly reduced lean mass, impaired exercise endurance, together with enhanced insulin-stimulated glucose disposal under normal chow diet conditions. The blood lactate level after exercise and the maximum grip strength were mitigated in both MCT4-mKO and MCT1/4-mKO mice. Plasma membrane localization of GLUT4 was robustly increased in the skeletal muscle in MCT1/4-mKO mice upon insulin treatment. These findings highlight that the intramuscular lactate shuttle mediated by MCT1 and MCT4 is critical for maintaining skeletal muscle mass, contractile performance, and insulin sensitivity.<b>NEW & NOTEWORTHY</b> The lactate shuttle within skeletal muscle is crucial for muscle functions, especially during exercise. It has long been proposed that two lactate transporters called MCT1 and MCT4 are involved in the lactate shuttle in the skeletal muscles. This study provides direct evidence that these two transporters are involved in maintaining the physiology and exercise performance of the skeletal muscle by utilizing a mouse model with muscle-specific ablation of these two lactate transporters.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C921-C931"},"PeriodicalIF":5.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148758580","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":"NAD⁺ or β-hydroxybutyrate each protects against tachypacing-induced metabolic remodeling through regulation of mitophagy in HL-1 cardiomyocytes.","authors":"Xi Qi, Liangyu Hu, Alexia van Rinsum, Werner J H Koopman, Jaap Keijer, Deli Zhang","doi":"10.1152/ajpcell.00253.2026","DOIUrl":"10.1152/ajpcell.00253.2026","url":null,"abstract":"<p><p>Atrial fibrillation is associated with metabolic remodeling and mitochondrial dysfunction, leading to impaired energy production, oxidative stress, and structural changes. Targeting metabolic pathways may therefore provide therapeutic benefit. We previously showed that nicotinamide adenine dinucleotide and β-hydroxybutyrate protect against pacing-induced contractile dysfunction, but their effects on mitochondrial and metabolic remodeling remain unclear. In this study, atrial cardiomyocytes were subjected to rapid electrical stimulation to mimic atrial fibrillation-related stress. Cells were treated with nicotinamide adenine dinucleotide, β-hydroxybutyrate, or control. Metabolic changes were evaluated by transcriptomic analysis, protein expression, and imaging of pathways related to fatty acid oxidation, glycolysis, and lipid accumulation. Glycolytic activity was assessed by measuring glucose consumption and lactate production, and mitochondrial function was determined by high-resolution respirometry. Markers of mitophagy and NLRP3 inflammasome activation were also examined. Tachypacing-induced metabolic remodeling is characterized by reduced fatty acid oxidation and fatty acid oxidation-linked mitochondrial respiration, increased glycolysis, oxidative stress, and lipid droplet accumulation, impaired mitophagy, and activation of NLRP3-related inflammatory signaling. Treatment with nicotinamide adenine dinucleotide or β-hydroxybutyrate attenuated many of these changes and partially restored mitochondrial respiratory capacity and metabolic balance. Notably, knockdown of mitophagy-related proteins (mitofusin 2, PTEN-induced kinase 1, and Parkin) caused contractile dysfunction and diminished the protective effects of both treatments on cardiomyocyte contractile function, suggesting that mitophagy may mediate the functional benefits of these compounds. These findings indicate that mitochondrial and metabolic remodeling are closely associated with tachypacing-induced cellular dysfunction and mitophagy and suggest that metabolic interventions may help preserve cardiomyocyte function partially by preserving mitophagy.<b>NEW & NOTEWORTHY</b> Nicotinamide adenine dinucleotide and β-hydroxybutyrate restore mitochondrial function and metabolic balance, in part by preserving PINK1-Parkin-MFN2-mediated mitophagy. Silencing key mitophagy regulators abolishes these protective effects, identifying mitophagy as a central mechanism linking metabolic interventions to functional recovery and as a potential therapeutic target in atrial fibrillation-associated remodeling.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C901-C920"},"PeriodicalIF":5.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148824017","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":"Effects of calcineurin inhibition on renal tubular transport.","authors":"Wouter H van Megen, Johannes Loffing","doi":"10.1152/ajpcell.00254.2026","DOIUrl":"10.1152/ajpcell.00254.2026","url":null,"abstract":"<p><p>Calcineurin inhibitors (CNIs), including tacrolimus and cyclosporin A, are potent immunosuppressive drugs that exert their effects by inhibiting protein phosphatase 3, also known as calcineurin. CNIs are widely used clinically, particularly for preventing organ rejection following transplantation. However, their use is frequently associated with significant adverse effects. In particular, CNIs commonly affect the kidney and can lead to acute and chronic kidney injury. In addition, they interfere with renal electrolyte reabsorption resulting in electrolyte disturbances (e.g., hyperkalemia and hypomagnesemia) and hypertension. Notably, calcineurin subunits are abundantly expressed throughout the nephron. Consequently, calcineurin inhibition affects electrolyte transport in virtually all nephron segments. In this review, we summarize the current knowledge on the effects of CNIs on renal tubular ion transport processes and highlight the underlying mechanism by which these effects contribute to CNI-induced electrolyte disturbances.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1061-C1074"},"PeriodicalIF":5.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886261","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":"Cadherin-11 regulation of type II alveolar epithelial cells during pulmonary fibrosis.","authors":"Mesias Pedroza, Sarah To, Jennifer Smith, Tingting W Mills, Thandiwe Chavula, Harry Karmouty-Quintana, Sandeep K Agarwal","doi":"10.1152/ajpcell.00164.2026","DOIUrl":"10.1152/ajpcell.00164.2026","url":null,"abstract":"<p><p>Type II alveolar epithelial cell (AT2) injury has been hypothesized to contribute to pulmonary fibrosis. Cadherin-11 (CDH11) is a mediator of fibrosis and is upregulated on AT2s during lung fibrosis. Herein, the regulation of AT2 by CDH11 during pulmonary fibrosis was investigated. CDH11 levels were increased in lung samples from patients with idiopathic pulmonary fibrosis compared with those from healthy controls. CDH11 expression was inversely correlated with lung function. <i>Cdh11</i>-deficient mice were compared with wild-type mice in the intraperitoneal bleomycin model (IP BLM), and the role of AT2 was investigated using <i>Cdh11</i> floxed-SPC-Cre mice and in vitro techniques. In the IP BLM model of pulmonary fibrosis, genetic removal of <i>Cdh11</i> and CDH11 neutralization with monoclonal antibodies reduced pulmonary fibrosis and expression of epithelial injury and mesenchymal markers. Colocalization studies demonstrated that CDH11 was coexpressed with α-SMA on AT2s during fibrosis, and inhibition of CDH11 prevented CDH11 coexpression. Furthermore, CDH11 expression was associated with the expression of the AT2 transitional cell marker KRT8 in both in vivo and in vitro studies. Finally, in vitro studies demonstrated that CDH11 engagement, but not N-cadherin engagement, could drive expression of mesenchymal markers in AT2s. Finally, AT2-selective deletion of <i>Cdh11</i> reduced pulmonary fibrosis in the IP BLM model, confirming that CDH11 regulates AT2 during the development of lung fibrosis. These data demonstrate that CDH11 is a key regulator of AT2 injury and mesenchymal gene expression during the development of lung fibrosis.<b>NEW & NOTEWORTHY</b> This study identifies CDH11 as a key regulator of AT2 during the development of lung fibrosis and further confirms the importance of CDH11 and AT2 in the development of lung fibrosis.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1076-C1091"},"PeriodicalIF":5.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148981906","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":"Hypertensive stretch regulates endothelial cell inflammation and apoptosis through ceramide metabolism.","authors":"Julia G Pietromicca-Victor, Shweta Chitkara, Erik Muñoz, Zahid A Manzar, Anu P Bharathi Rajan, Erhard Bieberich, G Ekin Atilla-Gokcumen, B Rita Alevriadou","doi":"10.1152/ajpcell.00283.2026","DOIUrl":"10.1152/ajpcell.00283.2026","url":null,"abstract":"<p><p>Hypertension and cardiovascular disease are associated with elevated plasma levels of ceramides (Cer), a type of membrane sphingolipids (SPLs). Increased cellular Cer levels are known to cause vascular endothelial cell (EC) dysfunction. However, Cer metabolism changes due to EC exposure to high-magnitude \"hypertensive\" cyclic stretch (HCS) and their role in EC dysfunction are poorly defined. Cultured human ECs exposed to HCS (15% elongation at 1 Hz, 24 h) exhibited increased oxidative stress, upregulation of genes for cytokines and leukocyte adhesion molecules, increased inflammatory response to a low concentration of tumor necrosis factor-α, and increased apoptosis compared with ECs exposed to \"normotensive\" CS (NCS; 5% elongation at 1 Hz, 24 h). Lipidomics analysis of EC pellets at 4 or 24 h of CS detected no difference in Cer levels and significantly higher sphingomyelin (SM) levels at 24 h of HCS compared with NCS. Cer immunostaining showed significantly higher Cer levels at both the perinuclear and peripheral subcellular regions in HCS compared with the corresponding regions in NCS. HCS significantly increased the concentrations of certain long-chain Cer in the extracellular media compared with NCS. Pharmacological inhibition of key enzymes in Cer biosynthesis, that is, de novo synthesis and SM hydrolysis pathways, significantly inhibited HCS-induced EC inflammation and apoptosis, suggesting that Cer generated from SM, via the sphingomyelinase family of enzymes, and accumulated at specific subcellular compartments may be responsible for the HCS-induced EC dysfunction. In summary, Cer act as mechanotransducers that connect hypertensive stretch to EC inflammation and apoptosis and promote CVD.<b>NEW & NOTEWORTHY</b> Human vascular endothelial cell (EC) exposure to high-magnitude (\"hypertensive\") cyclic stretch (HCS), via alterations in sphingolipid (SPL), specifically ceramide (Cer), metabolism, enhanced their sensitivity to proinflammatory stimuli and compromised their viability, compared with physiologic-magnitude (\"normotensive\") cyclic stretch (NCS). Pharmacological inhibitors of the de novo synthesis and sphingomyelin (SM) hydrolysis pathways protected ECs from the harmful effects of HCS, suggesting that these Cer-generating pathways may be appropriate targets for preventing vascular endothelial injury in early hypertension.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1010-C1026"},"PeriodicalIF":5.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13619160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879050","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":"5-Fluorouracil-based chemotherapy disrupts autophagy flux and protein synthesis in cultured myotubes: a role for mTORC1 signaling.","authors":"Jessica L Halle, Quan Zhang, Tanner Jenkins, James A Carson","doi":"10.1152/ajpcell.00321.2026","DOIUrl":"10.1152/ajpcell.00321.2026","url":null,"abstract":"<p><p>5-Fluorouracil-based chemotherapies, such as FOLFOX (5-fluorouracil, leucovorin, oxaliplatin), are used to treat colon cancer, but they also induce skeletal muscle toxicities. Although FOLFOX can disrupt muscle autophagy signaling in vivo, the upstream mechanisms underlying this effect, as well as the roles of mTORC1 and AMPK signaling, require further investigation. We investigated whether 5-FU, 5-FU + leucovorin, oxaliplatin, or the combined FOLFOX regimen disrupts protein synthesis or autophagy flux through altered mTORC1/AMPK signaling in C2C12 myotubes with or without tumor cell-conditioned media, and whether these effects were readily reversible. We also examined the effects of rapamycin or metformin administration on FOLFOX-induced disruptions to muscle protein synthesis and autophagy. FOLFOX was added to myotube cultures for 24 h; recovery was assessed by removing FOLFOX from the culture media for an additional 24 h. Cultured colon-26 tumor cells (CT26) were used for conditioned media. Autophagy flux was assessed using bafilomycin A1 and LC3BII/I immunoblotting. FOLFOX and CT26 each decreased myotube diameter and protein synthesis compared with the vehicle. CT26, but not FOLFOX, increased STAT3 phosphorylation. FOLFOX, but not CT26, increased atrogin-1 protein, whereas MURF-1 protein was increased by both CT26 and FOLFOX. FOLFOX reduced autophagy flux, AMPK, and ULK1(S555) phosphorylation, which did not recover upon FOLFOX removal. Rapamycin, but not metformin, altered autophagy flux in FOLFOX-treated myotubes and restored suppressed AMPK phosphorylation without increasing protein synthesis. We report that FOLFOX and oxaliplatin disrupt myotube mTORC1/AMPK regulation of autophagy flux, which was not easily reversible. However, rapamycin treatment increased autophagy flux in FOLFOX-treated myotubes.<b>NEW & NOTEWORTHY</b> FOLFOX chemotherapy is a common treatment for colorectal cancer, consisting of a combination of the antimetabolite 5-FU, leucovorin, and oxaliplatin. The disruption of muscle cellular signaling caused by 5-FU-based chemotherapies, which leads to fatigue and weakness, remains poorly understood. Our results provide evidence that FOLFOX can directly suppress myotube AMPK signaling, protein synthesis, and autophagy flux. Importantly, the effects of FOLFOX and the resulting disruptions to muscle protein turnover are long-lasting and are not easily reversible.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1109-C1127"},"PeriodicalIF":5.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13623018/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148962798","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}