American journal of physiology. Cell physiology最新文献

{"title":"Autonomic Imbalance in Cardiovascular Disease: Molecular Mechanisms and Emerging Therapeutics.","authors":"Lilian R Mott, Jessica L Caldwell","doi":"10.1152/ajpcell.00144.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00144.2025","url":null,"abstract":"<p><p>Autonomic imbalance is a key driver of cardiovascular disease progression, arising from disrupted interactions between sympathetic and parasympathetic signaling. This review explores the molecular mechanisms underpinning autonomic dysfunction, emphasizing the roles of β-adrenergic receptor (βAR) signaling, cyclic AMP (cAMP) compartmentation, and cholinergic regulation. Dysregulated cAMP nanodomain signaling, βAR desensitization, impaired vagal tone, and maladaptive autonomic nerve remodeling collectively promote structural, electrophysiological, and functional deterioration. Advances in high-resolution imaging and molecular mapping have revealed previously unrecognized pathways governing second-messenger compartmentation and neuromodulatory feedback loops. These insights are driving the development of next-generation therapeutics designed to selectively restore autonomic balance. Promising strategies include isoform-specific phosphodiesterase (PDE) inhibitors, vagus nerve stimulation (VNS), and axonal modulation therapy (AMT), which target norepinephrine (NE) and acetylcholine (ACh) pathways while preserving physiological responsiveness. Integrating pharmacological, neuromodulatory, and molecular approaches represents an evolving frontier for cardiovascular therapeutics. Future strategies will benefit from precision mapping of autonomic circuits, patient-specific profiling, and optimization of therapeutic timing. By linking fundamental molecular signaling with translational advances, this review highlights opportunities to improve treatment precision and efficacy for autonomic dysfunction in cardiovascular disease.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237770","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":"Glycosaminoglycans in gastrointestinal cancer: from biosynthesis to tumor signatures.","authors":"Ana Raquel Ribeiro, Catarina Marques, Celso A Reis, Ana Magalhães","doi":"10.1152/ajpcell.00295.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00295.2025","url":null,"abstract":"<p><p>Glycosaminoglycans (GAGs) are major components of the cells glycocalyx and extracellular matrix (ECM), with important roles in both physiological and disease contexts. The biosynthesis of the long and structurally diverse GAG chains is orchestrated by a complex cellular glycosylation machinery and regulated in an organ-, and cell-specific way. Moreover, altered GAG expression levels and structural features have been described in different pathological conditions, including cancer. Noteworthy, GAG chains are endowed with important functional features during cancer progression, such as cancer cell growth, motility, and metastasis formation. Particularly in gastrointestinal (GI) tumors, GAGs have been frequently associated with tumorigenesis and disease progression. This review provides insights on the aberrant GAG expression profiles in GI cancers, highlighting illustrative examples of GAG structural features for each disease model. Relevance is given to the molecular mechanisms underlying altered GAG biosynthesis and post-synthesis editing in GI cancers. Lastly, we address the potential of cancer-associated GAG expression signatures for improving GI clinical management.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237790","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":"Zinc inhibits cAMP-induced Cl^- secretion in intestinal epithelial cells via calcium-sensing receptor (CaSR).","authors":"Pattareeya Yottasan, Tifany Chu, Qi Gao, Parth Chhetri, Sadik Taskin Tas, Onur Cil","doi":"10.1152/ajpcell.00614.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00614.2025","url":null,"abstract":"<p><p>Zinc is a commonly used antidiarrheal supplement; however, its exact mechanism of action is not well understood. Calcium-sensing receptor (CaSR) is a regulator of intestinal ion transport and a therapeutic target for secretory diarrhea. CaSR is activated by various cations and here we investigated the roles of CaSR in the antidiarrheal effects of the divalent metal zinc (Zn²⁺). In human intestinal T84 cells expressing CaSR, zinc (100 μM) inhibited forskolin-induced secretory I_sc by 60% and its effect was comparable to CaSR activator cinacalcet. Zinc effect was via inhibition of apical CFTR Cl^- channel and basolateral K⁺ channels. In cell models, zinc was a CaSR agonist and its antisecretory effects were CaSR-dependent. Similarly, 100 μM zinc inhibited forskolin-induced secretory I_sc by 40% in wildtype mouse intestine with no antisecretory effects in intestinal epithelia-specific CaSR knockout mice (Casr^flox/flox;Vil1-cre). Zinc inhibited I_sc induced by clinically-relevant cAMP agonists (cholera toxin and vasoactive intestinal peptide) by 65% in T84 cells. Interestingly, zinc had no effect on cGMP agonists (heat-stable E. coli enterotoxin and linaclotide)-induced secretory I_sc, suggesting its antisecretory effects are specific to cAMP. The mechanisms of zinc effect in T84 cells involved intracellular Ca²⁺ release via ryanodine receptors and inhibition of cAMP synthesis. Our findings suggest that CaSR activation is a major mechanism for the antidiarrheal effects of zinc which specifically reduces cAMP levels. In addition to its use in cholera, zinc can be effective in other cAMP-mediated secretory diarrheas.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237795","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":"Skeletal Muscle Alterations and Functional Repercussions in Patients with Colorectal Cancer-associated Cachexia.","authors":"Britt van de Haterd, Michèlle Hendriks, Bert Houben, Michelle E G Weijzen, Frank Vandenabeele, Kenneth Verboven, Anouk Agten","doi":"10.1152/ajpcell.00533.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00533.2025","url":null,"abstract":"<p><p>Cancer cachexia causes skeletal muscle wasting and metabolic dysfunction, worsening clinical outcomes in colorectal cancer (CRC). This study examines microscopic and macroscopic skeletal muscle fiber characteristics, and muscle volume in cachectic and non-cachectic CRC patients compared to healthy controls (HCs), and explores how these factors relate to physical performance. In total, 12 cachectic CRC patients, 25 non-cachectic CRC patients, and 25 HCs were included. Cachexia was determined by weight loss and Cachexia Staging Score. Biopsies from the vastus lateralis and erector spinae muscles were analyzed using immunohistochemistry for muscle fiber type cross-sectional area (CSA) and distribution, myonuclear content, and capillary density. Muscle volume was assessed using three-dimensional ultrasound, and CSA and density by computerized tomography scans. Physical function was evaluated with the Short Physical Performance Battery test, handgrip strength, and the Physical Activity Scale for Individuals with Physical Disabilities. Quality of life was assessed using the 36-item Short Form Survey. Cachectic CRC patients showed reduced type II muscle fiber cross-sectional area in the vastus lateralis compared to HCs and non-cachectic CRC patients. Non-cachectic CRC patients exhibited a slow-to-fast muscle fiber shift compared to HCs. Myonuclear content was lower in both cancer groups. Muscle volume and density were reduced in cachectic CRC patients. Positive correlations were found between microscopic and macroscopic skeletal muscle characteristics, muscle strength, physical performance, and quality of life, respectively. CRC patients, especially those with cachexia, showed type II muscle fiber atrophy, reduced myonuclear content, and impaired physical function, emphasizing the need for targeted prehabilitation interventions.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237736","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":"Unravelling the Diversity Observed in Cancer Cachexia.","authors":"Thomas J Hawke, Tyrone A Washington, Yusuke Nishimura, Nicholas P Greene","doi":"10.1152/ajpcell.00731.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00731.2025","url":null,"abstract":"","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237744","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":"Cachexia progression differs among mouse models of metastatic triple-negative breast cancer.","authors":"Alastair A E Saunders, Chris Karagiannis, Wayne X Du, Lauren S James, Rachel E Thomson, Robin L Anderson, Paul Gregorevic","doi":"10.1152/ajpcell.00230.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00230.2025","url":null,"abstract":"<p><p>Cancer-associated cachexia decreases quality of life, reduces therapy response, and diminishes survival prospects. Effective cachexia countermeasures remain a significant unmet need. Research into cancer cachexia has made extensive use of models of colon, lung and pancreatic cancers. However, while cachexia also affects people with metastatic breast cancer, the mechanisms underlying breast cancer-associated cachexia are relatively understudied. Thus, we sought to investigate orthotopic mouse models of metastatic breast cancer for the progression of cachexia, with a focus on muscle wasting given its role in the frailty that is a hallmark of the condition. Female Balb/c mice received an intramammary fat pad injection of 4T1.2 or EMT6.5 cells, and NSG mice received MDA-MB-231-HM (231-HM) cells, to induce primary breast tumors that were subsequently excised. The resultant metastatic burden after approximately 4 weeks led to variable loss of muscle mass (tibialis anterior: EMT6.5: -17.1%, 231-HM: -13.5%, 4T1.2: -9.5%) and fat mass (gonadal fat: EMT6.5: -75.1%, 231-HM: -62.5%, 4T1.2: -30.2%). Muscle protein synthesis markers were decreased in EMT6.5 tumor-bearing mice. Distinct increases in the abundance of mRNA for E3-ubiquitin ligase and autophagy-related genes were observed between models. Neuromuscular junction perturbations were observed in EMT6.5 and 4T1.2 tumor-bearing mice. Neutrophilia was noted in the muscles of EMT6.5 tumor-bearing mice. The findings show that muscle mass and function are reduced in mouse models of metastatic breast cancer. Further study of these models could provide useful insights with which to better understand the diversity of cachexia progression across different cancer types.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224655","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":"Oxidized phosphatidylcholines activate NOX1-mediated oxidative stress response and shift glucose metabolism in cardiac cells.","authors":"Anna A Licznerska, Caitlin M Pavelec, Priyanka Rawat, Scott Yeudall, Clint M Upchurch, Hannah L Luviano, Kyla N Mucciarone, Norbert Leitinger","doi":"10.1152/ajpcell.00338.2025","DOIUrl":"10.1152/ajpcell.00338.2025","url":null,"abstract":"<p><p>In cardiometabolic syndrome, the development of cardiovascular disease is linked with an increase in systemic oxidative stress. The formation of free radical species leads to the oxidative modification of lipids, including oxidized phosphatidylcholines (OxPCs), which have been implicated in the progression of cardiovascular diseases in humans. We found that reducing plasma levels of OxPCs in mice by adeno-associated virus (AAV)-mediated hepatic expression of an OxPC-targeting antibody fragment (scFv-E06) resulted in significant transcriptional changes in the heart, particularly affecting genes involved in metabolism, redox processes, and fibrosis. To investigate the response of cardiac myoblasts to OxPCs in vitro, we exposed H9c2 cells to a defined mixture of OxPC species [oxidized 1-palmitoyl-2-arachidonoyl-<i>sn</i>-glycero-3-phosphocholine (OxPAPC)]. Treatment with OxPAPC resulted in transcriptional upregulation of key metabolic and redox regulatory pathways, most notably genes regulated by the nuclear factor erythroid 2-related factor 2 pathway, including heme oxygenase 1. OxPAPC-induced reactive oxygen species production in H9c2 cells through the activation of NADPH oxidase 1 (Nox1), which upregulated the production of oxidized glutathione. Key metabolic changes after exposure to OxPAPC included a shift toward the pentose phosphate pathway and suppression of glycolysis, resulting in overall decreased ATP production. Furthermore, OxPAPC downregulated oxidative phosphorylation in H9c2 cells through a mechanism involving activation of the MEK-ERK mitogen-activated protein kinase pathway. Together, these data demonstrate that in vitro cardiac myoblasts respond to OxPCs by upregulating redox regulatory pathways and shifts in cellular energy production. Furthermore, we identify NOX1 as a novel mediator of OxPC-induced redox stress that may induce cardiac cell damage in cardiometabolic syndrome.<b>NEW & NOTEWORTHY</b> We present for the first time that NOX1 plays a novel role in mediating OxPAPC (oxidized 1-palmitoyl-2-arachidonoyl-<i>sn</i>-glycero-3-phosphocholine)-induced oxidative stress injury in CMs. We show that OxPAPC induces glucose shuttling through the PPP and glutathione metabolism, with a suppression of glycolysis and overall ATP production in CMs. We demonstrate that the reduction in oxidative phosphorylation after OxPAPC exposure in CMs is in part due to MAPK pathway activation and can partially be rescued by its inhibition.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1046-C1060"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938967","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":"Norepinephrine-induced intracellular Ca²⁺ increase is coupled with astrocytic BK channel activation and capillary response.","authors":"Jelena Bogdanović Pristov, Danijela Bataveljić, Dunja Bijelić, Katarina Milićević, Jelena Korać Jačić, Ljiljana Nikolić","doi":"10.1152/ajpcell.00538.2025","DOIUrl":"10.1152/ajpcell.00538.2025","url":null,"abstract":"<p><p>Astrocytes are abundant glial cells organized in a meshwork in which each cell is in contact with both neuronal and vascular elements. They receive and respond to neuronal signals and modulate synaptic activity and diameter of blood vessels through changes in their intracellular Ca²⁺. Norepinephrine plays an important role in both of these astrocytic functions; however, it remains unclear whether norepinephrine-induced intracellular Ca²⁺ increase leads to further cellular adjustments in astrocyte activity. Here, we reveal a causal relationship between norepinephrine-induced intracellular Ca²⁺ increase, α1-adrenergic receptor activation and activation of large-conductance Ca²⁺-dependent potassium ion (BK) channel in cultured rat cortical astrocytes. BK channel activation was abolished by α1-adrenergic receptor blockade, depletion of intracellular Ca²⁺ stores, or dialysis of astrocytes with a Ca²⁺ chelator. We further show that this norepinephrine-induced astrocytic Ca²⁺-BK channel coupling contributes to a reduction in cortical capillary diameter. The capillary response was prevented by pharmacological silencing of astrocytes or BK channel blockade, whereas the norepinephrine effect was mimicked by direct BK channel activation with an agonist in acute brain slices. In summary, these results elucidate a previously unrecognized cellular response of astrocytes to norepinephrine that is coupled with modulation of capillary diameter and may represent an integral part of the astrocytic communication with neurons and blood vessels.<b>NEW & NOTEWORTHY</b> This study reveals adjustments of astrocyte activity in response to neurotransmitter norepinephrine. We provide compelling demonstration that norepinephrine-induced intracellular Ca²⁺ increase is coupled with BK channel activation in cultured cortical astrocytes. Our results further indicate that norepinephrine-induced astrocytic Ca²⁺-BK channel signaling participates in modulation of capillary diameter in the cortex. These findings provide better understanding of astrocyte communication with neurons and blood vessels.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1061-C1074"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938976","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":"Human deep subcutaneous adipose tissue is enriched for inflammatory and tissue remodeling pathways.","authors":"Kahoko Yamada, Yoshitaka Kubota, Kentaro Kosaka, Yoshihisa Yamaji, Shinsuke Akita, Hideki Tokumoto, Masayuki Kuroda, Nobuyuki Mitsukawa","doi":"10.1152/ajpcell.00463.2025","DOIUrl":"10.1152/ajpcell.00463.2025","url":null,"abstract":"<p><p>Subcutaneous superficial adipose tissue (SAT) and deep adipose tissue (DAT) are anatomically separated by the superficial fascia and differ in both function and histological organization. This study presents a comprehensive transcriptomic comparison between SAT and DAT using bulk and single-cell RNA sequencing. Bulk RNA sequencing revealed that DAT is enriched in genes related to inflammation, tissue remodeling, and oxidative stress. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed significant enrichment of inflammatory response, cytokine signaling, and TNF signaling pathways in DAT, indicating a proinflammatory and remodeling-prone environment. Single-ce7ll RNA sequencing identified distinct differences in immune and stromal cell composition. SAT exhibited higher proportions of anti-inflammatory M2 macrophages and CD8/NK cells, whereas DAT showed an increase in oxidative stress-associated Mox macrophages and specific subtypes of fibroblasts and preadipocytes. <i>MT1X</i> and <i>HMOX1</i> expression in FAPs of DAT supports a stress-responsive phenotype, whereas <i>CCN1</i> expression in FAPs of SAT may reflect a role in structural maintenance. In addition, <i>APOE</i> was upregulated in macrophages of DAT, consistent with its known roles in immune modulation and lipid metabolism. These findings highlight cellular and molecular differences between SAT and DAT, suggesting a more active involvement of DAT in inflammation and tissue remodeling.<b>NEW & NOTEWORTHY</b> This study reveals that human deep subcutaneous adipose tissue (DAT) exhibits a distinct proinflammatory and remodeling-prone gene expression profile compared with superficial adipose tissue (SAT). Using both bulk and single-cell RNA sequencing, the researchers identified an increased presence of oxidative stress-associated macrophages and stress-responsive fibroblasts in DAT, suggesting its stronger involvement in systemic inflammation and metabolic dysfunction.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1161-C1172"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938781","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":"Uncoupling protein 3 regulates energy and stress-related pathways in undifferentiated skeletal muscle myoblasts.","authors":"Austin Kindall, Yen Huynh, Jeesun Kim, Stefano Tiziani, John DiGiovanni","doi":"10.1152/ajpcell.00366.2025","DOIUrl":"10.1152/ajpcell.00366.2025","url":null,"abstract":"<p><p>Uncoupling protein 3 (UCP3), a member of the mitochondrial solute carrier family, shares high homology with both UCP1 and UCP2. Its exact functional role has been elusive since its discovery, with previous studies primarily focusing on studying UCP3 function in differentiated skeletal muscle myotubes or whole animal models because basal levels of UCP3 protein are low in undifferentiated myoblasts. In the present study, we demonstrate that UCP3 plays a role in modulating energy and redox stress-related pathways in undifferentiated muscle myoblasts. Although low, UCP3 mRNA and protein levels were detectable in wild-type (WT) myoblasts. Both whole body UCP3 knockout (wKO) and conditional UCP3 knockout (cKO) myoblasts displayed increased activation of AMP-activated protein kinase (phosphorylation of AMPK) and elevated levels of peroxisome proliferator-activated receptor delta/beta (PPARδ/β) and glucose transporter 4 (GLUT4) proteins compared with WT myoblasts. This altered energy signaling was further associated with UCP3 KO myoblasts exhibiting impaired insulin-stimulated glucose uptake, whereas WT cells and UCP3 KO cells expressing WT UCP3 were sensitive to insulin stimulation. Moreover, UCP3 KO myoblasts had an accumulation of fatty acids and upregulation of downstream PPARδ target genes in UCP3 KO cells. Finally, UCP3 KO myoblasts were found to be more sensitive to oxidative stress and hypoxia, due in part to a decrease in the reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio compared with WT myoblasts. Collectively, these findings demonstrate that UCP3 is a key modulator of energy sensing and oxidative stress in undifferentiated skeletal muscle myoblasts.<b>NEW & NOTEWORTHY</b> This article provides new information demonstrating that UCP3 plays a role in modulating energy and redox stress-related signaling pathways in proliferative muscle myoblasts. The studies used both UCP3 whole body knockout (KO) myoblasts as well as a novel UCP3 conditional KO mouse generated as part of the current study. Collectively, these findings show that, despite low levels, UCP3 is a key modulator of energy metabolism and oxidative stress in undifferentiated muscle myoblasts.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1108-C1120"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938910","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}