American journal of physiology. Cell physiology最新文献

{"title":"BDNF alters β-cleavage of APP and subcellular distribution of BACE1.","authors":"Ryan D Hallam, Gregory Foran, Natasha K Fletcher, Rebecca E K MacPherson, Aleksandar Necakov","doi":"10.1152/ajpcell.00642.2025","DOIUrl":"10.1152/ajpcell.00642.2025","url":null,"abstract":"<p><p>The accumulation and deposition of amyloid-beta (Aβ) peptides is detrimental to neuronal networks and is driven by the cleavage of amyloid precursor protein (APP) by beta-secretase 1 (BACE1). The proteolytic processing of APP is tightly regulated by the opposing activities of BACE1 and ADAM10, with the latter producing a truncated, nonamyloidogenic fragment. Maintaining this balance is critical for normal physiological function, as complete inhibition of BACE1 has proven detrimental owing to the important physiological roles of its many substrates. Brain-derived neurotrophic factor (BDNF), an important mediator of neuronal function and survival, has recently been shown to reduce BACE1 activity in neural tissue, but the mechanism for this remains unknown. Previous research suggests that BACE1 cleavage of APP is favored at acidic intracellular compartments, whereas nonamyloidogenic processing preferentially occurs at the plasma membrane. Hence, we hypothesized that BDNF alters the subcellular distribution of BACE1, reducing β-cleavage of APP. Here, we show that acute BDNF treatment of differentiated neural cells (SH-SY5Y) reduced levels of sAPPβ, a product of BACE1 cleavage of APP. Using confocal microscopy and quantitative image analysis, we found that this reduction in sAPPβ levels is coincident with increased BACE1 localization to the plasma membrane and a concomitant reduction of BACE1 localization to early endosomes. This effect appears to be independent of clathrin-mediated endocytosis (CME), as inhibition of CME by PitStop2 treatment increased α-cleavage of APP but did not reduce β-cleavage independent of BDNF treatment. Hence, BDNF may reduce the production of Aβ by altering BACE1 distribution and decreasing upstream β-cleavage.<b>NEW & NOTEWORTHY</b> BACE1 cleavage of APP generates amyloid-β, overproduction of which perturbs physiological function in the brain. The neurotrophic factor BDNF reduces BACE1 cleavage of APP, potentially reducing amyloid-β production in the brain. Here, we show that this may be the result of BDNF altering the subcellular distribution of BACE1, reducing localization to acidic compartments where enzymatic activity is increased. This effect is independent of clathrin-mediated endocytosis, as BACE1 cleavage of APP is unchanged by PitStop2 treatment.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1296-C1308"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502543","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 proANP_31-67 in a preclinical model of uninephrectomy and cardiac ischemia/reperfusion injury: cardiac remodeling and tissue biochemical profiling.","authors":"Gustavo Jose Justo Silva, Sara Stefani, Reza Parvan, Michael Frisk, Xin Shen, Martina Alunni Cardinali, Mari E Strand, Karoline Bjarnesdatter Rypdal, Mathis Korseberg Stokke, Håvard Attramadal, Ida G Lunde, Jan Magnus Aronsen, Kåre-Olav Stensløkken, William E Louch, Paola Sassi, Alessandro Cataliotti","doi":"10.1152/ajpcell.00339.2025","DOIUrl":"10.1152/ajpcell.00339.2025","url":null,"abstract":"<p><p>Concomitant cardiac and renal dysfunction represent a clinically relevant condition with limited therapeutic options. This study examined the effects of the linear ANP fragment proANP_31-67 in a preclinical model combining unilateral nephrectomy (UNX) and cardiac ischemia/reperfusion (I/R) injury. Wistar rats underwent UNX followed by I/R and were randomized to receive proANP_31-67 or vehicle for 4 wk. Cardiac structure and function were evaluated by echocardiography and isolated cardiomyocyte analyses. Fourier-transform infrared (FTIR) spectroscopy was used to assess biochemical composition in cardiac and renal tissue, as well as urine. Chronic UNX induced diastolic impairment with preserved systolic function, which was further aggravated by I/R. ProANP_31-67 prevented systolic deterioration, reduced myocardial fibrosis, attenuated cardiomyocyte hypertrophy, and improved Ca²⁺ handling, independent of blood pressure. FTIR imaging identified distinct cardiac (amino acid-, collagen-, and carbohydrate-associated) and renal (free amino acid-, protein-, and lipid-associated) spectral features across experimental groups. Conventional renal indices, including albumin-to-creatinine ratio and 24 h protein excretion, remained unchanged; however, vibrational spectroscopy detected subtle biochemical alterations in renal tissue and urine that were modulated by proANP_31-67. In this model of reduced nephron mass with superimposed cardiac injury, proANP_31-67 exerted marked cardioprotective effects and was associated with coordinated changes in tissue biochemical signatures, supporting further investigation of its therapeutic potential.<b>NEW & NOTEWORTHY</b> In a model of reduced nephron mass combined with cardiac ischemia/reperfusion injury, proANP_31-67 prevented adverse cardiac remodeling independent of blood pressure. Vibrational spectroscopy identified coordinated biochemical alterations in cardiac and renal tissues not detected by conventional assays, providing molecular-level insight into cardiorenal remodeling.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1246-C1259"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147455222","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":"Unacylated ghrelin counteracts mitochondrial dysfunction and neuromuscular junction disruption in cancer cachexia.","authors":"Bumsoo Ahn, Jonathan Wanagat, Caroline Cleary, Hannah C Ainsworth, Hyunyoung Kim","doi":"10.1152/ajpcell.00917.2025","DOIUrl":"10.1152/ajpcell.00917.2025","url":null,"abstract":"<p><p>Cancer cachexia is a multifactorial metabolic syndrome that profoundly reduces muscle mass, strength, efficacy of chemotherapy, and survival, yet no effective therapy exists. Unacylated ghrelin (UnAG), the predominant form of circulating ghrelin, promotes muscle growth and mitochondrial bioenergetics, but its role in cancer cachexia remains unknown. Four- to 5-mo-old male C57Bl/6N mice were assigned to three groups: nontumor-bearing (NTB), tumor-bearing (TB), and tumor-bearing treated with UnAG (TB + UnAG). Lewis lung carcinoma cells were inoculated subcutaneously in the flank of the mice. Body weight, food intake, and tumor size were monitored for 4 wk. Lower limb muscle mass, contractile function, mitochondrial respiration, and reactive oxygen species (ROS) production were measured, in conjunction with Western blot, proteomic, and immunohistochemical analyses. Compared with NTB controls, TB mice exhibited marked loss of muscle mass and function, whereas UnAG treatment preserved ∼50% of the muscle mass and ∼70% of the contractile force. UnAG enhanced mitochondrial oxygen consumption, reduced ROS generation, and preserved mitochondrial DNA copy number and downregulated DNA mutation frequency. TB mice demonstrated increased oxidative stress and activation of protein degradation pathways, along with neuromuscular junction disruption-both of which were normalized by UnAG. These findings collectively demonstrate that UnAG mitigates cancer cachexia by modulating mitochondrial bioenergetics, oxidative and proteolytic stress, and neuromuscular junction integrity. UnAG represents a promising therapeutic candidate that may mitigate cachexia and improve both chemotherapy efficacy and the quality of life of patients with cancer.<b>NEW & NOTEWORTHY</b> Unacylated ghrelin prevents muscle wasting and maintains neuromuscular junction integrity and contractile function in cancer cachexia. It enhances mitochondrial respiratory capacity through elevated mitochondrial DNA copy number while limiting DNA mutation. It reduces mitochondrial reactive oxygen species (mtROS) generation, oxidative stress, and proteasome-mediated proteolysis-driven muscle degradation.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1509-C1522"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147669885","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":"Exploring the diverse roles of ketones in cellular physiology.","authors":"Kaja Falkenhain, Jonathan P Little, Thomas J Hawke","doi":"10.1152/ajpcell.00125.2026","DOIUrl":"10.1152/ajpcell.00125.2026","url":null,"abstract":"","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1145-C1147"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147388780","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":"Cellular senescence in skeletal muscle: myogenic and nonmyogenic cell populations, mechanisms, and therapeutic opportunities.","authors":"Konstantinos Papanikolaou, Angad Yadav, Robert T Mankowski, Matthew S Alexander, Jorge L Gamboa, Anna E Thalacker-Mercer, Cory M Dungan, Davis A Englund","doi":"10.1152/ajpcell.00876.2025","DOIUrl":"10.1152/ajpcell.00876.2025","url":null,"abstract":"<p><p>Skeletal muscle plays a central role in systemic metabolism, physical function, and overall health. Aging and disease diminish the ability of myogenic and nonmyogenic skeletal muscle cells to coordinate adaptation and repair, but the mechanisms underlying this decline are not fully understood. Growing evidence implicates cellular senescence, a stress response marked by irreversible cell cycle arrest and proinflammatory signaling, as a key contributor to muscle pathology. In this review, we synthesize current insights into the molecular mechanisms that govern cellular senescence in skeletal muscle, its effects on myogenic and nonmyogenic cell populations, and recent technologies that have clarified key aspects of senescence biology. We further explore emerging therapeutic strategies aimed at targeting senescent cells and discuss key knowledge gaps that must be addressed to advance our understanding of senescent myogenic and nonmyogenic cells in skeletal muscle.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1148-C1171"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147519655","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":"Acute effects of ketone monoester ingestion on monocyte phenotype and cytokine secretion in healthy humans.","authors":"Alexis Marcotte-Chénard, Roderick E Sandilands, Alexandre Abílio Teixeira, Seth F McCarthy, Hashim Islam, Jonathan P Little","doi":"10.1152/ajpcell.00058.2026","DOIUrl":"10.1152/ajpcell.00058.2026","url":null,"abstract":"<p><p>Beta-hydroxybutyrate (BHB) exerts anti-inflammatory effects in cell and animal models, but translational work in humans remains limited. We investigated how exogenous ketone monoester (KME) ingestion in vivo and BHB treatment of human whole blood and monocytes ex vivo influence cytokine secretion and phenotype. Healthy adults (<i>n</i> = 13, age = 28 ± 7 yr) consumed a KME supplement containing (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (0.750 g/kg of body mass). Venous blood samples were taken before and 2 h postingestion. Cytokine secretion from lipopolysaccharide (LPS)-stimulated whole blood (4 h) and monocyte (24 h) cultures was used to determine BHB's anti-inflammatory effects, whereas flow cytometry assessed monocyte phenotype and polarization. Blood BHB concentration increased after KME consumption (<i>P</i> < 0.0001), peaking after 2 h (5.0 ± 0.8 mmol/L). Total white blood cells increased 2 h after KME consumption compared with baseline (<i>P</i> = 0.006), mainly due to higher total neutrophils (<i>P</i> = 0.0004). Tumor necrosis factor-alpha (TNF-α) secretion in LPS-stimulated (1 ng/mL) whole blood collected before and 2 h after KME consumption was unaltered (<i>P</i> = 0.616), suggesting that in vivo exposure to increased BHB did not alter blood leukocyte cytokine secretion. However, ex vivo BHB cotreatment of LPS-stimulated whole blood and monocyte cultures decreased TNF-α secretion in a dose-dependent manner (<i>P</i> ≤ 0.0012). BHB cotreatment during 24 h LPS stimulation also decreased monocyte CD80+ (\"<i>M1-like</i>\") expression. Lowering pH of whole blood cultures independent of BHB also reduced TNF-α secretion, albeit to a lesser extent than BHB (<i>P</i> = 0.012). Collectively, BHB lowers proinflammatory monocyte marker expression ex vivo and dose-dependently reduces TNF-α production in LPS-stimulated whole blood and monocyte cultures. These effects appear to be partly mediated by acidification of the extracellular environment.<b>NEW & NOTEWORTHY</b> Beta-hydroxybutyrate (BHB) decreased TNF-α production in LPS-stimulated whole blood and monocyte cultures, which appeared partly-although not completely-mediated by the acidification of the cellular environment. The presence of BHB in LPS-stimulated monocyte cultures reduced surface protein expression of CD80, suggesting a shift toward a less proinflammatory monocyte phenotype. Acute elevation of BHB via exogenous ketone supplementation did not appear to alter immune function or monocyte phenotype in healthy humans.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1399-C1409"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147637811","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":"Harnessing AlphaFold3 to elucidate BBSome structure and protein partners.","authors":"Deng Fu Guo, Younes Rouabhi, Mallory Tollefson, Kai Vorhies, Kamal Rahmouni","doi":"10.1152/ajpcell.00804.2025","DOIUrl":"10.1152/ajpcell.00804.2025","url":null,"abstract":"<p><p>The BBSome, an eight-protein complex implicated in Bardet-Biedl syndrome (BBS), plays a crucial role in various cellular processes including ciliary function. Although important aspects of its structural organization and protein interactions have been elucidated, additional questions remain regarding how these features relate to cargo recognition and complex dynamics. Using AlphaFold3, we generated a structural model closely matching recent cryo-EM data (α-carbon root means square deviation: 1.203 Å). Interface residue analysis of the model identified BBSome proteins BBS1 and BBS9 as central interaction hubs (most interface residues between two proteins), with BBS2 and BBS7 showing the most polar contacts. The common BBS1^M390R pathogenic mutation, known to cause BBS, was predicted to destabilize the complex. BBS4 was also found to interact stably with pericentriolar material 1, suggesting a role in centriolar satellite localization. AlphaFold3-mediated analysis of BBSome interactions with G protein-coupled receptors (GPCRs) led to the identification of contact hotspots on BBS1, BBS4, and BBS5. These predictions were supported by immunoprecipitation and peptide competition assays. The modeling also suggested plausible interfaces between specific BBS proteins and metabolic signaling proteins, including melanocortin receptor accessory protein 2 (MRAP2) [an melanocortin-4 receptor (MC4R) chaperonin], the leptin receptor, and the insulin receptor. These predicted interfaces align with previously reported biochemical associations between BBS proteins and these receptors, supporting the idea that the BBSome regulates trafficking and signaling in metabolic pathways. Together, these findings provide new insights into BBSome structure and receptor interactions, offering a predictive framework to explore its role in ciliary trafficking and human disease.<b>NEW & NOTEWORTHY</b> This study combines AI modeling and experimental validation to define key structural features and receptor interactions of the BBSome complex. The analysis identifies BBS1 and BBS9 as central hubs, reveals how the BBS1^M390R mutation destabilizes the complex, and uncovers novel contacts with various receptors including those involved in metabolic regulation. These findings provide a predictive framework linking BBSome structure to ciliary signaling and metabolic regulation in Bardet-Biedl syndrome.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1271-C1285"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147580109","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":"Cerebral capillary computation.","authors":"Thomas A Longden","doi":"10.1152/ajpcell.00065.2026","DOIUrl":"10.1152/ajpcell.00065.2026","url":null,"abstract":"<p><p>This article synthesizes recent evidence to propose a framework for control of energy delivery in the brain in which the capillary bed functions as an active, distributed signal-processing network that senses neuronal activity and metabolic state and converts these inputs into electrical commands that regulate upstream diameter to control blood flow. Capillary endothelial cells (ECs) form an electrically coupled syncytium via gap junctions, whereas pericytes are vertically integrated into this network at peg-socket junctions, enabling bidirectional electrical communication. It is proposed that thin-strand pericytes and their associated underlying ECs constitute a \"capillary computational unit\" (CCU): a local transformer-like module in which pericytes act as rich multimodal sensors and signal generators, whereas ECs are optimized for signal amplification and long-range transmission. Emphasis is placed on the ion channel toolkit that implements CCU computations, with discussion of how different conductances shape membrane voltage to encode local energetic demand and propagate signals over long distances. Kir2.1 channels emerge as a keystone conductor and regenerative carrier of hyperpolarizing signals; K_ATP channels couple energy status and adenosine levels/glucose availability with electrical output; small- and intermediate-conductance Ca²⁺-activated K⁺ channels in the arteriole-capillary transition zone provide amplification; transient receptor potential and Piezo1 channels impose depolarizing and mechanosensory feedback constraints; and chloride channels (notably TMEM16A) act as voltage tethers that clamp or reset local membrane potential. Framing these elements computationally suggests that addition and subtraction, gain control, shunting, and veto-like logic may arise naturally from network architecture and channel biophysics.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1220-C1236"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147472288","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":"CTLA4-Ig reduces proliferation and inflammatory gene expression in muscle fibroblasts, corresponding to less fibrosis and inflammation in <i>mdx</i> muscular dystrophy.","authors":"Michelle Wehling-Henricks, Pranav Kannan, Connor Thomas, Harsimer Bal, Vedant Balu, Eisuke Ochi, Kenneth Dorshkind, James G Tidball","doi":"10.1152/ajpcell.00860.2025","DOIUrl":"10.1152/ajpcell.00860.2025","url":null,"abstract":"<p><p>Muscle pathology in Duchenne muscular dystrophy (DMD) is greatly amplified by the immune response to dystrophic muscle, which provides the rationale for targeting the immune system in DMD therapies. Much of immune-driven pathology in the <i>mdx</i> mouse model of DMD is caused by T-lymphocytes and macrophages; thus, preventing T-cell activation by blocking pathways that cause their activation has the potential to reduce muscle damage and fibrosis in muscular dystrophy. CTLA4-Ig is a recombinant protein that blocks costimulatory signaling between T-cells and antigen-presenting cells, such as macrophages. In this investigation, we tested whether treatment of <i>mdx</i> mice until they reach advanced, fibrotic stages of the disease reduces pathology. Our findings show that CTLA4-Ig treatments reduced muscle damage and inflammation and also reduced numbers of fibrogenic cells and fibrosis of muscles in aging, <i>mdx</i> mice. However, the treatments did not reduce numbers of CD8+ T-cells or activated CD25+ cells, suggesting that the reduced pathology was not mediated by affecting T-cell activation. Complete blood counts and clinical histopathological scoring also showed that the treatments had little effect on hematopoietic tissues. In vitro, CTLA4-Ig acted directly on muscle fibroblasts, reducing their expression of proinflammatory genes without affecting the expression of genes encoding connective tissue proteins, assayed by quantitative PCR (qPCR). However, CTLA4-Ig-treated fibroblasts were less proliferative in vitro. Collectively, these findings show that CTLA4-Ig acts directly on fibroblasts to produce changes in proliferation and gene expression that are consistent with the reductions in muscle pathology that occurs in aging, <i>mdx</i> mice treated with CTLA4-Ig.<b>NEW & NOTEWORTHY</b> This investigation shows that CTLA4-Ig, which blocks costimulatory signaling between immune cells, is effective at reducing fibrosis and inflammation in aging, dystrophic muscle. CTLA4-Ig acts directly on muscle fibroblasts, causing reductions in their proliferation and expression of proinflammatory genes.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1172-C1187"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147484249","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":"Neuronal growth regulator 1 modulates actin dynamics to control intracellular GLUT4 trafficking.","authors":"Seo-Young Yun, Soojin Lee","doi":"10.1152/ajpcell.00084.2026","DOIUrl":"10.1152/ajpcell.00084.2026","url":null,"abstract":"<p><p>NEGR1 (neuronal growth regulator 1) has been genetically linked to metabolic and neuropsychiatric disorders; however, its cellular function in insulin-responsive tissues remains poorly understood. Here, we investigated the role of NEGR1 in regulating actin cytoskeletal dynamics and insulin-stimulated GLUT4 trafficking in skeletal muscle. We found that loss of <i>Negr1</i> reduced GLUT4 abundance selectively in predominantly glycolytic skeletal muscles in vivo. Despite preserved insulin-induced Akt phosphorylation, insulin-stimulated GLUT4 translocation was markedly impaired in both Negr1-deficient and NEGR1-overexpressing muscle cells. Mechanistically, <i>Negr1</i> deficiency was associated with enhanced PAK-cofilin signaling and excessive intracellular F-actin accumulation that likely impedes GLUT4 vesicle trafficking. In contrast, NEGR1 overexpression did not increase total F-actin content but induced abnormal peripheral actin organization, resulting in constitutive GLUT4 surface localization and elevated basal glucose uptake. Consistent with these findings, both loss and overexpression of NEGR1 disrupted insulin-induced Rac1-dependent actin remodeling without affecting Akt signaling. Collectively, these results identify NEGR1 as a critical modulator of actin homeostasis required for proper insulin-stimulated GLUT4 trafficking and glucose uptake in skeletal muscle, providing mechanistic insight into the metabolic abnormalities associated with NEGR1 dysregulation.<b>NEW & NOTEWORTHY</b> Neuronal growth regulator 1 (NEGR1) regulates actin cytoskeletal homeostasis required for insulin-stimulated GLUT4 trafficking in skeletal muscle. NEGR1 dysregulation alters PAK-cofilin signaling, induces aberrant F-actin organization, and impairs GLUT4 vesicle movement independent of Akt signaling. Because NEGR1 is a major genetic risk factor for major depressive disorder, these findings reveal a shared actin-based mechanism linking metabolic dysfunction and neuropsychiatric disease.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1354-C1363"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147571908","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}