American journal of physiology. Cell physiology最新文献

{"title":"Gut microbiome promotes succinate-induced ulcerative colitis by enhancing glycolysis through SUCNR1/NF-κB signaling pathway.","authors":"Long Huo, Qian Chen, Sailei Jia, Yuli Zhang, Lihui Wang, Xian Li, Zan Li, Boyun Sun, Jingyi Shan, Jiang Lin, Lili Yang, Hua Sui","doi":"10.1152/ajpcell.00411.2025","DOIUrl":"10.1152/ajpcell.00411.2025","url":null,"abstract":"<p><p>Ulcerative colitis (UC) is a chronic recurrent inflammatory disease. Previous studies demonstrate that excessive accumulation of gut microbial metabolites, especially succinate, increases the risk of disease progression. However, the role of succinate and its molecular mechanism have not been explored. We investigated the effects of succinate on colonic inflammation and intestinal microbiota and their association with succinate receptor (SUCNR1) signaling in 3% dextran sodium sulfate (DSS)-induced acute UC in C57BL/6J mice. After treatment, fecal bacteria from UC mice were evaluated by 16S rRNA sequencing. Colon tissues and cell lysates were collected and prepared for histological evaluation, immunohistochemistry, Western blotting, and inflammatory activity cytokine analysis. It was found that <i>Phascolarctobacterium</i> spp. (<i>Phascolarctobacterium faecium</i>), which consumed succinate, significantly decreased SUCNR1 expression, relieved colonic damage, reduced cytokine levels, and restored the integrity of the intestinal epithelial barrier in UC mice. In addition, the results of flow cytometry, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay indicated that succinate deficiency markedly suppressed secretion of proinflammatory cytokines (e.g., interleukin-1β, interleukin-6, interleukin-10, and tumor necrosis factor-α). Moreover, the SUCNR1 inhibitor (NF-56-EJ40) inhibited glycolysis of intestinal epithelial cells (IECs) in the coculture system with Th17 cells, including downregulation of oxygen consumption rate and increased extracellular acidification rate reflecting overall glycolytic flux, and regulated the expression of glycolysis-related proteins, such as GLUT1, HK-II, and LDHA. Collectively, our findings indicate that microbiota consumption of succinate can ameliorate DSS-induced UC through suppressing Th17, reducing IEC glycolysis, lowering the secretion of proinflammatory cytokines, maintaining epithelial barrier function, and improving dysbiosis.<b>NEW & NOTEWORTHY</b> The gut microbiota contributes to host physiology through the production of a myriad of metabolites. Owing to the high degree of cross talk both within and between biological kingdoms, metabolite-focused research has identified multiple actionable microbial targets that are relevant for host health. In this study, we demonstrated that the microbiota consumption of succinate can alleviate DSS-induced UC in mice responses by modulating glycolytic metabolism through the SUCNR1/NF-κB signaling pathway.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C440-C454"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473777","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":"Functional reassessment of Nav1.5 T559A reveals loss-of-function in a variant commonly used as wild type.","authors":"Dario Melgari, Marco Villa, Anthony Frosio, Serena Calamaio, Luigi Anastasia, Carlo Pappone, Ilaria Rivolta","doi":"10.1152/ajpcell.00424.2025","DOIUrl":"10.1152/ajpcell.00424.2025","url":null,"abstract":"<p><p><i>SCN5A</i> encodes the α-subunit of the cardiac voltage-gated sodium channel Nav1.5 that plays a fundamental role in the excitability and functionality of the human heart. Nav1.5 T559A is a rare variant that has never been functionally characterized nor clinically described. However, it is present in the hH1a <i>SCN5A</i> clone that has been used as a wild-type control over the years. In this work, we performed a functional electrophysiological characterization of T559A by comparing it with the reverted channel T559. When expressed in a heterologous system, T559A resulted in a significant reduction in sodium current density, suggesting a loss-of-function effect of the mutation. Also, mutation reversion slightly but significantly accelerated the kinetics of both channel activation and inactivation. Thus, caution should be exercised in choosing the most appropriate control and genetic background in functional studies.<b>NEW & NOTEWORTHY</b> This work represents the first functional characterization of the Nav1.5 T559A channel variant that has been widely used as a control wild type over the past decades. We found that the substitution T559A caused a loss-of-function reduction of current density, with smaller effects on channel kinetics and voltage-dependence.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C585-C591"},"PeriodicalIF":4.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607152","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":"Epigenetic modulation of cisplatin sensitivity by the M6A-linked ceRNA network in non-small cell lung cancer.","authors":"Qi Wang, He Yan, Jing Zhang, Jie Zhang, Xiaomin Su, Zhenzhong Su","doi":"10.1152/ajpcell.00881.2024","DOIUrl":"10.1152/ajpcell.00881.2024","url":null,"abstract":"<p><p>Cisplatin resistance significantly impedes effective treatment of non-small cell lung cancer (NSCLC). This study investigates the role of the N6-methyladenosine (M6A)-related circFUT8/miR-185-5p/HNRNPC competing endogenous RNA (ceRNA) axis in NSCLC cisplatin resistance. Bioinformatics analysis identified HNRNPC, a critical M6A modification-related gene, as a promoter of NSCLC proliferation and metastasis. Our in vitro and in vivo experiments reveal that circFUT8 upregulates HNRNPC by sponging miR-185-5p, thus enhancing NSCLC cell proliferation, migration, and invasion while reducing apoptosis and sensitivity to cisplatin. These findings highlight the circFUT8/miR-185-5p/HNRNPC axis as a potential target to overcome chemoresistance in NSCLC.<b>NEW & NOTEWORTHY</b> This study identifies the N6-methyladenosine (M6A)-linked circFUT8/miR-185-5p/HNRNPC competing endogenous RNA (ceRNA) network as a key regulator of cisplatin resistance in non-small cell lung cancer (NSCLC). By revealing how circFUT8 modulates HNRNPC through miR-185-5p, this work provides insights into the molecular mechanisms of chemoresistance. The findings suggest potential therapeutic strategies targeting the circFUT8/miR-185-5p/HNRNPC axis to overcome cisplatin resistance in NSCLC, opening new avenues for improved treatment outcomes.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C481-C499"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144061937","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":"Glucose transporter 1 is essential to maintain brain endothelial cell homeostasis under hyperglycemia condition.","authors":"Benjamin Miao, Mohammad Sarif Mohiuddin, Rashu Barua, Md Wahiduzzaman, Zhi Fang, Wenquan Hu, Munichandra Babu Tirumalasetty, Xiaoran Sun, Mayank Choubey, Qing Robert Miao","doi":"10.1152/ajpcell.00615.2024","DOIUrl":"10.1152/ajpcell.00615.2024","url":null,"abstract":"<p><p>Patients with diabetes are prone to developing cerebrovascular disease (CVD) due to a multitude of factors. Particularly, the hyperglycemic environment is a key contributor to the progression of diabetes-associated complications. However, there is a dearth of knowledge regarding glucose transporter 1 (GLUT1, also known as SLC2A1)-dependent mechanisms responsible for these adverse effects. Here, we revealed the importance of glucose transporter 1 in preserving brain endothelial cell homeostasis beyond regulating glucose uptake. To elucidate the GLUT1-mediated protective mechanism, we used bulk RNA sequencing (RNA-Seq) to analyze the transcriptomic alterations under hyperglycemia and GLUT1-deficient conditions and validated the critical gene changes in cultured human brain endothelial cells and diabetic mouse models. We found that GLUT1 downregulation is linked to increased expression levels of podocalyxin (PODXL) and decreased thioredoxin-interacting protein (TXNIP) within healthy brain endothelial cells incubated with high glucose, demonstrating an antistress response mechanism. Interestingly, brain endothelial cells isolated from diabetic mice no longer showed a similar protection mechanism. Instead, the diabetic endothelial cells are characterized by considerably enriched GLUT1 and TXNIP expression under a hyperglycemic state. GLUT1 overexpression recaptures the diabetic features, such as elevated expression of TXNIP and NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, along with increased IL-1β production and permeability. Our findings of a GLUT1-dependent regulatory mechanism for the endothelium provide a potentially deeper insight into mechanistic shifts that occur due to the diabetic disease state and the pathogenesis of diabetes-associated vascular complications.<b>NEW & NOTEWORTHY</b> Glucose transporter-1 is known for regulating glucose uptake in brain endothelial cells. This study used global transcriptome analysis and diabetic mouse models to reveal the novel role of glucose transporter 1 in regulating brain endothelial cell homeostasis by reducing the inflammation response and increasing the protection mechanism. Importantly, the glucose transporter 1-dependent protection mechanism is compromised in diabetic conditions, which explains why patients with diabetes have a high risk of cerebrovascular diseases.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C341-C354"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473776","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":"Pentagalloyl glucose inhibits monosodium urate-induced inflammation and NLRP3 inflammasome formation via TAK1.","authors":"Paul M Panipinto, Guihua E Yue, Bhagwat Prasad, Salahuddin Ahmed","doi":"10.1152/ajpcell.00673.2024","DOIUrl":"10.1152/ajpcell.00673.2024","url":null,"abstract":"<p><p>Monosodium urate (MSU)-induced inflammation is caused by the deposition of MSU crystals in the joints and periarticular tissues under conditions of hyperuricemia. These deposits can activate joint resident macrophages that form the NOD-, LRR-, and pyrin-containing protein 3 (NLRP3) inflammasome, cleaving pro-IL-1β and causing inflammation. The present study investigated the anti-inflammatory properties of a polyphenolic compound pentagalloyl glucose (PGG) in MSU-induced inflammation. Pretreatment of THP-1 monocyte-derived macrophages with PGG (0.1-10 µM) caused a dose-dependent inhibition of MSU-induced TAK1^184/187 and NF-κB p65 phosphorylation. PGG significantly reduced the production of pro-IL-1β during the priming phase, which correlated with its inhibition of NLRP3 inflammasome formation as observed by the reduced ASC speck formation and a consequent decrease in IL-8, monocyte chemoattractant protein (MCP-1), and IL-1β production. Using liquid chromatography/mass spectrometry (LC-MS/MS)-based untargeted phosphoproteomics analysis, we discovered 3,919 unique phosphorylation sites modulated by MSU. Of 667 phosphosites upregulated by MSU, PGG selectively suppressed 218, a TAK1 inhibitor (5<i>Z</i>-7-oxozeaenol; 5Z7o) inhibited 134, and both inhibitors commonly inhibited 181. Conversely, 443 total phosphosites were suppressed by MSU that were reduced to only 139 by PGG and 132 by 5Z7o. Administration of PGG (30 mg/kg ip) significantly suppressed MSU-induced paw inflammation in C57BL/6J mice and reduced the time to flare resolution. These findings showed that PGG significantly reduced MSU-induced proinflammatory mediators and inhibited the formation of NLRP3 inflammasomes by primarily targeting the TAK1 pathway. Our finding suggests that dietary supplementation of PGG may help reduce the onset and severity of acute gout flares.<b>NEW & NOTEWORTHY</b> Current treatment options for the management of pain and inflammation in gout are inadequate and expensive. Our study provides a novel mechanism for regulating inflammasome formation and gout flares by a natural polyphenol, pentagalloyl glucose (PGG), that is found in fruits and vegetables. PGG also inhibits xanthine oxidase activity, an enzyme that produces uric acid that contributes to monosodium urate crystal formation, making it a dual inhibitor to be further tested in treating gout.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C500-C512"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551729","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":"Cdk5rap3-mediated regulation of lysosomal and ER membrane proteins is pivotal for the survival and function of pancreatic acinar cells.","authors":"Yonghong Huang, Feng Zhou, Xin Xu, Yaqun Wang, Michaela Quintero, Siyang Liu, Cong Liu, Guangxun Zhu, Yafei Cai, Zheng Dong, Roni Bollag, Guangyu Wu, Maria Eugenia Sabbatini, Honglin Li","doi":"10.1152/ajpcell.00284.2025","DOIUrl":"10.1152/ajpcell.00284.2025","url":null,"abstract":"<p><p>The acinus is the functional unit of the exocrine pancreas that produces and secretes a large quantity of digestive enzymes. Damage and dysfunction of pancreatic acinar cells (PACs) may lead to malnutrition, pancreatitis, and other pathological conditions. CDK5 regulatory subunit-associated protein 3 (Cdk5rap3), a multifunctional protein, is essential for animal development and normal physiology of multiple organs and tissues. Interestingly, the recent studies suggest its involvement in endoplasmic reticulum (ER)-phagy, a lysosomal degradation of the subdomains of the endoplasmic reticulum (ER). Herein, we attempted to investigate its physiological function in pancreatic acinar cells. We found that <i>Cdk5rap3</i>-deficient PACs contained fewer zymogen granules and underwent acinar-to-ductal metaplasia (ADM) and apoptosis, thereby resulting in a significant loss of acinar compartment. Interestingly, <i>Cdk5rap3</i> ablation led to the increase of lysosomal hydrolase cathepsin B and lysosome-associated membrane protein 1 (LAMP1), indicating its novel function in the regulation of lysosomal homeostasis and activity. Elevated cathepsin B activity may lead to aberrant activation of trypsinogen and apoptosis of <i>Cdk5rap3</i>-deficient acinar cells, whereas the increase of lysosomal proteins may enhance lysosomal activity that in turn promotes ADM. Furthermore, <i>Cdk5rap3</i> knockout led to substantial changes in the rough ER structure and a significant increase in selective ER membrane proteins, including cytoskeleton-linking membrane protein 63 (CLIMP63). Our results from both mouse tissues and tissue culture cells strongly suggest that Cdk5rap3 plays a pivotal role in regulating homeostasis of the lysosome and the ER that is essential for the survival and physiological function of pancreatic acinar cells.<b>NEW & NOTEWORTHY</b> Our current study has demonstrated a critical role of Cdk5rap3 protein in the maintenance and function of pancreatic acinar cells. Cdk5rap3 functions as a key regulator of the homeostasis of subcellular organelles, such as the lysosome and the ER, and its deficiency leads to loss of pancreatic mass and may contribute to the pathogenesis of pancreatic diseases.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C513-C529"},"PeriodicalIF":4.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599122","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":"Glucose and methylglucose transport in human red blood cells and ghosts.","authors":"Jesper Brahm","doi":"10.1152/ajpcell.00057.2024","DOIUrl":"10.1152/ajpcell.00057.2024","url":null,"abstract":"<p><p>Radioactive labeled d-glucose (GL) or 3-O-methylglucose (MG) efflux from human resealed red ghosts (GHO) or red blood cells (RBC) were determined by means of rapid filtration techniques. All efflux curves show a monoexponential course. Under conditions of self-exchange (SE, equilibrium exchange) and net efflux (NE, zero-trans efflux) in GHO at 0, 10, 25, and 38°C simple Michaelis-Menten-like kinetics in terms of <i>K</i>_½ and <i>J</i>_max apply at 1-200 mM GL. SE conditions: <i>K</i>_½,SE is 19.9, 16.4, 11.2, and 18.0 mM and <i>J</i>_max,SE is 8.7, 42.7, 209, and 555 pmole/(cm² × s); NE conditions: <i>K</i>_½,NE is 9.0, 6.7, 6.5, and 11.5 mM and <i>J</i>_max,NE is 2.8, 18.7, 172, and 680 pmole/(cm² × s). GL SE shows a broad pH dependence with a maximum around pH 7-9. Under SE conditions at 0-38 °C, an overall apparent activation energy, <i>E</i>_A, is 76 kJ/mole. <i>E</i>_A decreases nonlinearly with increasing temperature. A simple two-phase analysis reveals <i>E</i>_A of ≈87 kJ/mole at 0-25°C and ≈49 kJ/mole at 25-38°C. Under NE conditions, <i>E</i>_A shows a linear dependence of 110 kJ/mole at 0-38°C. The data disagree with studies showing a nonlinear <i>E</i>_A of GL and MG transport related to temperature-dependent phase transitions of the lipids in the membrane. Effluxes of GL and MG in normal-sized and swollen RBC with/without 4 mM ATP are all monoexponential, rejecting that ATP generates a biphasic hexose flux pattern. Hetero-exchange with a series of hexoses shows that galactose is best in trans-stimulation, and fructose is best in trans-inhibition of GL efflux. The results disagree with current complicated kinetics models.<b>NEW & NOTEWORTHY</b> Self-exchange (SE) and net efflux (NE) of d-glucose in ghosts are monoexponential. At 0-38°C, glucose SE and NE follow Michaelis-Menten kinetics. Galactose is best in trans-stimulation, fructose is best in trans-inhibition of glucose NE. Temperature dependence of SE and NE is a property of GLUT1, not related to phase transitions of the membrane lipids. Glucose and 3-O-methylglucose SE in RBC with/without 4 mM ATP are monoexponential. ATP stimulates glucose and inhibits 3-O-methylglucose SE.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C395-C411"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293201","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":"Contribution of pannexin channels to afterimage signals in the amphibian retina.","authors":"Yufei Liu, Nick Libian, Zheng Jiang, Wen Shen","doi":"10.1152/ajpcell.00028.2025","DOIUrl":"10.1152/ajpcell.00028.2025","url":null,"abstract":"<p><p>Pannexin 1 (Panx1) forms large-pore, single-membrane channels that connect the intracellular and extracellular environments, permitting the passage of ions and small molecules, such as ATP. Panx1 channels are involved in diverse signaling pathways that contribute to various physiological processes, including sensory processing, although their precise mechanisms of action remain incompletely understood. This study reveals a Panx1-mediated mechanism regulating visual signal processing in the amphibian retina. Using immunolabeling and confocal imaging, we localized Panx1 channels in the cone-dominated On-bipolar cells, specifically at both somas and axon terminals. Whole cell patch-clamp recordings showed that these channels have high permeability to Cl^- ions, which can be blocked by ¹⁰Panx1 peptide, carbenoxolone, and mefloquine, all recognized as Panx1 inhibitors. Blocking Panx1 channels or reducing external Cl^- concentrations significantly increased bright light-induced delayed spontaneous excitatory responses in ganglion cells, indicating an inhibitory role of Panx1 channels at the bipolar cell synaptic release. These delayed spontaneous responses in ganglion cells, known as rebound currents, are associated with afterimage signals in the retina. Our findings suggest that Panx1 channels help prevent overexcitation associated with bright light-induced afterimage phenomena.<b>NEW & NOTEWORTHY</b> Cl^- permeable Panx1 channels in the On-bipolar cells serve as a novel mechanism for the negative control of overexcitation in afterimage signal processing in the retina.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C355-C365"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473775","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":"Combined angiogenic and hypertrophic gene therapy enhances skeletal muscle growth.","authors":"Aino Männistö, Kialiina Tonttila, Alfredo Ortega-Alonso, Harri Nurmi, Liina Uusitalo-Kylmälä, Karthik Amudhala Hemanthakumar, Erik Saikkala, Sami Myllykangas, Satu Vertainen, Tuuli A Nissinen, Arja Pasternack, Olli Ritvos, Kari Kustaa Alitalo, Juha J Hulmi, Riikka Kivelä","doi":"10.1152/ajpcell.00966.2024","DOIUrl":"10.1152/ajpcell.00966.2024","url":null,"abstract":"<p><p>Skeletal muscle atrophy in response to pathophysiological stimuli or disuse includes loss of muscle mass and strength. Targeting signaling pathways regulating muscle growth can counteract muscle loss, but also unwanted side effects on muscle vascularization, oxidative metabolism, and exercise tolerance have been reported. Here, we investigated whether combined induction of angiogenesis and muscle hypertrophy can promote physiological muscle growth and improve muscle function to overcome the limitations of current hypertrophic treatments. We used myostatin propeptide (Pro-MSTN) and vascular endothelial growth factor B (VEGF-B) gene therapies to increase muscle size and angiogenesis, respectively. Intramuscular and systemic adeno-associated viral vector (AAV) delivery was used to study their effects alone and in combination in healthy and diabetic mice. Single-cell RNA sequencing was used to investigate the effects on different cell types and on intercellular communication in the healthy mice. We demonstrate that in the healthy mice, the intramuscular delivery of VEGF-B rescued Pro-MSTN-induced capillary rarefaction and enhanced muscle growth in the combination group (VEGF-B + Pro-MSTN). The systemic combination treatment also improved body composition in the healthy mice and increased muscle mass and grip strength in the diabetic mouse model. The single-cell RNA sequencing data showed that among the nonmyocytes, endothelial cells and pericytes responded the most to both treatments resulting in enhanced intercellular communication. Our findings demonstrate beneficial effects of the combined gene delivery of Pro-MSTN and VEGF-B on muscle growth and body composition. The results also decipher the contribution of various cell types and their cross talk in skeletal muscle growth.<b>NEW & NOTEWORTHY</b> We used intramuscular and systemic adeno-associated viral vector (AAV) gene delivery of myostatin propeptide (Pro-MSTN) and vascular endothelial growth factor B (VEGF-B) to induce muscle growth and angiogenesis in skeletal muscle. The intramuscular delivery of VEGF-B and Pro-MSTN in combination enhanced skeletal muscle growth and rescued vascularization when compared with Pro-MSTN alone. Single-cell RNA sequencing data showed that the treatments had the greatest effect on endothelial cells and pericytes. The combination treatment also improved body composition and muscle mass in diabetic mice, when delivered systemically.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C540-C559"},"PeriodicalIF":4.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582828","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":"Asprosin attenuates diabetic cardiomyopathy through inhibiting autophagy mediated by AMPK/mTOR/ULK1 pathway.","authors":"Yuan Wang, Wentao Liu, Chen Liu, Zhitong Zhou, Sheng Chen, Qianqian Huang, Li Wang, Guohua Zeng, Qiren Huang","doi":"10.1152/ajpcell.01006.2024","DOIUrl":"10.1152/ajpcell.01006.2024","url":null,"abstract":"<p><p>Aberrant autophagy mediated by AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/unc-51 like kinase 1 (ULK1) pathway (a canonical autophagy pathway) plays important roles in diabetic cardiomyopathy (DCM). Asprosin (ASP) secreted by white adipose tissue involves in systemic metabolism disorders. However, its role in DCM remains poorly understood. Therefore, the purpose of this study was to investigate its roles and underlying mechanisms in the DCM from the perspective of autophagy and apoptosis. In the in vivo experiments, we observed the effects of ASP deficiency (ASP^-/-) or ASP intervention on cardiac function, fibrosis, autophagy, and apoptosis in a diabetes mellitus (DM) mouse model induced by high-fat feeding and streptozotocin (STZ) injection; in the in vitro experiments, we evaluated the effects of ASP intervention with or without 3-methyladenine (3-MA) (autophagy inhibitor) or siAMPK in a H9c2 model injured by high glucose (HG). Our results show that ASP intervention attenuates the myocardial injury induced by DM (<i>P</i> < 0.05) and HG (<i>P</i> < 0.05). In addition, the autophagy level markedly increases (<i>P</i> < 0.05) in diabetic mice, and ASP deficiency worsens the increase induced by DM (<i>P</i> < 0.05). In contrast, ASP intervention alleviates overautophagy induced by DM (<i>P</i> < 0.05) or HG (<i>P</i> < 0.05). Mechanistically, the protective effect of ASP against myocardial injury is through inhibiting the overautophagy mediated by AMPK/mTOR/ULK1 pathway (<i>P</i> < 0.05). Taken together, the findings suggest that ASP would be a potential therapeutic target and the recombinant ASP might be a promising candidate to treat metabolism-associated CVD. Although the findings would present a promise for the treatment of DCM, it is worth noting that the mouse model used fails to fully mimic the human DCM pathophysiology.<b>NEW & NOTEWORTHY</b> We demonstrated for the first time that asprosin (ASP) has protective effects against diabetic cardiomyopathy. We found that ASP could stimulate the AMPK/mTOR/ULK1 pathway to reduce the level of autophagy and apoptosis of cardiomyocytes, thereby maintaining the normal physiological function of the heart.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C377-C394"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493410","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}