American journal of physiology. Cell physiology最新文献

{"title":"Hydrogen sulfide-mediated inhibition of ROCK₂ exerts a vasoprotective effect on ischemic brain injury.","authors":"Ye Chen, Fangfang Xu, Fang Chen, Shuaishuai Li, Miao Wu, Shuo Chen, Jinhua Chen, Zhaoyi Yang, Zhongwu Sun, Zhiwu Chen","doi":"10.1152/ajpcell.00708.2024","DOIUrl":"10.1152/ajpcell.00708.2024","url":null,"abstract":"<p><p>As a gas molecule, hydrogen sulfide (H₂S) exerts neuroprotective effects. Despite its recognized importance, there remains a need for a deeper understanding of H₂S's impact on vascular smooth muscle cells and its role in ischemic brain injury. This study employs encompassing cultured primary cerebral vascular smooth muscle cells, oxygen-glucose deprivation/reoxygenation model, in vitro vascular tone assessments, in vivo middle cerebral artery occlusion and reperfusion experimentation in male rats, and the utilization of Rho-associated coiled-coil containing protein kinase 2 (<i>ROCK₂</i>) knockout, to unravel the intricate relationship between H₂S and cerebrovascular diastolic function. Our findings show that RhoA activation induces heightened vascular smooth muscle cell (VSMC) contraction, whereas the introduction of exogenous H₂S mitigates the relaxant effect of the middle cerebral artery in rats through the downregulation of both ROCK₁ and ROCK₂, with ROCK₂ exhibiting a more pronounced effect. Correspondingly, the attenuation of ROCK₂ expression yields a more substantial reduction in the protective impact of H₂S on cerebral blood flow, as well as learning and memory ability in ischemic injury, compared with the decrease in ROCK₁ expression. Moreover, we demonstrate that H₂S effectively mitigates the damage induced by oxygen-glucose deprivation/reoxygenation in male mouse primary vascular smooth muscle cells. This effect is characterized by enhanced cell proliferation, reduced lactate dehydrogenase leakage, elevated superoxide dismutase activity, and inhibited apoptosis. Notably, this protective effect is markedly diminished in cells derived from ROCK₂ knockout mice. Our study reveals that H₂S can relax cerebral vascular smooth muscle and ameliorate ischemic stroke injury by inhibiting the ROCK, with a particular emphasis on the role of ROCK₂.<b>NEW & NOTEWORTHY</b> This study employs a diverse array of methods; our collective findings indicate that H₂S safeguards against ischemic brain injury by inhibiting ROCK activity, thereby promoting relaxation of cerebral smooth muscle and mitigating the impairment of cerebral smooth muscle cell function caused by oxygen-glucose deprivation/reoxygenation. In addition, our data underscore the critical role of ROCK₂ in mediating the cerebral protective effects of H₂S, surpassing that of ROCK₁.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C986-C1000"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881070","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":"Microbiota protect against frailty and loss of skeletal muscle, and maintain inflammatory tone during aging in mice.","authors":"Meghan O Conn, Erica N DeJong, Daniel M Marko, Russta Fayyazi, Dana Kukje Zada, Kevin P Foley, Nicole G Barra, Dawn M E Bowdish, Jonathan D Schertzer","doi":"10.1152/ajpcell.00869.2024","DOIUrl":"10.1152/ajpcell.00869.2024","url":null,"abstract":"<p><p>Chronic low-level inflammation or \"inflammaging\" is hypothesized to contribute to sarcopenia and frailty. Resident microbiota are thought to promote inflammaging, frailty, and loss of skeletal muscle mass. We tested immunity and frailty in male C57BL6/N germ-free (GF), specific pathogen-free (SPF) mice, and mice that were born germ-free and colonized (COL) with an SPF microbiota. Male and female GF mice had lower systemic cellular inflammation indicated by lower blood Ly6C^high monocytes across their lifespan. Male GF mice had lower body mass, but relative to body mass, GF mice had smaller hindlimb muscles and smaller muscle fibers compared with SPF mice across the lifespan. Male and female GF mice had increased frailty at 18 mo or older. Colonization of female GF mice increased blood Ly6C^high monocytes but did not affect frailty at 18 mo or older. Colonization of male GF mice increased blood Ly6C^high monocytes, skeletal muscle size, myofiber fiber size, and decreased frailty at 18 mo or older. Transcriptomic analysis of the tibialis anterior muscle revealed a microbiota-muscle axis with over 550 differentially expressed genes in COL male mice at 18 mo or older. Colonized male mice had transcripts indicative of lower tumor necrosis factor (TNF)-α signaling via nuclear factor κB (NF-κB). Our findings show that microbiota can increase systemic cellular immunity while decreasing muscle inflammation, thereby protecting against muscle loss and frailty. We also found sex differences in the role of microbiota regulating frailty. We propose that microbiota components protect against lower muscle mass and frailty across the lifespan in mice.<b>NEW & NOTEWORTHY</b> Germ-free mice had increased frailty, lower muscle mass, and lower circulating inflammatory monocytes. Therefore, lower systemic inflammation coincided with worse frailty and muscle loss. Microbial colonization decreased frailty, restored muscle mass, and increased circulating inflammatory monocytes while lowering transcripts in inflammatory TNF and NF-κB pathways within muscle. Hence, microbiota can increase circulating inflammation but decrease muscle inflammation to protect against frailty. This microbiota-muscle axis should be investigated for therapeutic potential in muscle wasting and sarcopenia.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C887-C894"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381491","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":"Synergistic Effects of Olaparib and Palbociclib in Resistant epithelial ovarian cancer.","authors":"Shuo Wang, Yan Gao","doi":"10.1152/ajpcell.00481.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00481.2024","url":null,"abstract":"<p><p>This study investigates the mechanisms of poly ADP-ribose polymerase inhibitor (PARPi) resistance in epithelial ovarian cancer (EOC). It also explores strategies to overcome this resistance by combining PARPi with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). EOC cell lines A2780 and SKOV-3 were treated with PARPi to develop stable drug-resistant cell lines, A2780-ola-r and SKOV-3-ola-r. Low-dose treatments with Olaparib, Palbociclib, and their combination significantly reduced tumor proliferation in these resistant cells. Bioinformatics analysis identified potential therapeutic targets, KNSTRN and TRPC4AP. The combination treatment induced G1 phase cell cycle arrest at low drug concentrations. Immunofluorescence studies demonstrated reduced nuclear RAD51 and increased p-γH2AX levels following combination or Palbociclib treatment, compared to DMSO. Western blot analysis revealed elevated expression of homologous recombination repair (HRR) pathway-related proteins in the resistant cell lines. Post-treatment analysis indicated a negative correlation between KNSTRN levels and the efficacy of CDK4/6i or combination therapy, whereas TRPC4AP levels positively correlated with treatment response. These findings offer critical insights into the mechanisms of PARPi resistance in EOC and suggest that combining PARPi with CDK4/6i is a promising therapeutic strategy to overcome this resistance and improve outcomes for patients with EOC.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Long Road to Ithaca: A Physiologist's Journey.","authors":"Sadis Matalon","doi":"10.1152/ajpcell.00030.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00030.2025","url":null,"abstract":"","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490526","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":"Runx2-NLRP3 axis orchestrates matrix stiffness-evoked vascular smooth muscle cell inflammation.","authors":"Zhiqing Li, Hao Wu, Fang Yao, Yiran Li, Yanjie Li, Si-An Xie, Fang Yu, Yi Fu, Li Wang, Jing Zhou, Wei Kong","doi":"10.1152/ajpcell.00448.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00448.2024","url":null,"abstract":"<p><p>Arterial stiffening is a hallmark of chronic kidney disease (CKD)-related cardiovascular events and is primarily attributed to the elevated matrix stiffness. Stiffened arteries are accompanied by low-grade inflammation, but the causal effects of matrix stiffness on inflammation remain unknown. For analysis of the relationship between arterial stiffness and vascular inflammation, pulse-wave velocity (PWV) and aortic inflammatory markers were analyzed in an adenine-induced mouse model of CKD in chronological order. Compared with their control littermates, mice with CKD showed elevated arterial stiffness at the early stage of disease progression, which preceded the onset of vascular inflammation. Correspondingly, the increase of matrix stiffness induced vascular smooth muscle cells (VSMCs) to transdifferentiate into an inflammatory phenotype, as indicated by the increased expression and secretion of MCP-1, IL-6, IL-1β, and IL-18. RNA-sequencing analysis of stiff matrix-cultured VSMCs and bioinformatics analysis with the ChIP-Atlas database revealed the potential involvement of the transcription factor Runx2. The expression and the nuclear localization of Runx2 were significantly increased in stiff matrix-cultured VSMCs. High-throughput ChIP-sequencing and promoter luciferase assays further revealed that <i>NLRP3</i> was directly transcriptionally regulated by Runx2. The inhibition of Runx2 or NLRP3 inflammasome abrogated the proinflammatory effect of matrix stiffening on VSMCs. Together, these data revealed that arterial stiffness precedes vascular inflammatory responses in CKD mice and that the Runx2-NLRP3 axis orchestrates matrix stiffness and the VSMC inflammatory phenotype, which may contribute to the pathogenic role in arterial stiffness-related vascular inflammation and CKD-related cardiovascular complications.<b>NEW & NOTEWORTHY</b> As a hallmark of chronic kidney disease (CKD), arterial stiffening is related to increased vascular inflammation and cardiovascular morbidity, whereas the underlying mechanism is unclear. The study demonstrates that increased arterial stiffness precedes the onset of vascular inflammation, and matrix stiffness stimulates the transdifferentiation of vascular smooth muscle cells (VSMCs) to an inflammatory phenotype via activating Runx2-NLRP3 signaling, which provides novel insights into CKD-related cardiovascular disorder treatment.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"328 2","pages":"C467-C482"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021508","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":"Histone lactylation-mediated overexpression of RASD2 promotes endometriosis progression via upregulating the SUMOylation of CTPS1.","authors":"Ziwei Wang, Yanhong Mao, Zihan Wang, Shuwei Li, Zhidan Hong, Rong Zhou, Shaoyuan Xu, Yao Xiong, Yuanzhen Zhang","doi":"10.1152/ajpcell.00493.2024","DOIUrl":"10.1152/ajpcell.00493.2024","url":null,"abstract":"<p><p>Histone lactylation is crucial in a variety of physiopathological processes; however, the function and mechanism of histone lactylation in endometriosis remain poorly understood. Therefore, the objective of this investigation was to illuminate the function and mechanism of histone lactylation in endometriosis. Immunohistochemistry was used to investigate the expression of histone lactylation. Cell Counting Kit-8 assay (CCK8), Transwell assay, and endometriosis mouse models were used to investigate the effects of histone lactylation in vitro and in vivo. Transcriptomics and immunoprecipitation-mass spectrometry (IP-MS), Western blot, co-immunoprecipitation (Co-IP), quantitative reverse transcription polymerase chain reaction (qRT-PCR), and chromatin immunoprecipitation-qPCR (ChIP-qPCR) were used to explore the intrinsic mechanisms. In this study, we found that histone lactylation was upregulated in endometriosis and could promote endometriosis progression both in vivo and in vitro. Mechanistically, histone lactylation H3K18la promoted the transcription of Ras homolog enriched in striatum (RASD2), and RASD2, in turn, increased the stability of CTP synthase 1 (CTPS1) by promoting the SUMOylation and inhibiting the ubiquitination of CTPS1, thereby promoting endometriosis progression. Overall, our findings indicated that histone lactylation could promote the progression of endometriosis through the RASD2/CTPS1 axis. This investigation uncovered a novel mechanism and identified prospective targets for endometriosis diagnosis and therapy.<b>NEW & NOTEWORTHY</b> Our finding reveals a novel mechanism that promotes the progression of endometriosis, namely the histone lactylation/RASD2/CTPS1 axis. This finding suggests that inhibiting histone lactylation or inhibiting RASD2 and CTPS1 might be a potential therapeutic strategy to inhibit endometriosis lesion growth.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C500-C513"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142821823","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":"dEREGulated pathways: unraveling the role of epiregulin in skin, kidney, and lung fibrosis.","authors":"Aysan Ezaddoustdar, Daniel Kalina, Maximilian Bielohuby, Mario Boehm, Malgorzata Wygrecka","doi":"10.1152/ajpcell.00813.2024","DOIUrl":"10.1152/ajpcell.00813.2024","url":null,"abstract":"<p><p>The epidermal growth factor receptor (EGFR) signaling pathway is an evolutionary conserved mechanism to control cell behavior during tissue development and homeostasis. Deregulation of this pathway has been associated with abnormal cell behavior, including hyperproliferation, senescence, and an inflammatory cell phenotype, thereby contributing to pathologies across a variety of organs, including the kidneys, skin, and lungs. To date, there are seven distinct EGFR ligands described. Although binding of these ligands to the receptor is cell type-specific and spatio-temporally controlled with distinct affinities and kinetics, epiregulin (EREG) stands out as a long-acting EGFR ligand that emerges under pathological conditions, particularly in tissue fibrosis. Although EREG has been extensively studied in cancer, its contribution to the maladaptive remodeling of tissue is elusive. The aim of this review is to highlight the role of EREG in skin, kidney, and lung fibrosis and to discuss opportunities for therapeutic intervention.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C617-C626"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920397","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":"Gut-kidney interaction reinforces dapagliflozin-mediated alleviation in diabetic nephropathy.","authors":"Yinhua Ni, Haimei Du, Lehui Ke, Liujie Zheng, Sujie Nan, Liyang Ni, Yuxiang Pan, Zhengwei Fu, Qiang He, Juan Jin","doi":"10.1152/ajpcell.00651.2024","DOIUrl":"10.1152/ajpcell.00651.2024","url":null,"abstract":"<p><p>Intestinal microbiota are pathophysiologically involved in diabetic nephropathy (DN). Dapagliflozin, recognized for its blood glucose-lowering effect, has demonstrated efficacy in improving DN. However, the mechanisms beyond glycemic control that mediate the impact of dapagliflozin on DN remain unclear. Here, we investigated the effects of dapagliflozin on DN and gut microbiota, elucidating how it mitigates DN via the gut-kidney axis. Low-dose dapagliflozin markedly ameliorated renal inflammation and fibrosis and improved gut barrier function in high-fat diet (HFD)/streptozotocin (STZ)-induced DN mice and <i>db</i>/<i>db</i> mice without affecting blood glucose levels. These effects were associated with altered gut microbial composition and function. Eradication of the resident microbiota abolished the protective effects of dapagliflozin against kidney injury in DN mice. Moreover, dapagliflozin significantly altered microbial metabolites in DN mice, decreasing argininosuccinic acid (ASA) and palmitic acid (PA), while increasing <i>S</i>-allylcysteine (SAC) levels. ASA and PA increased the expression of renal inflammation- and fibrosis-related markers in HK-2 cells, whereas SAC ameliorated renal damage and altered the microbial composition in a manner similar to dapagliflozin in DN mice. Notably, <i>Muribaculaceae</i> and <i>Desulfovibrionaceae</i> were correlated with the alleviation of DN-associated renal dysfunction by low- and high-dose dapagliflozin treatments in DN mice. These findings demonstrate a potential application of dapagliflozin in managing DN by targeting the gut microbiota.<b>NEW & NOTEWORTHY</b> We demonstrated that dapagliflozin administration alleviated renal inflammation and fibrosis in vivo and in vitro, along with reshaping the gut microbiota composition and altering levels of key microbial metabolites, including argininosuccinic acid (ASA) and palmitic acid (PA), while increasing <i>S</i>-allylcysteine (SAC). Importantly, the genera <i>Muribaculaceae</i> and <i>Desulfovibrionaceae</i> emerged as pivotal microbial genera mediating the protective effects of dapagliflozin against diabetic nephropathy.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C452-C466"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909085","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":"METTL14 promotes ferroptosis in smooth muscle cells during thoracic aortic aneurysm by stabilizing the m⁶A modification of ACSL4.","authors":"Wenjun Wang, Jiayi Chen, Songqing Lai, Ruiyuan Zeng, Ming Fang, Li Wan, Yiying Li","doi":"10.1152/ajpcell.00577.2024","DOIUrl":"10.1152/ajpcell.00577.2024","url":null,"abstract":"<p><p>Thoracic aortic aneurysm (TAA) is a vascular disease associated with high mortality rates. Ferroptosis has been shown to mediate the transformation of vascular smooth muscle cells (VSMCs). However, the regulatory mechanisms by which ferroptosis influences TAA remain unclear. In this study, we induced TAA mouse models using angiotensin II (Ang II) and evaluated the impact of ferroptosis on the pathological changes observed in TAA mice, employing liproxstatin-1 as a treatment. In addition, we assessed the regulatory effect of METTL14 on the ferroptosis of VSMCs after treating them with a ferroptosis activator (imidazole ketone erastin, IKE). RNA binding protein immunoprecipitation (RIP) and RNA pull-down assays were conducted to investigate the interaction between acyl-CoA synthase long-chain family member 4 (<i>ACSL4</i>) mRNA and the proteins METTL14 or IGF2BP2. The results indicated that the level of ferroptosis was elevated in the thoracic aorta of TAA mice, and METTL14 was upregulated in TAA models and IKE-induced VSMCs. Knockdown of METTL14 was found to inhibit the progression of TAA by reducing the ferroptosis of VSMCs. Furthermore, IGF2BP2 recognized METTL14-modified <i>ACSL4</i> mRNA and regulated its stability, thereby mediating the ferroptosis of VSMCs. Collectively, the effects of METTL14 on VSMC ferroptosis present therapeutic potential for the treatment of TAA.<b>NEW & NOTEWORTHY</b> Our study confirmed that METTL14 can induce ferroptosis in vascular smooth muscle cells during the progression of thoracic aortic aneurysm by mediating the m⁶A modification of <i>ACSL4</i> mRNA.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C387-C399"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142821824","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":"Sulforaphane treatment mimics contractile activity-induced mitochondrial adaptations in muscle myotubes.","authors":"Sabrina Champsi, David A Hood","doi":"10.1152/ajpcell.00669.2024","DOIUrl":"10.1152/ajpcell.00669.2024","url":null,"abstract":"<p><p>Mitochondria are metabolic hubs that govern skeletal muscle health. Although exercise has been established as a powerful inducer of quality control processes that ultimately enhance mitochondrial function, there are currently limited pharmaceutical interventions available that emulate exercise-induced mitochondrial adaptations. To investigate a novel candidate for this role, we examined sulforaphane (SFN), a naturally occurring compound found in cruciferous vegetables. SFN has been documented as a potent antioxidant inducer through its activation of the nuclear factor erythroid 2-related factor 2 (Nrf-2) antioxidant response pathway. However, its effects on muscle health have been underexplored. To investigate the interplay between chronic exercise and SFN, C2C12 myotubes were electrically stimulated to model chronic contractile activity (CCA) in the presence or absence of SFN. SFN promoted Nrf-2 nuclear translocation, enhanced mitochondrial respiration, and upregulated key antioxidant proteins including catalase and glutathione reductase. These adaptations were accompanied by reductions in cellular and mitochondrial reactive oxygen species (ROS) emission. Signaling toward biogenesis was enhanced, demonstrated by increases in mitochondrial transcription factor A (TFAM), peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α nuclear translocation, PGC-1α promoter activity, mitochondrial content, and organelle branching, suggestive of a larger, more interconnected mitochondrial pool. These mitochondrial adaptations were accompanied by an increase in lysosomal proteins, suggesting coordinated regulation. There was no difference in mitochondrial and antioxidant-related proteins between CCA and non-CCA SFN-treated cells. Our data suggest that SFN activates signaling cascades that are common to those produced by contractile activity, indicating that SFN-centered therapeutic strategies may improve the mitochondrial phenotype in skeletal muscle.<b>NEW & NOTEWORTHY</b> Nrf-2 is a transcription factor that has been implicated in mitigating oxidative stress and regulating mitochondrial homeostasis. However, limited research has demonstrated how Nrf-2-mediated adaptations compare with those produced by exercise. To investigate this, we treated myotubes with Sulforaphane, a well-established Nrf-2 activator, and combined this with stimulation-induced chronic contractile activity to model exercise training. Our work is the first to establish that sulforaphane mimics training-induced mitochondrial adaptations, including enhancements in respiration, biogenesis, and dynamics.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C335-C354"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142821827","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}