Role of TGF-β/SMAD/YAP/TAZ signaling in skeletal muscle fibrosis.

IF 5 2区 生物学 Q2 CELL BIOLOGY
Felipe S Gallardo, Meilyn Cruz-Soca, Alexia Bock-Pereda, Jennifer Faundez-Contreras, Cristian Gutiérrez-Rojas, Alessandro Gandin, Veronica Torresan, Juan Carlos Casar, Andrea Ravasio, Enrique Brandan
{"title":"Role of TGF-β/SMAD/YAP/TAZ signaling in skeletal muscle fibrosis.","authors":"Felipe S Gallardo, Meilyn Cruz-Soca, Alexia Bock-Pereda, Jennifer Faundez-Contreras, Cristian Gutiérrez-Rojas, Alessandro Gandin, Veronica Torresan, Juan Carlos Casar, Andrea Ravasio, Enrique Brandan","doi":"10.1152/ajpcell.00541.2024","DOIUrl":null,"url":null,"abstract":"<p><p>Skeletal muscle fibrosis is strongly associated with the differentiation of its resident multipotent fibro/adipogenic progenitors (FAPs) toward the myofibroblast phenotype. Although transforming growth factor type β (TGF-β) signaling is well-known for driving FAPs differentiation and fibrosis, due to its pleiotropic functions its complete inhibition is not suitable for treating fibrotic disorders such as muscular dystrophies. Here, we describe that TGF-β operates through the mechanosensitive transcriptional regulators Yes-associated protein (YAP)/ transcriptional coactivator with PDZ-binding motif (TAZ) to determine the myofibroblast fate of FAPs and skeletal muscle fibrosis. Spatial transcriptomics analyses of dystrophic and acute injured muscles showed that areas with active fibrosis and TGF-β signaling displayed high YAP/TAZ activity. Using a TGF-β-driven fibrotic mouse model, we found that activation of YAP/TAZ in activated FAPs is associated with the fibrotic process. Mechanistically, primary culture of FAPs reveals the remarkable ability of TGF-β1 to activate YAP/TAZ through its canonical SMAD3 pathway. Moreover, inhibition of YAP/TAZ, either by disrupting its activity (with Verteporfin) or cellular mechanotransduction (with the Rho inhibitor C3 or soft matrices), decreased TGF-β1-dependent FAPs differentiation into myofibroblasts. In vivo, administration of Verteporfin in mice limits the deposition of collagen and fibronectin, and the activation of FAPs during the development of fibrosis. Overall, our work provides robust evidence for considering YAP/TAZ as a potential target in muscular fibroproliferative disorders.<b>NEW & NOTEWORTHY</b> The understanding of the nuclear factors governing the differentiation of muscular fibro/adipogenic progenitors (FAPs) into myofibroblasts is in its infancy. Here, we comprehensively elucidate the status, regulation, and role of the mechanotransducers Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) in the muscular fibrotic process. Our findings reveal that inhibiting cellular mechanotransduction limits FAP differentiation and the extent of muscular fibrosis exerted by transforming growth factor type β (TGF-β). This research shed new lights on the molecular mechanisms dictating the cell fate of FAPs and the muscular fibrosis.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1015-C1028"},"PeriodicalIF":5.0000,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of physiology. Cell physiology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1152/ajpcell.00541.2024","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/2/10 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Skeletal muscle fibrosis is strongly associated with the differentiation of its resident multipotent fibro/adipogenic progenitors (FAPs) toward the myofibroblast phenotype. Although transforming growth factor type β (TGF-β) signaling is well-known for driving FAPs differentiation and fibrosis, due to its pleiotropic functions its complete inhibition is not suitable for treating fibrotic disorders such as muscular dystrophies. Here, we describe that TGF-β operates through the mechanosensitive transcriptional regulators Yes-associated protein (YAP)/ transcriptional coactivator with PDZ-binding motif (TAZ) to determine the myofibroblast fate of FAPs and skeletal muscle fibrosis. Spatial transcriptomics analyses of dystrophic and acute injured muscles showed that areas with active fibrosis and TGF-β signaling displayed high YAP/TAZ activity. Using a TGF-β-driven fibrotic mouse model, we found that activation of YAP/TAZ in activated FAPs is associated with the fibrotic process. Mechanistically, primary culture of FAPs reveals the remarkable ability of TGF-β1 to activate YAP/TAZ through its canonical SMAD3 pathway. Moreover, inhibition of YAP/TAZ, either by disrupting its activity (with Verteporfin) or cellular mechanotransduction (with the Rho inhibitor C3 or soft matrices), decreased TGF-β1-dependent FAPs differentiation into myofibroblasts. In vivo, administration of Verteporfin in mice limits the deposition of collagen and fibronectin, and the activation of FAPs during the development of fibrosis. Overall, our work provides robust evidence for considering YAP/TAZ as a potential target in muscular fibroproliferative disorders.NEW & NOTEWORTHY The understanding of the nuclear factors governing the differentiation of muscular fibro/adipogenic progenitors (FAPs) into myofibroblasts is in its infancy. Here, we comprehensively elucidate the status, regulation, and role of the mechanotransducers Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) in the muscular fibrotic process. Our findings reveal that inhibiting cellular mechanotransduction limits FAP differentiation and the extent of muscular fibrosis exerted by transforming growth factor type β (TGF-β). This research shed new lights on the molecular mechanisms dictating the cell fate of FAPs and the muscular fibrosis.

TGF-β/SMAD/YAP/TAZ信号在骨骼肌纤维化中的作用
骨骼肌纤维化与其驻留的多能纤维/脂肪生成祖细胞(FAPs)向肌成纤维细胞表型的分化密切相关。虽然TGF-β信号在驱动FAPs分化和纤维化方面是众所周知的,但由于其多效性,其完全抑制不适合用于治疗肌营养不良等纤维化疾病。在这里,我们描述了TGF-β通过机械敏感的转录调节因子YAP/TAZ来决定FAPs和骨骼肌纤维化的肌成纤维细胞命运。对营养不良和急性损伤肌肉的空间转录组学分析显示,纤维化活动区和TGF-β信号传导区表现出较高的YAP/TAZ活性。通过TGF-β驱动的纤维化小鼠模型,我们发现激活的FAPs中YAP/TAZ的激活与纤维化过程有关。机制上,FAPs的原代培养揭示了TGF-β1通过其典型的SMAD3途径激活YAP/TAZ的显著能力。此外,通过破坏YAP/TAZ的活性(使用维替波芬)或细胞机械转导(使用Rho抑制剂C3或软基质)来抑制YAP/TAZ,可以减少TGF-β1依赖性FAPs向肌成纤维细胞的分化。在小鼠体内,给药椎泊芬限制了胶原和纤维连接蛋白的沉积,以及纤维化发展过程中FAPs的激活。总之,我们的工作为考虑YAP/TAZ作为肌肉纤维增殖性疾病的潜在靶点提供了强有力的证据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
9.10
自引率
1.80%
发文量
252
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Cell Physiology is dedicated to innovative approaches to the study of cell and molecular physiology. Contributions that use cellular and molecular approaches to shed light on mechanisms of physiological control at higher levels of organization also appear regularly. Manuscripts dealing with the structure and function of cell membranes, contractile systems, cellular organelles, and membrane channels, transporters, and pumps are encouraged. Studies dealing with integrated regulation of cellular function, including mechanisms of signal transduction, development, gene expression, cell-to-cell interactions, and the cell physiology of pathophysiological states, are also eagerly sought. Interdisciplinary studies that apply the approaches of biochemistry, biophysics, molecular biology, morphology, and immunology to the determination of new principles in cell physiology are especially welcome.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信