Bmi-1 Overexpression Improves Sarcopenia Induced by 1,25(OH)2D3 Deficiency and Downregulates GATA4-Dependent Rela Transcription
Bmi-1 Overexpression Improves Sarcopenia Induced by 1,25(OH)2D3 Deficiency and Downregulates GATA4-Dependent Rela Transcription
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Bmi-1 过表达可改善 1,25(OH)2D3 缺陷引起的肌肉减少症，并下调 GATA4-依赖性 Rela 转录
DOI：
10.1002/jbmr.4770
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发表时间：
2023-01-24
影响因子：
6.2
通讯作者：
Jin，Jianliang
中科院分区：
文献类型：
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作者：
Wang，Qiuyi;Zhao，Jingyu;Jin，Jianliang
骨质疏松症随着年龄的增长而增加，需要确定潜在的机制，以帮助设计更有效的治疗方法。本研究旨在探讨1，25(OH)2D3缺乏是否可导致骨骼肌细胞衰老和衰老相关的分泌表型(SASP)，1，25(OH)2D3缺乏是否可上调GATA4促进SASP，BMI-1是否可降低1，25(OH)2D3缺乏所诱导的骨骼肌细胞GATA4及其依赖的SASP的表达。利用生理性衰老小鼠和幼年小鼠骨骼肌的RNA测序数据进行了生物信息学分析。观察了2个月龄幼龄和2岁生理性衰老野生型(WT)和8周龄WT、Bmi-1间充质转基因(Bmi-1TG)、Cyp27b1纯合(Cyp27b1−/−)和Bmi-1TgCyp27b1−/−小鼠骨骼肌的握力、细胞衰老、DNA损伤和核因子-κB介导的SASPB信号转导。我们发现，随着生理年龄的增长，肌源性BMI-1和维生素D受体(VDR)减少，DNA损伤和GATA4依赖的SASP激活导致骨骼肌减少。此外，1，25(OH)2D3缺乏促进了DNA损伤诱导的GATA4在肌肉中的积累。GATA4在转录水平上调−1448~−1412 BP区域的RelA，导致核因子-κB依赖的SASP加重细胞衰老、肌肉功能障碍和肌萎缩症。Bmi-1过表达通过结合Ring1b促进GATA4的泛素化和降解，从而阻止细胞衰老、SASP和肌肉功能障碍，并改善1，25(OH)2D3缺乏引起的骨骼肌减少。因此，Bmi-1的过表达改善了1，25(OH)2D3缺乏引起的骨骼肌减少，下调了依赖GATA4的RelA转录，从而抑制了GATA4依赖的肌肉细胞SASP。因此，Bmi-1的过表达可用于GATA4泛素化的翻译基因治疗和预防石棉减少症。摘要DNA双链断裂(DSB)在1，25(OH)2D3缺乏引起的骨质疏松症的进展过程中增加，导致共济失调毛细血管扩张突变基因(ATM)和共济失调毛细血管扩张及Rad-3相关蛋白(ATR)的磷酸化，从而引起DNA损伤反应(DDR)。GATA4由于DDR而上调，与启动子区域结合，并提高了RelA的转录水平。Bmi-1的过表达通过与Ring1b结合促进GATA4的泛素化和降解，进而降低RelA转录，从而抑制了NF-κB-p65信号介导的SASP，从而改善了1，25(OH)2D3缺陷小鼠的骨骼肌减少症。
Sarcopenia increases with age, and an underlying mechanism needs to be determined to help with designing more effective treatments. This study aimed to determine whether 1,25(OH)2D3deficiency could cause cellular senescence and a senescence‐associated secretory phenotype (SASP) in skeletal muscle cells to induce sarcopenia, whether GATA4 could be upregulated by 1,25(OH)2D3deficiency to promote SASP, and whether Bmi‐1 reduces the expression of GATA4 and GATA4‐dependent SASP induced by 1,25(OH)2D3deficiency in skeletal muscle cells. Bioinformatics analyses with RNA sequencing data in skeletal muscle from physiologically aged and young mice were conducted. Skeletal muscles from 2‐month‐old young and 2‐year‐old physiologically aged wild‐type (WT) mice and 8‐week‐old WT, Bmi‐1 mesenchymal transgene (Bmi‐1Tg), Cyp27b1 homozygous (Cyp27b1−/−), and Bmi‐1TgCyp27b1−/−mice were observed for grip strength, cell senescence, DNA damage, and NF‐κB‐mediated SASP signaling of skeletal muscle. We found that muscle‐derived Bmi‐1 and vitamin D receptor (VDR) decreased with physiological aging, and DNA damage and GATA4‐dependent SASP activation led to sarcopenia. Furthermore, 1,25(OH)2D3deficiency promoted DNA damage‐induced GATA4 accumulation in muscles. GATA4 upregulated Rela at the region from −1448 to −1412 bp at the transcriptional level to cause NF‐κB‐dependent SASP for aggravating cell senescence and muscular dysfunction and sarcopenia. Bmi‐1 overexpression promoted the ubiquitination and degradation of GATA4 by binding RING1B, which prevented cell senescence, SASP, and dysfunctional muscle, and improved sarcopenia induced by 1,25(OH)2D3deficiency. Thus, Bmi‐1 overexpression improves sarcopenia induced by 1,25(OH)2D3deficiency, downregulates GATA4‐dependent Rela transcription, and sequentially inhibits GATA4‐dependent SASP in muscle cells. Therefore, Bmi‐1 overexpression could be used for translational gene therapy for the ubiquitination of GATA4 and prevention of sarcopenia. © 2023 American Society for Bone and Mineral Research (ASBMR).AbstractDNA double‐strand break (DSB) increased in the progress of sarcopenia caused by 1,25(OH)2D3deficiency, which contributed to the phosphorylation of ataxia telangiectasia‐mutated genes (ATM) and ataxia telangiectasia and Rad‐3‐related protein (ATR), and then caused DNA damage response (DDR). GATA4 was upregulated as a result of DDR, bound to the promoter region, and increased the transcriptional level of Rela. Bmi‐1 overexpression ameliorated sarcopenia in 1,25(OH)2D3‐deficient mice by promoting the ubiquitination and degradation of GATA4 by binding to RING1B and subsequently decreased Rela transcription, which inhibited NF‐κB‐p65 signaling‐mediated SASP.