Identification of the co-differentially expressed hub genes involved in the endogenous protective mechanism against ventilator-induced diaphragm dysfunction.

IF 5.3 2区医学 Q2 CELL BIOLOGY Skeletal Muscle Pub Date : 2022-09-09 DOI:10.1186/s13395-022-00304-w

Dong Zhang, Wenyan Hao, Qi Niu, Dongdong Xu, Xuejiao Duan

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Abstract

Background: In intensive care units (ICU), mechanical ventilation (MV) is commonly applied to save patients' lives. However, ventilator-induced diaphragm dysfunction (VIDD) can complicate treatment by hindering weaning in critically ill patients and worsening outcomes. The goal of this study was to identify potential genes involved in the endogenous protective mechanism against VIDD.

Methods: Twelve adult male rabbits were assigned to either an MV group or a control group under the same anesthetic conditions. Immunostaining and quantitative morphometry were used to assess diaphragm atrophy, while RNA-seq was used to investigate molecular differences between the groups. Additionally, core module and hub genes were analyzed using WGCNA, and co-differentially expressed hub genes were subsequently discovered by overlapping the differentially expressed genes (DEGs) with the hub genes from WGCNA. The identified genes were validated by western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR).

Results: After a VIDD model was successfully built, 1276 DEGs were found between the MV and control groups. The turquoise and yellow modules were identified as the core modules, and Trim63, Fbxo32, Uchl1, Tmprss13, and Cst3 were identified as the five co-differentially expressed hub genes. After the two atrophy-related genes (Trim63 and Fbxo32) were excluded, the levels of the remaining three genes/proteins (Uchl1/UCHL1, Tmprss13/TMPRSS13, and Cst3/CST3) were found to be significantly elevated in the MV group (P < 0.05), suggesting the existence of a potential antiproteasomal, antiapoptotic, and antiautophagic mechanism against diaphragm dysfunction.

Conclusion: The current research helps to reveal a potentially important endogenous protective mechanism that could serve as a novel therapeutic target against VIDD.

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鉴定参与呼吸机诱导膈肌功能障碍内源性保护机制的共差异表达枢纽基因。

背景:在重症监护病房(ICU)，机械通气(MV)是常用的挽救患者生命的手段。然而，呼吸机诱发的隔膜功能障碍(VIDD)会阻碍危重患者的脱机并恶化预后，从而使治疗复杂化。本研究的目的是确定参与内源性抗VIDD保护机制的潜在基因。方法:选取成年雄性家兔12只，在相同麻醉条件下分为MV组和对照组。采用免疫染色和定量形态测定法评估膈肌萎缩，采用RNA-seq法研究各组间的分子差异。此外，使用WGCNA分析核心模块和枢纽基因，随后通过将差异表达基因(deg)与WGCNA中的枢纽基因重叠，发现了共差异表达的枢纽基因。经western blotting (WB)和定量实时聚合酶链反应(qRT-PCR)验证所鉴定的基因。结果:成功建立VIDD模型后，MV组与对照组之间差异1276个deg。绿松石色和黄色模块被鉴定为核心模块，Trim63、Fbxo32、Uchl1、Tmprss13和Cst3被鉴定为5个共差异表达的枢纽基因。在排除这两个萎缩相关基因(Trim63和Fbxo32)后，其余3个基因/蛋白(Uchl1/ Uchl1、Tmprss13/ Tmprss13、Cst3/ Cst3)在MV组中表达水平显著升高(P < 0.05)，提示膈肌功能障碍存在潜在的抗蛋白酶体、抗凋亡和抗自噬机制。结论:本研究有助于揭示一种潜在的重要内源性保护机制，该机制可能作为治疗VIDD的新靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Skeletal Muscle CELL BIOLOGY-

CiteScore

9.10

自引率

0.00%

发文量

审稿时长

12 weeks

期刊介绍： The only open access journal in its field, Skeletal Muscle publishes novel, cutting-edge research and technological advancements that investigate the molecular mechanisms underlying the biology of skeletal muscle. Reflecting the breadth of research in this area, the journal welcomes manuscripts about the development, metabolism, the regulation of mass and function, aging, degeneration, dystrophy and regeneration of skeletal muscle, with an emphasis on understanding adult skeletal muscle, its maintenance, and its interactions with non-muscle cell types and regulatory modulators. Main areas of interest include: -differentiation of skeletal muscle- atrophy and hypertrophy of skeletal muscle- aging of skeletal muscle- regeneration and degeneration of skeletal muscle- biology of satellite and satellite-like cells- dystrophic degeneration of skeletal muscle- energy and glucose homeostasis in skeletal muscle- non-dystrophic genetic diseases of skeletal muscle, such as Spinal Muscular Atrophy and myopathies- maintenance of neuromuscular junctions- roles of ryanodine receptors and calcium signaling in skeletal muscle- roles of nuclear receptors in skeletal muscle- roles of GPCRs and GPCR signaling in skeletal muscle- other relevant aspects of skeletal muscle biology. In addition, articles on translational clinical studies that address molecular and cellular mechanisms of skeletal muscle will be published. Case reports are also encouraged for submission. Skeletal Muscle reflects the breadth of research on skeletal muscle and bridges gaps between diverse areas of science for example cardiac cell biology and neurobiology, which share common features with respect to cell differentiation, excitatory membranes, cell-cell communication, and maintenance. Suitable articles are model and mechanism-driven, and apply statistical principles where appropriate; purely descriptive studies are of lesser interest.