Inhibition of the expression of TRIM63 alleviates ventilator-induced diaphragmatic dysfunction by modulating the PPARα/PGC-1α pathway

IF 4.5 3区生物学 Q2 CELL BIOLOGY Mitochondrion Pub Date : 2025-07-01 Epub Date: 2025-03-04 DOI:10.1016/j.mito.2025.102025

Jun Liu , Yuhan Chen , Dong Han , Ming Huang

{"title":"Inhibition of the expression of TRIM63 alleviates ventilator-induced diaphragmatic dysfunction by modulating the PPARα/PGC-1α pathway","authors":"Jun Liu , Yuhan Chen , Dong Han , Ming Huang","doi":"10.1016/j.mito.2025.102025","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Ventilator-induced diaphragmatic dysfunction (VIDD) significantly affects the prognosis of critically ill patients and has attracted considerable attention. Tripartite motif-containing protein 63 (TRIM63) plays a pivotal role in muscle protein degradation and muscle mass regulation. Its overexpression is closely associated with VIDD; however, data on the specific effects of TRIM63 on this pathological process remain insufficient.</div></div><div><h3>Objectives</h3><div>The aim of this study is to elucidate the role of TRIM63 in VIDD and to assess the correlation between the TRIM63-peroxisome proliferator activated receptor α (PPARα)/PPAR gamma coactivator (PGC-1α) pathway and mitochondrial function.</div></div><div><h3>Methods</h3><div>Specific pathogen-free grade female Wistar rats were divided into four groups: Sham + NS, Sham + MyoMed-205, MV + NS, and MV + MyoMed-205. The inhibitor group received MyoMed-205 to suppress the expression of TRIM63. After the experiment, diaphragmatic contractility, mitochondrial structure and function, oxidative stress levels, autophagy, apoptosis, and the involvement of the PPARα/PGC-1α pathway were evaluated.</div></div><div><h3>Results</h3><div>Our findings indicated that inhibiting TRIM63 prevented mechanical ventilation (MV)-induced diaphragmatic contractile dysfunction and atrophy. Mechanistically, inhibition of the expression of TRIM63 resulted in significant upregulation of the PPARα and PGC-1α expression levels, improved mitochondrial dynamics, enhanced the mitochondrial membrane potential, and reduced mitophagy and apoptosis. Structurally, inhibition of the expression of TRIM63 ameliorated MV-induced mitochondrial fragmentation, fusion, and fission.</div></div><div><h3>Conclusions</h3><div>The upregulated expression of TRIM63 in VIDD exacerbated mitochondrial damage by inhibiting the PPARα/PGC-1α signaling pathway, leading to increased reactive oxygen species, mitophagy, and apoptosis. Inhibition of the expression of TRIM63 enhanced mitochondrial function, decreased mitophagy and apoptosis, and mitigated VIDD. Thus, TRIM63 may serve as a potential target for the prevention and treatment of VIDD.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"83 ","pages":"Article 102025"},"PeriodicalIF":4.5000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Mitochondrion","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1567724925000224","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/3/4 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Background

Ventilator-induced diaphragmatic dysfunction (VIDD) significantly affects the prognosis of critically ill patients and has attracted considerable attention. Tripartite motif-containing protein 63 (TRIM63) plays a pivotal role in muscle protein degradation and muscle mass regulation. Its overexpression is closely associated with VIDD; however, data on the specific effects of TRIM63 on this pathological process remain insufficient.

Objectives

The aim of this study is to elucidate the role of TRIM63 in VIDD and to assess the correlation between the TRIM63-peroxisome proliferator activated receptor α (PPARα)/PPAR gamma coactivator (PGC-1α) pathway and mitochondrial function.

Methods

Specific pathogen-free grade female Wistar rats were divided into four groups: Sham + NS, Sham + MyoMed-205, MV + NS, and MV + MyoMed-205. The inhibitor group received MyoMed-205 to suppress the expression of TRIM63. After the experiment, diaphragmatic contractility, mitochondrial structure and function, oxidative stress levels, autophagy, apoptosis, and the involvement of the PPARα/PGC-1α pathway were evaluated.

Results

Our findings indicated that inhibiting TRIM63 prevented mechanical ventilation (MV)-induced diaphragmatic contractile dysfunction and atrophy. Mechanistically, inhibition of the expression of TRIM63 resulted in significant upregulation of the PPARα and PGC-1α expression levels, improved mitochondrial dynamics, enhanced the mitochondrial membrane potential, and reduced mitophagy and apoptosis. Structurally, inhibition of the expression of TRIM63 ameliorated MV-induced mitochondrial fragmentation, fusion, and fission.

Conclusions

The upregulated expression of TRIM63 in VIDD exacerbated mitochondrial damage by inhibiting the PPARα/PGC-1α signaling pathway, leading to increased reactive oxygen species, mitophagy, and apoptosis. Inhibition of the expression of TRIM63 enhanced mitochondrial function, decreased mitophagy and apoptosis, and mitigated VIDD. Thus, TRIM63 may serve as a potential target for the prevention and treatment of VIDD.

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

抑制TRIM63表达可通过调节PPARα/PGC-1α通路减轻呼吸机诱导的膈功能障碍。

背景：呼吸机诱发的膈肌功能障碍（VIDD）显著影响危重患者的预后，已引起人们的广泛关注。Tripartite motif-containing protein 63 （TRIM63）在肌肉蛋白降解和肌肉质量调节中起关键作用。其过表达与VIDD密切相关；然而，关于TRIM63在这一病理过程中的具体作用的数据仍然不足。目的：本研究旨在阐明TRIM63在VIDD中的作用，并评估TRIM63-过氧化物酶体增殖物激活受体α (PPARα)/PPAR γ辅激活因子（PGC-1α）通路与线粒体功能的相关性。方法：将特异性无致病性级雌性Wistar大鼠分为4组：Sham + NS、Sham + MyoMed-205、MV + NS、MV + MyoMed-205。抑制剂组给予MyoMed-205，抑制TRIM63的表达。实验结束后，观察大鼠膈肌收缩力、线粒体结构和功能、氧化应激水平、自噬、细胞凋亡以及PPARα/PGC-1α通路的参与情况。结果：我们的研究结果表明，抑制TRIM63可预防机械通气（MV）引起的膈肌收缩功能障碍和萎缩。机制上，抑制TRIM63表达可显著上调PPARα和PGC-1α表达水平，改善线粒体动力学，增强线粒体膜电位，减少线粒体自噬和凋亡。在结构上，抑制TRIM63的表达改善了mv诱导的线粒体断裂、融合和裂变。结论：TRIM63在VIDD中的表达上调通过抑制PPARα/PGC-1α信号通路加重线粒体损伤，导致活性氧增加、线粒体自噬增加和细胞凋亡。抑制TRIM63的表达可增强线粒体功能，减少线粒体自噬和凋亡，减轻VIDD。因此，TRIM63可能作为预防和治疗VIDD的潜在靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Mitochondrion 生物-细胞生物学

CiteScore

9.40

自引率

4.50%

发文量

审稿时长

13.6 weeks

期刊介绍： Mitochondrion is a definitive, high profile, peer-reviewed international research journal. The scope of Mitochondrion is broad, reporting on basic science of mitochondria from all organisms and from basic research to pathology and clinical aspects of mitochondrial diseases. The journal welcomes original contributions from investigators working in diverse sub-disciplines such as evolution, biophysics, biochemistry, molecular and cell biology, genetics, pharmacology, toxicology, forensic science, programmed cell death, aging, cancer and clinical features of mitochondrial diseases.