Aerobic exercise training attenuates ischemia-reperfusion injury in mice by decreasing the methylation level of METTL3-associated m6A RNA in cardiomyocytes

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Life sciences Pub Date : 2025-01-15 DOI:10.1016/j.lfs.2024.123294

Xinmin Zhang , Dong-Xu Huang , Chengluan Xuan , Yanhui Li , Yuting Jiang , Xuehan Wu , Wenqian Zhou , Yang Lei , Fan Yang , Haichun Ma , Kun Hou , Xue Han , Guichen Li

{"title":"Aerobic exercise training attenuates ischemia-reperfusion injury in mice by decreasing the methylation level of METTL3-associated m6A RNA in cardiomyocytes","authors":"Xinmin Zhang , Dong-Xu Huang , Chengluan Xuan , Yanhui Li , Yuting Jiang , Xuehan Wu , Wenqian Zhou , Yang Lei , Fan Yang , Haichun Ma , Kun Hou , Xue Han , Guichen Li","doi":"10.1016/j.lfs.2024.123294","DOIUrl":null,"url":null,"abstract":"<div><h3>Background and aims</h3><div>Ischemic heart disease (IHD) presents a significant global health challenge, with myocardial ischemia-reperfusion injury (MIRI) being a major pathophysiological contributor and lacking effective interventions. While aerobic exercise training (AET) enhances cardiovascular health, its protective mechanism in MIRI remains elusive. This study aims to elucidate the protective effect of AET in MIRI and its underlying mechanism.</div></div><div><h3>Methods</h3><div>A mouse model of AET and MIRI was established to evaluate basic indices, cardiac ultrasound, and myocardial injury markers. Dot Blot, qRT-PCR, and Western blot were employed to assess m<sup>6</sup>A RNA methylation levels and related protein expression in myocardial tissue. In vitro, primary cardiomyocyte culture was utilized to mimic MIRI, evaluating cell viability, mitochondrial membrane potential, etc. Finally, myocardial tissues of MIRI mice were immunoprecipitated for m<sup>6</sup>A RNA methylation and sequenced to analyze related signaling pathways.</div></div><div><h3>Key results</h3><div>AET significantly improved cardiac function and mitigated myocardial injury and fibrosis. Moreover, AET protected myocardium from MIRI by reducing m<sup>6</sup>A RNA methylation levels and modulating METTL3 expression. In vitro experiments demonstrated that the decrease in m<sup>6</sup>A RNA methylation levels and METTL3 expression conferred resistance to hypoxia/reoxygenation-induced injury. Furthermore, sequencing results indicated elevated myocardial tissue m<sup>6</sup>A RNA methylation levels during MIRI, activation of the Nrf2-related signaling pathway, and AET-mediated regulation of the Nrf2/HO-1 signaling pathway, thereby attenuating MIRI through modulation of METTL3-related m<sup>6</sup>A methylation.</div></div><div><h3>Conclusion and significance</h3><div>AET attenuates MIRI by reducing the level of METTL3-related m<sup>6</sup>A RNA methylation in cardiomyocytes and activating the Nrf2/HO-1 antioxidant signaling pathway. This finding provides a novel insight and strategy for the prevention and treatment of IHD, holding significant clinical implications.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"361 ","pages":"Article 123294"},"PeriodicalIF":5.2000,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Life sciences","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0024320524008841","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}

引用次数: 0

Abstract

Background and aims

Ischemic heart disease (IHD) presents a significant global health challenge, with myocardial ischemia-reperfusion injury (MIRI) being a major pathophysiological contributor and lacking effective interventions. While aerobic exercise training (AET) enhances cardiovascular health, its protective mechanism in MIRI remains elusive. This study aims to elucidate the protective effect of AET in MIRI and its underlying mechanism.

Methods

A mouse model of AET and MIRI was established to evaluate basic indices, cardiac ultrasound, and myocardial injury markers. Dot Blot, qRT-PCR, and Western blot were employed to assess m⁶A RNA methylation levels and related protein expression in myocardial tissue. In vitro, primary cardiomyocyte culture was utilized to mimic MIRI, evaluating cell viability, mitochondrial membrane potential, etc. Finally, myocardial tissues of MIRI mice were immunoprecipitated for m⁶A RNA methylation and sequenced to analyze related signaling pathways.

Key results

AET significantly improved cardiac function and mitigated myocardial injury and fibrosis. Moreover, AET protected myocardium from MIRI by reducing m⁶A RNA methylation levels and modulating METTL3 expression. In vitro experiments demonstrated that the decrease in m⁶A RNA methylation levels and METTL3 expression conferred resistance to hypoxia/reoxygenation-induced injury. Furthermore, sequencing results indicated elevated myocardial tissue m⁶A RNA methylation levels during MIRI, activation of the Nrf2-related signaling pathway, and AET-mediated regulation of the Nrf2/HO-1 signaling pathway, thereby attenuating MIRI through modulation of METTL3-related m⁶A methylation.

Conclusion and significance

AET attenuates MIRI by reducing the level of METTL3-related m⁶A RNA methylation in cardiomyocytes and activating the Nrf2/HO-1 antioxidant signaling pathway. This finding provides a novel insight and strategy for the prevention and treatment of IHD, holding significant clinical implications.

Abstract Image

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

有氧运动训练通过降低心肌细胞中mettl3相关m6A RNA的甲基化水平来减轻小鼠缺血再灌注损伤。

背景和目的：缺血性心脏病（IHD）是一个重大的全球健康挑战，心肌缺血再灌注损伤（MIRI）是一个主要的病理生理因素，缺乏有效的干预措施。虽然有氧运动训练（AET）可以增强心血管健康，但其在MIRI中的保护机制尚不明确。本研究旨在阐明AET对MIRI的保护作用及其机制。方法：建立小鼠AET和MIRI模型，评价其基本指标、心脏超声及心肌损伤指标。采用Dot Blot、qRT-PCR和Western Blot检测心肌组织中m6A RNA甲基化水平及相关蛋白表达。体外，利用原代心肌细胞培养模拟MIRI，评估细胞活力、线粒体膜电位等。最后，对MIRI小鼠心肌组织进行m6A RNA甲基化免疫沉淀，并测序分析相关信号通路。关键结果：AET可显著改善心功能，减轻心肌损伤和纤维化。此外，AET通过降低m6A RNA甲基化水平和调节METTL3表达来保护心肌免受MIRI。体外实验表明，m6A RNA甲基化水平和METTL3表达的降低有助于抵抗缺氧/再氧诱导的损伤。此外，测序结果表明，MIRI期间心肌组织m6A RNA甲基化水平升高，Nrf2相关信号通路激活，aet介导的Nrf2/HO-1信号通路调节，从而通过调节mettl3相关m6A甲基化减弱MIRI。结论及意义：AET通过降低心肌细胞中mettl3相关的m6A RNA甲基化水平，激活Nrf2/HO-1抗氧化信号通路来减轻MIRI。这一发现为IHD的预防和治疗提供了新的见解和策略，具有重要的临床意义。

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

文献相关原料

公司名称

产品信息

索莱宝

BSA

索莱宝

eosin

索莱宝

hematoxylin

索莱宝

BSA

索莱宝

eosin

索莱宝

hematoxylin

来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.