Sex differences in mitochondrial gene expression during viral myocarditis.

IF 4.9 2区医学 Q1 ENDOCRINOLOGY & METABOLISM Biology of Sex Differences Pub Date : 2024-12-18 DOI:10.1186/s13293-024-00678-0

Damian N Di Florio, Gabriel J Weigel, David J Gorelov, Elizabeth J McCabe, Danielle J Beetler, Katie A Shapiro, Katelyn A Bruno, Isha Chekuri, Angita Jain, Emily R Whelan, Gary R Salomon, Sami Khatib, Natalie E Bonvie-Hill, Jessica J Fliess, Presley G Giresi, Charwan Hamilton, Cameron J Hartmoyer, Varsini Balamurugan, Ashley A Darakjian, Brandy H Edenfield, S Christian Kocsis, Christopher J McLeod, Leslie T Cooper, Étienne Audet-Walsh, Michael J Coronado, Jon Sin, DeLisa Fairweather

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Abstract

Background: Myocarditis is an inflammation of the heart muscle most often caused by viral infections. Sex differences in the immune response during myocarditis have been well described but upstream mechanisms in the heart that might influence sex differences in disease are not completely understood.

Methods: Male and female BALB/c wild type mice received an intraperitoneal injection of heart-passaged coxsackievirus B3 (CVB3) or vehicle control. Bulk-tissue RNA-sequencing was conducted to better understand sex differences in CVB3 myocarditis. We performed enrichment analysis and functional validation to understand sex differences in the transcriptional landscape of myocarditis and identify factors that might drive sex differences in myocarditis.

Results: As expected, the hearts of male and female mice with myocarditis were significantly enriched for pathways related to an innate and adaptive immune response compared to uninfected controls. Unique to this study, we found that males were enriched for inflammatory pathways and gene changes that suggested worse mitochondrial electron transport function while females were enriched for pathways related to mitochondrial homeostasis. Mitochondria isolated from the heart of males were confirmed to have worse mitochondrial respiration than females during myocarditis. Unbiased TRANSFAC analysis identified estrogen-related receptor alpha (ERRα) as a transcription factor that may mediate sex differences in mitochondrial function during myocarditis. Transcript and protein levels of ERRα were confirmed as elevated in females with myocarditis compared to males. Differential binding analysis from chromatin immunoprecipitation (ChIP) sequencing confirmed that ERRα bound highly to select predicted respiratory chain genes in females more than males during myocarditis.

Conclusions: Females with viral myocarditis regulate mitochondrial homeostasis by upregulating master regulators of mitochondrial transcription including ERRα.

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病毒性心肌炎期间线粒体基因表达的性别差异。

背景：心肌炎是一种心肌炎症，通常由病毒感染引起。心肌炎期间免疫反应的性别差异已被很好地描述，但心脏中可能影响疾病性别差异的上游机制尚未完全了解。方法：雄性和雌性BALB/c野生型小鼠腹腔注射心脏传代柯萨奇病毒B3 （CVB3）或对照。为了更好地了解CVB3型心肌炎的性别差异，进行了大组织rna测序。我们进行了富集分析和功能验证，以了解心肌炎转录格局中的性别差异，并确定可能导致心肌炎性别差异的因素。结果：正如预期的那样，与未感染的对照组相比，患有心肌炎的雄性和雌性小鼠的心脏中与先天和适应性免疫反应相关的途径显著丰富。这项研究的独特之处在于，我们发现雄性的炎症途径和基因变化丰富，这表明线粒体电子传递功能较差，而雌性的线粒体稳态相关途径丰富。证实心肌炎期间，从男性心脏分离的线粒体比女性有更差的线粒体呼吸。无偏倚的TRANSFAC分析发现，雌激素相关受体α (ERRα)是一种转录因子，可能介导心肌炎期间线粒体功能的性别差异。与男性相比，女性心肌炎患者的ERRα转录物和蛋白水平被证实升高。染色质免疫沉淀（ChIP）测序的差异结合分析证实，在心肌炎期间，ERRα在女性中比男性更多地高度结合以选择预测的呼吸链基因。结论：病毒性心肌炎女性通过上调包括ERRα在内的线粒体转录主调控因子来调节线粒体稳态。

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

Biology of Sex Differences ENDOCRINOLOGY & METABOLISM-GENETICS & HEREDITY

CiteScore

12.10

自引率

1.30%

发文量

审稿时长

14 weeks

期刊介绍： Biology of Sex Differences is a unique scientific journal focusing on sex differences in physiology, behavior, and disease from molecular to phenotypic levels, incorporating both basic and clinical research. The journal aims to enhance understanding of basic principles and facilitate the development of therapeutic and diagnostic tools specific to sex differences. As an open-access journal, it is the official publication of the Organization for the Study of Sex Differences and co-published by the Society for Women's Health Research. Topical areas include, but are not limited to sex differences in: genomics; the microbiome; epigenetics; molecular and cell biology; tissue biology; physiology; interaction of tissue systems, in any system including adipose, behavioral, cardiovascular, immune, muscular, neural, renal, and skeletal; clinical studies bearing on sex differences in disease or response to therapy.