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
{"title":"Sex differences in mitochondrial gene expression during viral myocarditis.","authors":"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","doi":"10.1186/s13293-024-00678-0","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>Females with viral myocarditis regulate mitochondrial homeostasis by upregulating master regulators of mitochondrial transcription including ERRα.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"15 1","pages":"104"},"PeriodicalIF":4.9000,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biology of Sex Differences","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13293-024-00678-0","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0
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.
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.
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