病毒性心肌炎期间线粒体基因表达的性别差异。

Sex differences in mitochondrial gene expression during viral myocarditis.

作者信息

Di Florio Damian, Gorelov David, McCabe Elizabeth, Beetler Danielle, Shapiro Katie, Bruno Katelyn, Chekuri Isha, Jain Angita, Whelan Emily, Salomon Gary, Khatib Sami, Bonvie-Hill Natalie, Giresi Presley, Balamurugan Varsini, Weigel Gabriel, Fliess Jessica, Darakjian Ashley, Edenfield Brandy, Kocsis Christian, McLeod Christopher, Cooper Leslie, Audet-Walsh Etienne, Coronado Michael, Sin Jon, Fairweather DeLisa

机构信息

Mayo Clinic in Florida.

University of Florida.

出版信息

Res Sq. 2023 Dec 19:rs.3.rs-3716881. doi: 10.21203/rs.3.rs-3716881/v1.

DOI:10.21203/rs.3.rs-3716881/v1

PMID:38196574

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10775395/

Abstract

BACKGROUND

Myocarditis is an inflammation of the heart muscle most often caused by an immune response to 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 to understand sex differences in the transcriptional landscape of myocarditis and identify candidate transcription factors that might drive sex differences in myocarditis.

RESULTS

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. When comparing females to males with myocarditis, males were enriched for inflammatory pathways and gene changes that suggested worse mitochondrial transcriptional support (e.g., mitochondrial electron transport genes). In contrast, females were enriched for pathways related to mitochondrial respiration and bioenergetics, which were confirmed by higher transcript levels of master regulators of mitochondrial function including peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1α), nuclear respiratory factor 1 (NRF1) and estrogen-related receptor alpha (ERRα). TRANSFAC analysis identified ERRa as a transcription factor that may mediate sex differences in mitochondrial function during myocarditis.

CONCLUSIONS

Master regulators of mitochondrial function were elevated in females with myocarditis compared to males and may promote sex differences in mitochondrial respiratory transcript expression during viral myocarditis resulting in less severe myocarditis in females following viral infection.

摘要

背景

心肌炎是一种心肌炎症，最常见的病因是对病毒感染的免疫反应。心肌炎期间免疫反应的性别差异已有充分描述，但心脏中可能影响疾病性别差异的上游机制尚未完全明确。

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）或赋形剂对照。进行批量组织RNA测序以更好地了解CVB3心肌炎中的性别差异。我们进行了富集分析，以了解心肌炎转录图谱中的性别差异，并确定可能驱动心肌炎性别差异的候选转录因子。

结果

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性和适应性免疫反应相关的通路显著富集。将患有心肌炎的雌性与雄性进行比较时，雄性中与炎症通路和基因变化相关的基因富集，这表明线粒体转录支持较差（例如线粒体电子传递基因）。相比之下，雌性中与线粒体呼吸和生物能量学相关的通路富集，这通过线粒体功能主要调节因子的较高转录水平得到证实，包括过氧化物酶体增殖物激活受体γ辅激活因子1（PGC1α）、核呼吸因子1（NRF1）和雌激素相关受体α（ERRα）。TRANSFAC分析确定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。