Sex differences in mitochondrial gene expression during viral myocarditis.

Autor: Di Florio, Damian N., Weigel, Gabriel J., Gorelov, David J., McCabe, Elizabeth J., Beetler, Danielle J., Shapiro, Katie A., Bruno, Katelyn A., Chekuri, Isha, Jain, Angita, Whelan, Emily R., Salomon, Gary R., Khatib, Sami, Bonvie-Hill, Natalie E., Fliess, Jessica J., Giresi, Presley G., Hamilton, Charwan, Hartmoyer, Cameron J., Balamurugan, Varsini, Darakjian, Ashley A., Edenfield, Brandy H.
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Zdroj: Biology of Sex Differences; 12/18/2024, Vol. 15 Issue 1, p1-27, 27p
Abstrakt: 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. Plain English summary: Many viruses can infect the heart. Immune cells go to the heart to get rid of the virus but sometimes this response can damage the heart. When immune cells go to the heart it is called "myocarditis," which means 'myo' for muscle and 'carditis' for heart inflammation. More men get myocarditis after viral infections than women. When we study viral infection in mice as a model of human disease, we see the same sex differences as in humans. To know why this happens, we gave mice a viral infection and looked at how their hearts changed. We found that a special gene acts like a light switch to turn on the genes that help cell energy factories called "mitochondria." Females used this light switch to turn on the genes that help mitochondria, but males did not and turned most of these genes off. We learned that the light switch works better in females compared to males, so it may play an important role in protecting female's hearts during myocarditis. More research is needed to better understand how this light switch works. Understanding how to turn on mitochondria genes in the heart could help doctors also do this in men after a viral infection to prevent myocarditis and save patients' lives. Highlights: • Females maintain mitochondrial homeostasis with less severe myocarditis. • Several master regulators of mitochondrial homeostasis are elevated in females. • Transcription factor ERRα RNA and protein are elevated in female hearts. • ERRα binds mitochondrial genes more in females during myocarditis. [ABSTRACT FROM AUTHOR]
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