Sex differences in mitochondrial gene expression during viral myocarditis

Area of Science:

• Cardiovascular Research
• Immunology
• Mitochondrial Biology

Background:

• Myocarditis, often viral, causes heart muscle inflammation.
• While immune response sex differences are known, upstream cardiac mechanisms remain unclear.

Purpose of the Study:

• To investigate sex differences in the transcriptional landscape of coxsackievirus B3 (CVB3)-induced myocarditis.
• To identify molecular factors driving sex-specific differences in myocarditis pathogenesis.

Main Methods:

• Male and female BALB/c mice were infected with CVB3 or vehicle.
• Bulk-tissue RNA-sequencing and functional assays were performed.
• Enrichment analysis, TRANSFAC, and ChIP-sequencing identified key regulatory factors.

Main Results:

• Both sexes showed immune response enrichment; males had heightened inflammation and impaired mitochondrial electron transport.
• Females exhibited pathways related to mitochondrial homeostasis.
• Estrogen-related receptor alpha (ERRα) was identified as a key regulator, upregulated in females and binding to respiratory chain genes.

Conclusions:

• Female mice utilize ERRα to upregulate mitochondrial transcription and maintain homeostasis during viral myocarditis.
• This study elucidates a novel sex-specific mechanism in viral myocarditis, involving ERRα-mediated mitochondrial regulation in females.