Sex differences in mitochondrial gene expression during viral myocarditis
Bibliographic record
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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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".