Estrogen Stabilizes Interferon-Inducible Genes During Skeletal Muscle Regeneration

Background: Inflammation is essential for skeletal muscle repair following acute injury, and successful muscle regeneration requires a balance between pro- and anti-inflammatory signaling. Estrogen regulates inflammatory responses, suggesting a role in tissue repair. CD169+ macrophages are also associated with tissue repair. However, these cells and related interferon-inducible genes have not been investigated in regenerating muscle. Objective: To examine how 17β-estradiol treatment influences the expression and co-expression network of Siglec1 (encoding CD169), an interferon-inducible gene, during muscle regeneration. Methods: Ovariectomized mice received either 17β-estradiol or placebo before undergoing a standardized crush injury to hindlimb muscle groups and exposure to simulated flight. Mice were euthanized at 32-h, 96-h, or 192-h postinjury. Differential gene expression analysis was performed on injured muscles to assess treatment-related transcriptional changes, and additional muscles were evaluated for regeneration stage and CD169 protein expression. Results: At 192-h postinjury, Siglec1 was among the top upregulated genes in 17β-estradiol-treated mice relative to placebo mice, which reflected a decline in Siglec1 expression over time in the placebo group. Correlation analysis revealed that Siglec1 was strongly associated with interferon-related genes under placebo treatment, whereas the connectivity of Siglec1 under 17β-estradiol treatment was weakened. Immunohistochemistry confirmed stronger CD169 staining in regenerating muscle of 17β-estradiol-treated mice. Conclusion: Siglec1 expression is more stable in an estrogen state compared to an ovarian-hormone-deficient state. Understanding how estrogen deficiency alters inflammatory signaling after muscle injury may inform interventions to promote recovery in postmenopausal women, who may be at risk for impaired muscle repair.