Faculty, Staff and Student Publications
Publication Date
2-4-2025
Journal
Journal of Clinical Investigation
Abstract
Fibrosis of the lower abdominal muscle (LAM) contributes to muscle weakening and inguinal hernia formation, an ailment that affects a noteworthy 50% of men by age 75 and necessitates surgical correction as the singular therapy. Despite its prevalence, the mechanisms driving LAM fibrosis and hernia development remain poorly understood. Using a humanized mouse model that replicates the elevated skeletal muscle tissue estrogen concentrations seen in aging men, we identified estrogen receptor-α (ESR1) as a key driver of LAM fibroblast proliferation, extracellular matrix deposition, and hernia formation. Fibroblast-specific ESR1 ablation effectively prevented muscle fibrosis and herniation, while pharmacological ESR1 inhibition with fulvestrant reversed hernias and restored normal muscle architecture. Multiomics analyses of in vitro LAM fibroblasts from humanized mice unveiled an estrogen/ESR1-mediated activation of a distinct profibrotic cistrome and gene expression signature, concordant with observations in inguinal hernia tissues in human males. Our findings hold significant promise for prospective medical interventions targeting fibrotic conditions and present non-surgical avenues for addressing inguinal hernias.
Keywords
Animals, Mice, Estrogen Receptor alpha, Fibrosis, Hernia, Inguinal, Humans, Male, Fibroblasts, Female, Mice, Knockout, Cell biology, Muscle biology, Reproductive biology, Fibrosis, Sex hormones, Skeletal muscle
DOI
10.1172/JCI179137
PMID
39903526
PMCID
PMC11910215
PubMedCentral® Posted Date
2-4-2025
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes