# Estrogen and Abdominal Muscle Fibrosis

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $600,299

## Abstract

Although more than 1 in 4 men can be expected to develop symptomatic inguinal hernia, its mechanism is
currently unknown. A subset of hernias may develop due to muscle fibrosis and myofiber atrophy leading to
lower abdominal wall weakness. The long-term objective of this application is to determine the role of estrogen
action in the etiology of lower abdominal muscle tissue (LAMT) fibrosis and atrophy associated with a subset of
inguinal hernias. Aromatase, which converts testosterone to estradiol, is expressed only in the brain and testes
of male mice. However, in men, aromatase is expressed in many additional tissues (muscle, fat) to provide
physiologically necessary local quantities of estrogen. We generated transgenic humanized aromatase
(Aromhum) mouse lines, each containing a single copy of the full-length human aromatase gene including its
regulatory region, to mimic human patterns of estrogen production. Aromhum mice express the aromatase gene
in peripheral tissues including the fibroblast component of the skeletal muscle tissue. LAMT has been found to
be more sensitive to estradiol than the upper abdominal or quadriceps muscles, because the stroma of LAMT
contains strikingly larger amounts of estrogen receptor- (ER)-expressing fibroblasts. Locally increased
concentrations of estradiol in LAMT was associated with LAMT fibrosis characterized by progressive
replacement of atrophic myocytes (muscle fibers) with ER-rich fibroblasts and excessive extracellular matrix,
resulting in formation of large inguinal hernias in >90% of Aromhum male mice by 24 weeks. However, there
were no hernias observed in any of the wild-type (WT) littermates. Microarray expression analysis of LAMT at
four weeks (before the appearance of hernias) showed activated profibrotic pathways in Aromhum vs. WT mice.
We hypothesize that enhanced estrogen action caused by locally formed estradiol drives muscle fibrosis and
myocyte atrophy, leading to the hernia phenotype affecting highly estrogen-sensitive portions of skeletal
muscle tissue, which is LAMT in Aromhum mice. This resonates with the remarkable and parallel increases in
inguinal hernia incidence and increased aromatase expression in skeletal muscle and fat in aging men. To
ascertain the underlying mechanisms, we propose the following aims: 1. Determine whether treatment with an
aromatase inhibitor, an estradiol antagonist, or a highly selective ERα antagonist prevents fibrosis, LAMT
muscle atrophy, and hernia formation in Aromhum mice. The estradiol/ER-mediated genomic mechanisms
responsible for disordered proliferation of fibroblasts and extracellular matrix formation will be determined using
integrative analysis of RNA-seq and ER-ChIP-seq on LAMT and fibroblasts. 2. Determine whether the
genetic disruption of ER selectively in skeletal muscle fibroblasts affects LAMT fibrosis and hernia formation
in Aromhum mice. In parallel, we will assess tissue steroid levels, aromatase and ERexpression, and estrogen
r...

## Key facts

- **NIH application ID:** 9916751
- **Project number:** 5R01DK121529-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Serdar E. Bulun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $600,299
- **Award type:** 5
- **Project period:** 2019-04-16 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9916751

## Citation

> US National Institutes of Health, RePORTER application 9916751, Estrogen and Abdominal Muscle Fibrosis (5R01DK121529-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9916751. Licensed CC0.

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