# Functions of skeletal muscle mineralocorticoid receptor signaling in chronic and acute injury

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $404,388

## Abstract

PROJECT SUMMARY
Mineralocorticoid receptor antagonists are FDA-approved drugs that have a long history of safety and
efficacy for treating heart failure. These drugs block activation of mineralocorticoid receptors (MR) by
the endogenous mineralocorticoid aldosterone and prevent these steroid hormone receptors from
translocating to the nucleus and regulating gene transcription. Chronic overactivation of MR by the
natural hormone aldosterone is known to exacerbate cell damage in cardiovascular diseases. We have
repeatedly demonstrated that treatment with a MR antagonist plus an angiotensin converting enzyme
inhibitor, which acts upstream to inhibit aldosterone production, have therapeutic benefits on both heart
and skeletal muscles in mouse models of Duchenne muscular dystrophy. The observed preclinical
efficacy of MR antagonists on dystrophic skeletal muscle function and pathology was a surprise, given
that MR had never been identified in skeletal muscles. We have now demonstrated that MR are
present in skeletal muscles and function in gene expression. We have also shown that MR antagonists
prevent ongoing dystrophic muscle damage, supporting these drugs act at an early stage of the
pathogenic process. Inflammatory cells present in damaged muscles contain high levels of the enzyme
required for aldosterone synthesis and increased levels of aldosterone may contribute to chronic
muscle damage in muscular dystrophy. Efficacy of drugs that prevent activation of MR in muscular
dystrophy models and the presence of local aldosterone production during chronic and acute skeletal
muscle injuries support the scientific premise that MR may be a therapeutic target for chronic skeletal
muscle diseases and acute injuries. However, the role of mineralocorticoid receptors in normal skeletal
muscle function and pathogenesis is not known. In this application, we will use a genetic approach to
dissect MR functions and downstream molecular mechanisms in acute and chronic muscle injuries.
Information about the role of these receptors in skeletal muscle will provide the basis for modulating MR
as a therapeutic target for a wide variety of muscle pathologies.

## Key facts

- **NIH application ID:** 9888322
- **Project number:** 5R01AR072574-03
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Jill A Rafael-Fortney
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $404,388
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9888322

## Citation

> US National Institutes of Health, RePORTER application 9888322, Functions of skeletal muscle mineralocorticoid receptor signaling in chronic and acute injury (5R01AR072574-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9888322. Licensed CC0.

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