# Interaction of estrogen, age, and activity on musculoskeletal strength in females

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2021 · $475,480

## Abstract

Age-induced strength loss, dynapenia, is accentuated in females due to estradiol (E2) deficiency that naturally
occurs with aging. The overall goal of this project remains on determining the cellular and molecular
mechanisms through which E2 deficiency perturbs muscle and myosin contractile functions and how E2
improves strength in aging females. This is a competitive renewal submission of a funded proposal that
continues to produce exciting discoveries and numerous publications. Results from the previous funding
periods have led to the novel hypotheses outlined in this proposal. Aim 1 tests the hypothesis that E2
deficiency causes loss of muscle strength due to compromised phosphorylation of contractile proteins
impairing force generation as well as affecting the myosin super relaxed state during relaxation. Furthermore, it
is predicted that treatment with physiological levels of E2 rescues strength through activation of the α estrogen
receptor (ERα) and the G protein ER (GPER) and downstream activation of key kinases. Innovative in vivo
experimental approaches and contemporary phosphoproteomics techniques, combined with manipulation of E2
and ERs pharmacologically, surgically, and genetically will be used to deduce estrogenic mechanisms acting
on aging muscle. Skeletal muscle endures repetitive injury throughout life and aging as well as E2 deficiency
impair the recovery of strength following such injury. In Aim 2, a systematic review and meta-analysis of the
literature paired with experimental testing of E2 treatment in ovariectomized adult and ovarian-senescent, aged
mice will address the hypothesis that muscle inflammation, necessary for recovery of strength from injury, is
enhanced with physiological levels of E2 but blunted with supraphysiological levels. Aim 2 also tests the
hypothesis that E2 deficiency disrupts neutrophil functions in injured muscle, and will utilize state-of-the-art
mass cytometry (CyTOF) to determine E2 responsiveness of other inflammatory cells in injured muscle,
identifying those cells that release E2-sensitive chemokines/cytokines as well. Completion of these aims will
culminate in substantial contributions to our knowledge of aging skeletal muscle, especially in females.
Specifically, results will provide clinically-relevant information about estrogenic treatments beyond those for
reproductive tissues with the goal of understanding how E2 can most effectively maintain muscle strength and
movement quality in aging women.

## Key facts

- **NIH application ID:** 10112787
- **Project number:** 5R01AG031743-13
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** DAWN A LOWE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $475,480
- **Award type:** 5
- **Project period:** 2009-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112787

## Citation

> US National Institutes of Health, RePORTER application 10112787, Interaction of estrogen, age, and activity on musculoskeletal strength in females (5R01AG031743-13). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10112787. Licensed CC0.

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