# Interaction of estrogen, age, and activity on musculoskeletal strength in females > **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2024 · $595,136 ## Abstract Strength loss occurs with age affecting quality of life and impinges upon healthspan. 17β-estradiol (E2) deficiency in females also causes strength loss. The overall goal of this project is to determine the cellular and molecular mechanisms through which E2 deficiency perturbs skeletal muscle and contractile functions with age. The sole focus of our research has been on aging females and in this competitive renewal submission, we also seek to determine mechanisms of E2 in male muscle as the impact of estrogens in male non- reproductive physiology is becoming increasingly recognized. Results from the previous funding periods have led to novel hypotheses outlined in this proposal. Specifically, Aim 1 tests the hypothesis that E2 signals through estrogen receptor α (ERα) and the G protein-coupled ER (GPER) in skeletal muscle to enhance dynamic strength in male as well as female mice. We use genetic, surgical, and pharmacologic approaches to probe both the ligand and receptor sides of E2-ER signaling. We pair this approach with comprehensive in vivo and in vitro measures of muscle contractile functions to elucidate mechanisms and determine the long- term consequence of E2-ER disruption in muscle. While the particular muscle proteins to be analyzed in the first aim are guided by specific contractile outcomes that are affected by E2-ER signaling, Aim 2 takes an unbiased approach to quantitate phosphoproteins that are critical for strength yet altered in aged and E2- deficient muscle. This will be accomplished through the development of a novel parallel reaction monitoring (PRM) assay with computational modeling, which is based on our global phosphoproteomic work that identified differentially expressed phospho-peptides related to calcium signaling and contractile proteins in several E2-replete vs E2-deficient muscle conditions. Our customized PRM assay will further predict candidate E2-sensitive kinases that will be validated in high-throughput assays to yield potential gerotherapeutic targets for preserving muscle strength with age. It has been shown that 17alpha-E2, the minor and weak epimer of E2, extends lifespan and improves several characteristics of healthspan in male mice. Aim 3 is designed to test the hypothesis that skeletal muscle will be enhanced by 17alpha-E2 in both aged males and females through activation of ERα and downstream signaling. This aim brings forth the intriguing prospect that 17alpha-E2 is a non-feminizing geroprotector that extends healthspan by supporting muscle strength and thus physical activity, movement, and quality of life. Accomplishing these three aims will solidify that change in sex hormones and their receptors is one of the pleiotropic mechanisms underlying muscle weakness with age and addresses the long-term goal of our research program, which is to determine estrogenic mechanisms that preserve strength with aging, regardless of sex. ## Key facts - **NIH application ID:** 10985655 - **Project number:** 2R01AG031743-16A1 - **Recipient organization:** UNIVERSITY OF MINNESOTA - **Principal Investigator:** DAWN A LOWE - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $595,136 - **Award type:** 2 - **Project period:** 2009-02-01 → 2029-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10985655 ## Citation > US National Institutes of Health, RePORTER application 10985655, Interaction of estrogen, age, and activity on musculoskeletal strength in females (2R01AG031743-16A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10985655. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*