# Leveraging senotherapeutic properties of metformin to improve collagen remodeling during muscle regrowth in older adults

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $635,090

## Abstract

Abstract
A hallmark of aging is an impaired ability to adequately recover following a stressor, such as muscle disuse,
resulting in muscle fibrosis and weakness thereby increasing the risk for falls and loss of independence.
Mechanistic-based therapeutic strategies to enhance muscle recovery in older adults do not exist. Synchronized
muscle interstitial cellular events involving immune cells (e.g., macrophages), fibro-adipogenic progenitor (FAP)
cells and satellite cells are critical to promote myogenesis, extracellular matrix (ECM) remodeling, and ultimately,
restore muscle size and function. However, in aging, senescence cells exceed the rate of removal during
recovery from injury resulting in excessive senescence associated secretory phenotype (SASP; secretion of
factors such as pro-inflammatory and pro-fibrotic mediators) thereby amplifying dysfunction in macrophages,
FAPs and satellite cells and resulting in poor ECM remodeling. Metformin has been implicated to have positive
effects on muscle size and function through non-glycemic mechanisms. Of interest to the current proposal,
metformin has been shown to enhance macrophage function and lessen cellular senescence burden by targeting
SASP in a variety of muscle interstitial cell. However, the role of metformin to improve ECM remodeling and
muscle recovery in older adults following disuse atrophy through immunomodulating and senomorphic
mechanisms have not been examined. We provide compelling data in older adult skeletal muscle that a clinical
dose of metformin can potentially improve muscle macrophage, FAP and satellite cell function while also
decrease muscle fibrosis and cellular senescence and SASP. Therefore, the purpose of this application is to
conduct a randomized, double blind, placebo-controlled clinical trial in older adults to determine if short-term
metformin delivery (vs placebo) during the recovery phase following disuse atrophy can improve macrophage
function, reduce cellular senescence and SASP, and enhance ECM remodeling thereby facilitating muscle
regrowth. We will use state-of-the-art methodologies and elegant in vivo and vitro approaches to identify the
impact metformin treatment on macrophage, FAP and satellite cell senescence and SASP, collagen
organization, and muscle regrowth in aging. We anticipate that the findings will aid in the repurposing of
metformin to be timely delivered to accelerate the recovery of aged muscle following disuse related events (e.g.,
surgery, illness).

## Key facts

- **NIH application ID:** 10853674
- **Project number:** 1R01AG086328-01
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Micah J Drummond
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $635,090
- **Award type:** 1
- **Project period:** 2024-06-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10853674

## Citation

> US National Institutes of Health, RePORTER application 10853674, Leveraging senotherapeutic properties of metformin to improve collagen remodeling during muscle regrowth in older adults (1R01AG086328-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10853674. Licensed CC0.

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