# The opposing effects of matrix aging and muscle activity on extracellular vesicle promotion of muscle regeneration

> **NIH AG R01** · SPAULDING REHABILITATION HOSPITAL · 2026 · $656,164

## Abstract

ABSTRACT
 Young skeletal muscle displays remarkable resilience following an acute injury event, evidenced by a
robust regenerative response and functional recovery. In contrast, even a relatively minor injury to aged
muscle can result in significant functional impairments owing to compromised regeneration. Numerous studies
have identified muscle stem cells (MuSCs) as a major culprit in the failed healing response of aged muscle.
MuSCs represent a reserve cell population that play a primary role in muscle regeneration. However, with
aging, MuSCs display a myogenic-to-fibrogenic conversion, resulting in fibrosis at the expense of myofiber
regeneration. Although cell-autonomous deficits play an important role in cellular declines with aging, the
contribution of biophysical cues from the surrounding microenvironment has been increasingly appreciated.
 Tissue regeneration involves a tightly-regulated and bi-directional communication between stem cells and
their biophysical microenvironment. Elegant in vitro studies have demonstrated that substrates engineered to
mimic the elasticity typical of young, healthy muscle promoted stem cell myogenicity, whereas stiffer substrates
drove stem cell chondrogenic/osteogenic differentiation. In vivo, compositional and physical changes in the
extracellular matrix (ECM) similarly exert deleterious effects on stem cell function. We and others have shown
that age-related alterations in ECM biophysical features contribute to disrupted MuSC lineage specification.
Whereas the bulk of studies to date, including our own, have focused on the direct effects of the ECM on stem
cell responses through mechanotransductive signaling cascades, our latest data suggest a novel role of
extracellular vesicles (EVs) in mediating the effect of the ECM on stem cell responses. We have found that
substrates engineered to mimic the stiffness of aged skeletal muscle promoted the cellular release of EVs that
inhibited MuSC myogenicity. In contrast, EVs released 

## Key facts

- **NIH application ID:** 11326809
- **Project number:** 5R01AG087565-03
- **Recipient organization:** SPAULDING REHABILITATION HOSPITAL
- **Principal Investigator:** Fabrisia  Ambrosio; Philip R LeDuc
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** AG
- **Fiscal year:** 2026
- **Award amount:** $656,164
- **Award type:** 5
- **Project period:** 2024-08-15T00:00:00 → 2029-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11326809

## Citation

> US National Institutes of Health, RePORTER application 11326809, The opposing effects of matrix aging and muscle activity on extracellular vesicle promotion of muscle regeneration (5R01AG087565-03). Retrieved via AI Analytics 2026-06-26 from https://api.ai-analytics.org/grant/nih/11326809. Licensed CC0.

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