# Role of extracellular matrix in age-related declines of muscle regeneration

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $444,255

## Abstract

ABSTRACT
 Skeletal muscle trauma resulting from an injury or surgery often results in significant functional declines
in older adults. These declines are at least partially attributed to failed muscle healing. Muscle regeneration is
predominantly dictated by the action of muscle stem, or “satellite”, cells (MuSCs), a reserve cell population that
typically demonstrates considerable dysfunction with increasing age. According to the stem cell “niche”
concept, stem cell responses are largely determined by biophysical and biochemical cues that emanate from
the surrounding microenvironment. Indeed, expanding recognition of the influence of the microenvironment on
stem cell behavior has led to a recent surge in the development of bioinspired and engineered extracellular
matrix (ECM) approaches for the treatment of skeletal muscle injuries. Still lacking, however, is an in-depth
knowledge of whether and how pathogenic instructional characteristics of the native ECM disrupt MuSC
function and skeletal muscle regeneration. While it is evident that MuSC activation, self-renewal, proliferation
and differentiation are influenced by physical and dynamic niche interactions, a mechanistic understanding of
the direct impact of age-related ECM alterations on skeletal muscle regenerative capacity is unknown.
 The over-arching goal of this project is to test our central hypothesis that age-related biophysical
alterations in the skeletal muscle ECM promotes a fibrogenic conversion in MuSCs, ultimately driving
impaired skeletal muscle regeneration. Further, we hypothesize that these pathogenic biophysical
changes may be reverted, at least partially, by mechanical stimulation. To achieve this goal, we will
employ an integrated approach that encompasses cutting-edge super-resolution imaging and 3-D tissue
engineering methods to address two specific aims. Aim 1 studies will measure, manipulate, and mimic the
biophysical properties of young and aged skeletal muscle ECM in order to dissect the effect of age-related
architectural and elastic ECM modifications on MuSC fate. Aim 2 studies will identify mechanisms by which
mechanical stimulation modulates biophysical properties of the aged ECM to promote MuSC myogenicity and
muscle regeneration. Successful achievement of these aims will further our understanding of 1) the
instructional capabilities of the native ECM on MuSC lineage specification, 2) how these instructional
capabilities change over time, and 3) the molecular mechanisms controlling age-related declines in skeletal
muscle regenerative potential. Taken together, successful completion of these studies may provide a
foundation for the identification of novel ECM targets in the treatment of skeletal muscle injuries for a geriatric
population. More broadly, an improved insight into how age-associated alterations in biomechanical,
architectural and dynamic ECM properties direct MuSC function will expand our fundamental understanding of
aging and stem cell biology.

## Key facts

- **NIH application ID:** 9983543
- **Project number:** 5R01AG061005-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Fabrisia Ambrosio
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $444,255
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983543

## Citation

> US National Institutes of Health, RePORTER application 9983543, Role of extracellular matrix in age-related declines of muscle regeneration (5R01AG061005-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9983543. Licensed CC0.

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