# Interdependency of fibroadipogenic progenitors and extracellular matrix that drive skeletal muscle fibrosis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2022 · $472,819

## Abstract

PROJECT SUMMARY
Fibrosis is the accumulation of extracellular matrix components that disrupt tissue function and is prevalent
across many muscle diseases. Muscle functions compromised in fibrosis include muscles primary function to
contract as well as its ability to be compliantly stretched when not active. This results in weak and stiff muscle
decreasing mobility and producing joint contractures. Skeletal muscle regenerates following injury from resident
muscle stem cells, however those cells are sensitive to the organization and mechanics of fibrotic extracellular
matrix. Another muscle resident stem cell, fibro-adipogenic progenitors, support myogenesis following injury, but
in the context of fibrosis contribute to the pathologic buildup of extracellular matrix. However, the sensitivity of
fibro-adipogenic progenitors to their mechanical environment is unknown. Nor is it known how fibro-adipogenic
progenitors production of extracellular matrix signals to muscle stem cells to support or impair myogenesis. In
order to target effective anti-fbrotic therapies the mechanisms that of communication between fibro-adipogenic
progenitors and the extracellular matrix that defines fibrosis must be revealed. Further, the fibrotic environment
can act as a barrier to restorative gene therapies for muscular dystrophy, but how fibrosis may influence the
efficacy of promising gene therapies is unknown.
Fibrosis is particularly common in Duchenne muscular dystrophy, with associated joint contractures. Yet, even
removal of functional dystrophin from more fibrotic mouse strains yields a less severe fibrosis, motivating a
conjunction of studies in both mice and humans. Fibro-adipogenic progenitors can be activated into pro-
fibrogenic cells to resist apoptotic signals and produce excessive extracellular matrix components. This fibrotic
extracellular matrix is mainly made of fibrillar collagen, which is the dominant load-bearing structure within
healthy and fibrotic extracellular matrix. However, the organization of collagen fibers in the extracellular matrix
can alter both the mechanics and adherent cell phenotypes. Fibro-adipogenic progenitors are similar to
mesenchymal stromal cells, yet how extracellular matrix organization and mechanical signals drive conversion
to the pro-fibrotic state are not known. Nor is it known how one of the primary functions of fibro-adipogenic
progenitors, to secrete extracellular matrix, impacts the muscle stem cells responsible for myogenesis. This the
potential to create a positive feedback cycle between fibro-adipogenic protenitors and the extracellular matrix.
Promising gene therapy using micro-dystrophin is able to largely restore the integrity of myofibers. However, it
isn’t known if once the pro-fibrotic cycle is in place if restoring the myofiber integrity and the initiating signals of
fibrosis will be sufficient to reverse prominent fibrosis and the associated decline in function. Thus, our objective
is to reveal fibro-adipo...

## Key facts

- **NIH application ID:** 10454078
- **Project number:** 1R01AR079545-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** LUCAS R SMITH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $472,819
- **Award type:** 1
- **Project period:** 2022-04-05 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10454078

## Citation

> US National Institutes of Health, RePORTER application 10454078, Interdependency of fibroadipogenic progenitors and extracellular matrix that drive skeletal muscle fibrosis (1R01AR079545-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10454078. Licensed CC0.

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