# Regulation of Muscle Fibrosis in Response to Injury and Aging

> **NIH VA I01** · VETERANS ADMIN PALO ALTO HEALTH CARE SYS · 2020 · —

## Abstract

Fibrotic and adipogenic infiltration is a hallmark of injured and aged skeletal muscle. This muscle
fibroadipogenic degeneration (or “MFD”) is responsible in part for the functional decline of skeletal muscle and
the increased prevalence of metabolic disorders in aged individuals. The origins of the major cellular
contributors (fibrocytes and adipocytes) of this MFD remain to be identified. Fibroadipogenic progenitors
(“FAPs”), mesenchymal stem cells that reside in the muscle interstitium, are a leading candidate as they
display robust fibrogenic and adipogenic potential in vitro and in vivo following transplantation. However, FAPs
as undifferentiated progenitors are believed to have a positive influence on muscle regeneration and
homeostasis. Thus, FAPs have been hypothesized to have either a positive or negative influence on muscle
depending on their state. Studies in vivo to directly test these dual effects have been limited by the lack of
specific tools to genetically label and target FAPs, and this has impaired our understanding of the biology of
FAPs in their endogenous milieu. We have recently developed such tools by taking advantage of the highly
specific expression of PDGFRα in FAPs among the mononucleated cells of muscle. Our Preliminary Data
using a PDGFRαCreER strain that we developed to either genetically label or specifically deplete FAPs
support the hypothesis that FAPs are essential for normal muscle regeneration (positive effect) and contribute
to MFD under pathologic conditions (negative effect).
 In the studies of this proposal, we will explore the biology of FAPS along several directions. In Aim 1, we
will examine the contribution of FAPs to the cellular components of MFD during aging or during pathologic
regeneration using genetic lineage tracing and genetic depletion. In the studies of Aim 2, we will focus on
testing the positive role of FAPs in normal muscle regeneration and how changes that occur in FAPs with age
may both contribute to age-related decline in muscle regenerative potential and also to age-related changes in
muscle homeostasis. In the studies of Aim 3, we will examine the regulation of FAP fate determination,
specifically focusing on the role of miRNAs as determinants of lineage based up on our Preliminary Data. We
will screen for miRNAs that are important for driving FAPs down particular lineages or for maintaining those
differentiated states, and we will test for the ability of specific miRNAs to maintain FAPs in their
undifferentiated, progenitor state.
 Through our studies of FAPs, we aim to understand the mechanisms that guide their activation in healthy
muscle to assess their role in the fibroadipogenic pathology of aged muscle. Our investigation will both
capitalize on new experimental tools to study this population and lend insight into therapeutic strategies to
prevent age-related MFD. This will have direct relevance to Veterans who are suffering from skeletal muscle
injuries, injuries that have limi...

## Key facts

- **NIH application ID:** 9815416
- **Project number:** 5I01BX002324-07
- **Recipient organization:** VETERANS ADMIN PALO ALTO HEALTH CARE SYS
- **Principal Investigator:** THOMAS A. RANDO
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-10-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9815416

## Citation

> US National Institutes of Health, RePORTER application 9815416, Regulation of Muscle Fibrosis in Response to Injury and Aging (5I01BX002324-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9815416. Licensed CC0.

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