# Mechanisms of adipogenic and fibrotic degeneration of muscle

> **NIH VA I01** · VETERANS ADMIN PALO ALTO HEALTH CARE SYS · 2022 · —

## Abstract

Fibrotic and adipogenic infiltration are hallmarks of injured, diseased, and aged skeletal muscle. This
fibrofatty degeneration (“FFD”) results not only in functional decline of skeletal muscle but also to the increased
prevalence of metabolic disorders. The origins of the major cellular contributors (fibrogenic and adipogenic
progenitors) of this FFD remain to be definitively identified, but recent evidence (including Preliminary Studies
included herein) suggest a population of mesenchymal progenitors termed “fibroadipogenic progenitors”
(FAPs) are major sources. FAPs reside in the muscle interstitium and display robust fibrogenic and adipogenic
potential in vitro and in vivo following transplantation. Studies in vivo to directly test whether endogenous FAPs
are responsible for fibrosis and adiposity in the setting of injury and disease have been limited by the lack of
specific tools to genetically label and target FAPs. 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 Studies using a PDGFRαCreER strain that we developed to either genetically label or specifically
deplete FAPs support the hypothesis that FAPs are sources of both fibrogenic and adipogenic cells in the
setting of aberrant muscle regeneration associated with FFD. In Preliminary Studies, we also identified a
microRNA, miR-206, as a candidate regulator of FAP adipogenic differentiation, and a transcription factor,
Runx1, as a likely target of mIR-206 in this process. We have, in addition, identified candidate microRNAs
involved in the regulation of FAP fibrogenic differentiation.
 In the studies of this proposal, we will explore the regulation of FAP adipogenic and fibrogenic
differentiation, and the essential role of FAPs in FFD in two clinically relevant models. In the studies of Aim 1,
we will examine the role of the miR-206/Runx1 axis in FAP adipogenic differentiation in vitro and in fatty
infiltration in glycerol-induced muscle injury in vivo. In the studies of Aim 2, we will work collaboratively with our
colleague, Dr. Brian Feeley, at UCSF to explore the role of FAPs in general, and of the miR-206/Runx1 axis in
particular, in the fatty infiltration that occurs in the setting of rotator cuff injury (RCI). Dr. Feeley has developed
a robust murine model of RCI that exhibits the kind of fatty infiltration and muscle atrophy seen in humans. We
will use a novel tamoxifen analog delivery method we have developed to allow for the depletion of FAPs only in
the region of the RCI. In the studies of Aim 3, we will examine the regulation of FAP fibrogenic differentiation,
again focusing on the key role of miRNAs in such cell fate decisions. We will identify functional targets of
candidate miRNAs using a recently developed pull-down technology combine with RNA sequencing (LAMP-
seq). Furthermore, we will address the role of FAPs in the extensive fibrosis seen in the common e...

## Key facts

- **NIH application ID:** 10259577
- **Project number:** 1I01BX005669-01
- **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:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-10-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10259577

## Citation

> US National Institutes of Health, RePORTER application 10259577, Mechanisms of adipogenic and fibrotic degeneration of muscle (1I01BX005669-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10259577. Licensed CC0.

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