# Genetic and Therapeutic Approaches to Alleviate the Pathology of Massive Rotator Cuff Tears

> **NIH NIH R21** · DUKE UNIVERSITY · 2024 · $171,863

## Abstract

SUMMARY
The rotator cuff is composed of 4 muscles that stabilize the shoulder and controls upper arm range of motion. Tears in the
tendons of these muscles, known as rotator cuff tears (RCTs), are among the most common debilitating shoulder injuries. While
RCTs can be surgically repaired, the rate of retear is significant and has been correlated to high levels of rotator cuff muscle fatty
infiltration, fibrosis, and muscle atrophy. A heterogeneous population of muscle resident non-myogenic mesenchymal cells,
known as fibro-adipogenic progenitors (FAPs), have been implicated in many skeletal muscle pathologies in which
intramuscular fat and fibrosis are abundant. We and others have recently demonstrated that PDGFRa-expressing FAPs expand
during a 2-week period following massive RCTs in mice and contribute to the accumulation of intramuscular fat and fibrosis that
accompanies rotator cuff muscle atrophy by 8-weeks post injury (wpi). While these findings are important, virtually nothing is
known regarding the molecular signals associated with the promotion of FAP differentiation into fibrogenic and adipogenic fates,
nor the factors that may be secreted by FAPs to drive rotator cuff muscle atrophy following RCT. Utilizing a murine model of
massive RCTs, genetic lineage tracing/reporter analysis, as well as sophisticated bulk RNA-sequencing assays from isolated
FAPs and other gene expression studies in muscle fibers, we identified several important molecular regulators of adipogenesis,
fibrosis, and muscle atrophy that are likely key factors in promoting the RCT pathology. Validation of signaling and functionality
of these molecules/pathways were demonstrated in our mouse model of RCTs (in vivo). In this application we will utilize
conditional genetic approaches to delete the relevant genes specifically in FAPs and muscle fibers following RCTs, while also
performing genetic reporter analysis, histology, IHC/IF, bulk-RNA sequencing, and sophisticated single cell RNA-sequencing
assays, to determine whether cell-type specific signaling activation is necessary to promote the RCT pathology following
massive RCTs in mice and determine whether the presence or absence of these molecular regulators affects FAP heterogeneity
of rotator cuff muscles following RCTs. Further, we will perform proof-of-concept studies demonstrating the utility of prophylactic
and therapeutic pharmacologic approaches to the inhibition of this pathway following RCTs. This work will provide vital
information to our understanding of the cellular and molecular roles for FAPs in RCT induced fatty infiltration, fibrosis, and the
muscle atrophy associated with massive RCTs, while also testing clinically relevant therapies for the treatment of the RCT
pathology.

## Key facts

- **NIH application ID:** 10896041
- **Project number:** 1R21AR083041-01A1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Matthew J. Hilton
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $171,863
- **Award type:** 1
- **Project period:** 2024-06-27 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10896041

## Citation

> US National Institutes of Health, RePORTER application 10896041, Genetic and Therapeutic Approaches to Alleviate the Pathology of Massive Rotator Cuff Tears (1R21AR083041-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10896041. Licensed CC0.

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