# Cellular mechanisms for the degeneration and aging of human rotator cuff tears

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA-IRVINE · 2023 · $235,500

## Abstract

Abstract
The rotator cuff muscles allow for movement of the arm and shoulder and are particularly
susceptible to tear with age. Age-related muscle degeneration is alarming as an ever-increasing
aging US population burdens our health care system. While surgical intervention strategies for
rotator cuff tears exist, in many instances the muscle fails to regenerate after surgery, leading to
a significant and variable rate of retear for 10-50% of patients, depending on the study. Risk
factors for retear include age, gender, and pre-operative tear size; however, the interdependency
of each risk factor is unknown. Moreover, at the cellular and molecular level, myofibers, satellite
cells, stromal cells, and immune cells dynamically regulate the regeneration processes. While its
known cell populations shift occurs with age, gender, and rotator cuff tear, no study has evaluated
the dynamics of cell pathology across patient populations. In this proposal, the Hicks and Gupta
labs will test two hypothesis that 1) the cellular composition of chronic human RCTs inhibits SC
regeneration through inflammatory factors and/or fibrosis, and 2) chronic human muscle injury
leads to exhaustion and senescence of the SC pool, thereby leading to accelerated degeneration.
In Aim 1, we will use high-dimensional imaging mass cytometry to quantify immune-stromal-
muscle heterogeneity as well as phenotypic markers of senescence and activation. Imaging mass
cytometry can achieve multiplex staining upwards of 40 antibodies on a single tissue, enabling
significant refinement of complex cellular phenotypes and histopathological classification of
clinical tissue samples. We expect to find will unique molecular signatures clustered by age,
gender, and Goutallier grade, thus providing predictive measures of muscle regeneration
following rotator cuff tear. In Aim 2, we will test the functional status of SCs and stromal cells in
vitro using three main assays, senescence: via live cell imaging, trans differentiation: via fibrotic
and adipogenic stimulating factors, and stromal cell regulation of muscle regeneration: via co-
culturing stromal populations with satellite cells. Results from these assays will guide the use of
anti-senescent or anti-fibrotic drugs in vitro. This study serves as a basis for understanding the
intrinsic and extrinsic defects in skeletal muscle repair and will shed light on both predicting
outcomes of rotator cuff tear surgery and identifying new treatments that could improve muscle
regeneration for aging and muscle tears.

## Key facts

- **NIH application ID:** 10648672
- **Project number:** 1R21AG081739-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Michael Ryan Hicks
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $235,500
- **Award type:** 1
- **Project period:** 2023-05-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10648672

## Citation

> US National Institutes of Health, RePORTER application 10648672, Cellular mechanisms for the degeneration and aging of human rotator cuff tears (1R21AG081739-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10648672. Licensed CC0.

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