# Targeting p21 to stimulate irradiated muscle stem cell function and muscle regeneration

> **NIH NIH F31** · UNIVERSITY OF ROCHESTER · 2020 · $45,520

## Abstract

Abstract
Over the last 30 years, the survival rate of juvenile cancer patients has improved dramatically. Today, 80% of
children and adolescents will survive five years beyond initial diagnosis. However, as juvenile cancer survivors
live longer, they experience the after-effects of cytotoxic cancer therapies into adulthood. To this end, juvenile
cancer survivors suffer from early-onset sarcopenia. Sarcopenia, normally afflicting the elderly population, is
the severe and accelerated loss of skeletal muscle. Because radiation therapy can target active progenitors, it
is possible that irradiation of juvenile muscle can have long-term consequences. Skeletal muscle is endowed
with a population of muscle stem cells (satellite cells, SCs). In adult skeletal muscle, SCs reside in a quiescent
state. However during postnatal growth, SCs contribute myonuclei to the development and maturation of
juvenile skeletal muscle. We have recently demonstrated a role for SC-derived myonuclear contribution to the
development of prepubertal murine skeletal muscle (Bachman et al, Development 2018). Loss of juvenile SCs
results in immediate and significant deficits in muscle fiber size and force generation capacity. It is has not
been established if irradiation to juvenile murine skeletal muscle can disrupt the cycling SC population.
Additionally, neither the consequences nor mechanism of irradiated SC dysfunction have been elucidated. Our
preliminary data indicates that that a fractionated radiation treatment (8.2 Gy MWF) can result in an immediate
reduction in the juvenile SC pool. However, a population of radio-resistant SCs does persist. These radio-
resistant SCs have a reduced capacity to proliferate and undergo myogenic commitment in vitro. Consistent
with these deficits, irradiated juvenile skeletal muscle has impaired regenerative potential. Intrinsic irradiated
SC dysfunction coincides with upregulated expression of the cell cycle inhibitor and sensor of DNA stress p21
(Cdkn1a). Thus, the goal of my proposal is to determine the impact of irradiation on the juvenile SC pool and
identify if elevated p21 expression is responsible for irradiated SC dysfunction. We will address these
questions in the following aims: Aim 1) To determine if the radio-resistant SC pool primarily consists of
infrequently dividing label-retaining cells (LRCs) Aim 2) To examine whether fractionated irradiation of juvenile
skeletal muscle leads to severely delayed regeneration due to intrinsic SC dysfunction Aim 3) To determine if
knockdown of p21 stimulates irradiated SC function and muscle regeneration. Together, these aims will shed
light on the cellular and molecular mechanisms of juvenile radiotherapy-mediated skeletal muscle decline and
potential therapies.

## Key facts

- **NIH application ID:** 10057215
- **Project number:** 5F31AR076175-02
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** John Bachman
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2019-07-15 → 2021-07-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10057215

## Citation

> US National Institutes of Health, RePORTER application 10057215, Targeting p21 to stimulate irradiated muscle stem cell function and muscle regeneration (5F31AR076175-02). Retrieved via AI Analytics 2026-06-24 from https://api.ai-analytics.org/grant/nih/10057215. Licensed CC0.

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