# Revealing muscle stem cell heterogeneity in mice and humans through deep single-cell analysis

> **NIH NIH R01** · CORNELL UNIVERSITY · 2021 · $602,936

## Abstract

PROJECT SUMMARY/ABSTRACT
Muscle stem cells (MuSCs), also known as satellite cells, are essential to skeletal muscle regeneration
throughout life. In aged individuals, muscle mass and regenerative capacity after injury progressively decline,
leading to diminished quality of life. We have recently demonstrated that MuSCs prospectively isolated from
aged mice are highly heterogeneous and, as a population, have a marked reduction in regenerative capacity
relative to young adult MuSCs, revealing a previously undetected intrinsic stem cell defect in aged MuSCs. The
dysfunction of aged MuSCs is characterized by a shift from reversible quiescence to cellular senescence, driven
by elevation of the p16Ink4a cell-cycle inhibitor, and inefficient self-renewal, caused by aberrant cell-autonomous
activation of the p38 mitogen-activated protein kinase and STAT3 pathways. What causes these inherent
alterations and how to prospectively identify and treat dysfunctional MuSCs in aged mice and humans remain
unanswered questions. We propose to combine high-throughput deep single-cell RNA-sequencing across varied
adult mouse and human muscle samples and stem-cell population reconstruction algorithms to identify cell-
surface antigen profiles that unambiguously distinguish between health and diseased MuSCs in mouse and
human aging. We hypothesize that this approach will enable discovery of heterogeneously expressed MuSC
cell-surface antigens that demark differing stem-cell capacities within a new-found functional hierarchy. We will
prospectively isolate and transplant mouse and human MuSCs sub-populations and perform limiting dilution
transplantation assays and self-renewal assays using bioengineered culture microenvironments. We will perform
conditional deletion and transient knockdown studies to investigate if the identified antigens have mechanistic
roles in self-renewal dysfunction in vivo and in vitro. These proposed studies will provide a deeply-profiled
organized cellular atlas of muscle stem and progenitor cells in mouse and human aging that should enable
rational therapeutic development targeting dysregulated stem cells for enhancing muscle repair in the elderly
following trauma.

## Key facts

- **NIH application ID:** 10174661
- **Project number:** 5R01AG058630-04
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Benjamin David Cosgrove
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $602,936
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10174661

## Citation

> US National Institutes of Health, RePORTER application 10174661, Revealing muscle stem cell heterogeneity in mice and humans through deep single-cell analysis (5R01AG058630-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10174661. Licensed CC0.

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