# Stem Cell Dysfunction in Aged Skeletal Muscle

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2024 · $543,123

## Abstract

Abstract
One of the greatest mysteries in ageing biology is to understand why many tissues and organs in our body,
including skeletal muscle, decline in function as we get older? Recent studies suggest that the inability of
muscle stem cells (MuSCs) to turn on the repair program after trauma is a major factor leading to the loss of
muscle mass and strength observed in the elderly. However, given that the signals driving MuSCs into the
regenerative state remains a mystery even in young adults, we are left with virtually no therapeutic options for
boosting the repair potential of aging MuSCs in the clinic. To address this unmet need, my laboratory recently
discovered a new “Super-Healing” adult stem cell activation program, driven by the transcription factor, FBJ
osteosarcoma oncogene (FOS), that speeds up adult stem cell activation and enhances muscle repair.
Intriguingly, a key downstream target gene of FOS in adult MuSCs is the NAD-consuming, cell surface
enzyme, ADP-Ribosyl-Transferase 1 (Art1), which attaches an understudied post-translational modification
(PTM), mono-ADP-Ribosylation (MARylation), to protein substrates. Excitingly, our preliminary data suggests
that the FOS/ART1-MARylation pathway is disrupted in aged MuSCs, and thus, representing one of the
earliest molecular alterations that diminish the regenerative potential of aged skeletal muscle. Thus, in this
proposal, we will test the hypothesis that the FOS/AP-1 tissue regenerative program (including the ART1
pathway) is mis-regulated in aged skeletal muscle, triggering a cascade of molecular events that dampen stem
cell activation potential and lead to the progressive deterioration of skeletal muscle with increasing age; and
most importantly, that reversal of this molecular dysfunction will correct the stem cell activation and
regenerative deficits seen in aged skeletal muscle. In Aim1, we will determine the expression patterns and
functional significance of FOS/AP-1 gene targets in adult and aged MuSCs. In Aim2, we will determine the
expression dynamics, functional requirements, and MARylated protein substrates of the newly discovered
NAD/ART1-MARylation stem cell activation pathway in adult and aged MuSCs. Collectively, this work will
highlight a new FOS/NAD/ART1-MARylation stem cell activation pathway that has been largely ignored in
aging biology until now and whose further study will open new therapeutic avenues for improving muscle
health in the elderly population.

## Key facts

- **NIH application ID:** 10918347
- **Project number:** 5R01AR080753-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Albert Ernesto Almada
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $543,123
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10918347

## Citation

> US National Institutes of Health, RePORTER application 10918347, Stem Cell Dysfunction in Aged Skeletal Muscle (5R01AR080753-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10918347. Licensed CC0.

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