# The role of cellular senescence in skeletal muscle loss and dysfunction

> **NIH NIH R00** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2024 · $248,724

## Abstract

PROJECT SUMMARY/ABSTRACT
The objectives of this proposal are to (1) obtain the experimental skills and career training necessary to
develop a translational research program investigating mechanisms underlying skeletal muscle wasting and (2)
generate the data necessary to determine the feasibility of targeting senescent cells to restore muscle size and
function. Sarcopenia is a debilitating age-related skeletal muscle wasting syndrome associated with poor
quality of life and high health care utilization. The etiology of sarcopenia is not fully understood, and there are
currently no effective treatments. Identifying the processes mediating sarcopenia is critical for developing
pharmacologic therapies. Senescent cells accumulate with age and at the anatomical sites of disease. Thus,
they are regarded as a logical therapeutic target. Indeed, in mice, the targeted elimination of senescent cells
improves function and parameters of health in multiple tissues. Our preliminary data show (1) senescent post-
mitotic muscle fibers accumulate in sarcopenic mice, (2) the cyclin-dependent kinase inhibitor p21 is a critical
regulator of muscle fiber senescence, and (3) a subset of myonuclei within multi-nucleated muscle fibers are
uniquely vulnerable to senescence induction. I will use mouse models that allow for muscle fiber-specific
labeling and modulation of p21 to advance our understanding for muscle fiber senescence and examine the
direct contribution of senescence to muscle dysfunction. In Aim 1, I will overexpress p21 in muscle fibers in
vivo and apply well-validated markers of senescence together with transcriptome-wide analyses to determine
the core properties of muscle fiber senescence and identify regulatory processes that may serve as therapeutic
targets. In Aim 2, I will use gain-of-function and loss-of-function p21 models and assess measures of muscle
health, function, and size to determine the clinical relevance of senescent cell burden in skeletal muscle. In
Aim 3, I will use myonuclear identification and isolation techniques together multiomic profiling to examine
differences between senescent and non-senescent subsets of myonuclei to gain new insight into the factors
regulating myonuclear senescence. The K99 phase will be conducted at Mayo Clinic and will focus on
obtaining mentored training in methods required to complete the proposed aims. The R00 phase will be
conducted in my independent lab and will focus on analyzing mouse tissues and data, publishing findings, and
developing an R01 application based on these results. This proposal synergizes new skills in advanced
senescent cell identification, imaging, bioinformatics, and drug target discovery techniques to create a research
trajectory that is distinct from my mentors’ foci. This work will produce a robust foundation for an independent
research career elucidating cellular mechanisms of skeletal muscle dysfunction with the aim of translating
these findings into therapies to improve human ...

## Key facts

- **NIH application ID:** 11143353
- **Project number:** 4R00AR081898-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Davis A. Englund
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $248,724
- **Award type:** 4N
- **Project period:** 2024-09-20 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11143353

## Citation

> US National Institutes of Health, RePORTER application 11143353, The role of cellular senescence in skeletal muscle loss and dysfunction (4R00AR081898-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11143353. Licensed CC0.

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