# Molecular Mechanisms of Age-related Muscle Loss

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2022 · —

## Abstract

Age-related skeletal muscle atrophy, also known as sarcopenia, diminishes the health and quality of life of
many Veteran patients. However, the molecular mechanisms of age-related muscle atrophy are poorly
understood, and a pharmacologic therapy does not exist. As a result, many elderly Veterans suffer the
consequences of muscle atrophy, including weakness, impaired activity, falls, prolonged hospitalization,
delayed rehabilitation, loss of independent living, and increased mortality. This places enormous burdens on
elderly Veterans, their families, and society in general. Importantly, despite its prevalence and severity,
skeletal muscle atrophy lacks a specific and effective pharmacologic therapy and thus represents an enormous
unmet medical need. Development of pharmacologic interventions for muscle atrophy has been hindered by
the fact that the molecular basis of muscle atrophy is highly complex, poorly understood, and still largely
unexplored. The research proposed here would help to address this issue by investigating a newly identified
signaling pathway in skeletal muscle fibers that appears to be critically important for skeletal muscle aging. We
originally discovered this pathway through unbiased systems-based strategies, which have, to date, identified
several critical pathway components, including the transcriptional regulator ATF4 (the first and only known
example of a skeletal muscle protein that is required for the loss of strength, muscle quality, muscle mass and
endurance exercise capacity during aging), the p21 gene (a key ATF4 target gene in elderly skeletal muscle),
and the p21 protein (a novel mediator of muscle fiber atrophy). Our proposed studies will build upon these
important initial findings to more deeply investigate and understand the mechanisms by which ATF4 activates
the p21 gene (Aim 1), the pathophysiological consequences of p21 expression in skeletal muscle fibers (Aim
2), and the downstream mechanism(s) by which p21 promotes muscle atrophy (Aim 3). Through these
studies, we hope to elucidate fundamental molecular mechanisms and new therapeutic targets for age-related
muscle atrophy, a disabling condition that affects many Veteran patients.

## Key facts

- **NIH application ID:** 10368017
- **Project number:** 5I01BX000976-11
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** Mark A. Yorek
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2011-07-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10368017

## Citation

> US National Institutes of Health, RePORTER application 10368017, Molecular Mechanisms of Age-related Muscle Loss (5I01BX000976-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10368017. Licensed CC0.

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