# Myonuclear dynamics during skeletal muscle aging

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $423,410

## Abstract

Project Summary/Abstract
Sarcopenia is a devastating skeletal muscle condition that occurs in advanced age and due to various chronic
conditions. Despite the widespread prevalence of sarcopenia there are no treatment options and the
mechanisms underlying this process are not completely understood. A major hallmark of skeletal muscle aging
is a reduction in myofiber size, which can be controlled by the hundreds of myonuclei within a single myofiber.
Myonuclei are accrued during development, and new nuclei can also be added in the adult through cellular fusion
of muscle stem cells (MuSCs). The presence of hundreds of nuclei and the need to add more has led to questions
if the pre-existing myonuclei are at their transcriptional ceiling and thus require the myofiber to add new nuclei
for adaptations. To begin to understand the requirement for myonuclei to maintain muscle size, we generated a
unique mouse model that allows titration of myonuclear numbers and utilized strategies to track specific
myonuclear populations. Our recent studies showed that myonuclear numbers ultimately determine size of
myofibers, but that myonuclei possess a transcriptional reserve capacity to increase biosynthetic output and
maintain larger cytoplasmic volumes. While the compensatory adaptations in mice with reduced nuclear numbers
were advantageous during development, they were associated with evidence of accelerated aging and muscle
loss, leading to the hypothesis that loss of functional gene copy numbers is a contributor to sarcopenia. Indeed,
by utilizing snRNA-seq technology, we detected altered myonuclear populations during mouse aging suggesting
dysregulated transcription, which could be one mechanism to explain a reduction in gene copy numbers. In
addition to altered transcription, another mechanism for reductions of gene copy numbers is if myonuclei are lost
from the syncytium and not replaced by MuSC fusion, and it is known that MuSCs have reduced activity in aged
muscle. Based on these preliminary data, we will utilize unique models and myonuclear tracking systems, to
uncover the transcriptional reserve in myonuclei of aging myofibers, elicited either through dysregulated
transcriptional profiles or myonuclear loss, and elucidate the link between such myonuclear infidelity and the
development of sarcopenia. Specifically, we propose to: 1) understand the molecular and cellular consequences
of reductions in myonuclear number during aging 2) molecularly dissect the mechanisms of activation of
myonuclear transcriptional reserve during development and aging 3) determine if myonuclei turnover during
homeostasis, aging, and atrophy. Successful completion of these studies will provide unique insight into the
myonuclear control of sarcopenia and provide new knowledge that will identify new therapeutic strategies to
combat muscle loss.

## Key facts

- **NIH application ID:** 10901923
- **Project number:** 5R01AG082697-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Douglas Paul Millay
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $423,410
- **Award type:** 5
- **Project period:** 2023-08-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10901923

## Citation

> US National Institutes of Health, RePORTER application 10901923, Myonuclear dynamics during skeletal muscle aging (5R01AG082697-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10901923. Licensed CC0.

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