# Lamin A/C is required for maintaining subsynaptic myonuclei integrity

> **NIH NIH R36** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $52,082

## Abstract

Project Summary / Abstract
Sarcopenia, the age-related decline in skeletal muscle mass and force, is characterized by muscle wasting and
diminished contractile strength leading to physical frailty, decreased mobility, increased disability, and a loss of
independence. The neuromuscular junction (NMJ) is the synapse responsible for transmitting action potentials
from motor neurons to the motor endplate of muscle fibers. NMJs exhibit structural and functional disruptions
including a complete loss of innervation during aging, but the mechanisms for this detrimental phenotype remain
unknown. This study aims to investigate the role in NMJ degeneration of changes in subsynaptic myonuclei
(SSM). Skeletal muscle fibers are large multinucleated cells, with different individual nuclei responsible for
supporting localized domains. SSM are a population of nuclei positioned near the NMJ that play a crucial role in
NMJ development and maintenance. Previous studies have produced conflicting results regarding associations
between aging, SSM number, and NMJ degeneration emphasizing the need for further investigations to clarify
the role of changes in SSM as potential cause or consequence of a loss of innervation. Our own data indicates
no change in SSM number with age, despite high numbers of disrupted and denervated endplates in muscles of
old animals. We also found no changes in SSM number following acute denervation, but denervated muscles
showed a significant increase in LMNA gene expression as well as in the levels of the protein product Lamin
A/C. Lamin A/C is the primary intermediate filament protein of the nuclear lamina and a key component in
maintaining myonuclear structural integrity. The nuclear lamina plays a critical role in regulating gene expression
by interacting with chromatin and nuclear membrane proteins. The expression of Lamin A/C has been reported
to decrease with age, and its muscle-specific deletion accelerates NMJ degradation, resembling age-related
NMJ decline. Our overall hypothesis is that Lamin A/C is required for mediating the process of reinnervation
following a denervation event. We will address this hypothesis using a combination of powerful mouse models,
surgical interventions, assessments of neuromuscular functional properties, and an array of molecular
techniques combined with high-resolution confocal imaging. Specifically, we will [1] define the impact of
denervation on the integrity of subsynaptic myonuclei in young and aged mice, and [2] determine the impact of
skeletal muscle-specific LMNA deletion on reinnervation following nerve injury. We expect to see a denervation-
induced upregulation of Lamin A/C that contributes to the maintenance SSM shape and SSM number leading to
improved reinnervation of endplates. Therefore, we also predict that lack of Lamin A/C will result in impaired
reinnervation after nerve injury leading to poor neuromuscular function. By elucidating key regulators of
reinnervation, we aim to identify the...

## Key facts

- **NIH application ID:** 10890934
- **Project number:** 1R36AG087309-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Lloyd Phillip Ruiz
- **Activity code:** R36 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $52,082
- **Award type:** 1
- **Project period:** 2024-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890934

## Citation

> US National Institutes of Health, RePORTER application 10890934, Lamin A/C is required for maintaining subsynaptic myonuclei integrity (1R36AG087309-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10890934. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*