# PROJECT 1: Contribution of altered synapse function to muscle atrophy and weakness in aging

> **NIH NIH P01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $451,455

## Abstract

ABSTRACT – PROJECT 1
With aging, skeletal muscle displays atrophy and weakness that limits mobility, contributes to disability, and
reduces quality of life. Strong associations are reported between declines with aging in muscle structure and
function and degenerative changes in the morphology of neuromuscular junctions (NMJ); however, events with
aging that trigger disruption of NMJs and the downstream mechanisms of impaired muscle function and fiber
loss are all unknown. Studies from our groups collectively show a recapitulation, in an accelerated fashion, of
key attributes of muscle aging in mice deficient in copper zinc superoxide dismutase (CuZnSOD; Sod1KO
mice). Additional studies using novel mouse models we developed with tissue specific modulation of Sod1
collectively suggest that redox homeostasis in motor neurons is a critical factor regulating the maintenance of
NMJs, but that the progression of sarcopenia is determined by interactions between changes in both neurons
and muscle. The goal of Project 1 is to establish mechanisms by which alterations in motor neuron redox
homeostasis cause post-synaptic changes in muscle. Increased production of reactive oxygen species (ROS)
by muscle mitochondria is a hallmark of manipulations that cause NMJ degeneration and muscle atrophy, e.g.
Sod1 deficiency, aging, and denervation. Thus, our hypothesis is that with aging, altered redox homeostasis in
peripheral motor neurons impairs NMJ formation and maintenance during synaptic turnover and the resultant
disruption in innervation alters muscle mitochondrial function that causes increased oxidative damage to the
muscle activation and contractile machinery. We will test this hypothesis by determining the impact of oxidative
stress in motor neurons on NMJ formation and maintenance and the impact of directly disrupting NMJs on key
postsynaptic muscle functions. Oxidative stress and NMJ disruption will be induced using novel tissue-specific
mouse models provided by the Animal Core. These powerful new mouse models coupled with innovative
methods for studying NMJ formation and regeneration, mitochondrial function, calcium homeostasis, and force
generation, provide a potent paradigm for impacting scientific knowledge of skeletal muscle aging to drive
successful interventions to prevent sarcopenia.

## Key facts

- **NIH application ID:** 9920087
- **Project number:** 5P01AG051442-05
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Susan V Brooks
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $451,455
- **Award type:** 5
- **Project period:** — → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9920087

## Citation

> US National Institutes of Health, RePORTER application 9920087, PROJECT 1: Contribution of altered synapse function to muscle atrophy and weakness in aging (5P01AG051442-05). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/9920087. Licensed CC0.

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