# Molecular Mechanisms of Neuromuscular Interactions Underlying Age-Related Atrophy

> **NIH NIH P01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $1,663,511

## Abstract

OVERALL ABSTRACT.
The goal of this Program Project (P01) Grant is to provide much needed information regarding the
mechanisms underlying age-associated loss of skeletal muscle mass and strength, often referred to as
sarcopenia. Studies from our team show that mice deficient in copper zinc superoxide dismutase (CuZnSOD,
Sod1KO mice) display progressive declines in muscle structure and function throughout early adulthood, such
that by middle age the Sod1KO mice resemble very old wild type mice. These findings support a mechanistic
link between chronic oxidative stress and sarcopenia. A key feature of the initiation of muscle declines with
aging and in Sod1KO mice is the degeneration of neuromuscular junctions (NMJs). To probe the importance of
pre- and post-synaptic factors in sarcopenia, we developed new mouse models with nerve- or muscle-specific
deficiency of Sod1 or with Sod1 restored in neurons of Sod1KO mice. These mice have produced several key
findings: 1-partial rescue of CuZnSOD only in neurons of Sod1KO mice prevented premature muscle atrophy,
2-deficiency of CuZnSOD only in neurons caused less severe atrophy than is observed in Sod1KO mice, and
3-lack of CuZnSOD only in muscle resulted in weakness without atrophy. These data indicate that motor
neuron deficits arising from an oxidized redox status are critical in sarcopenia, but reduction of Sod1 in either
neurons or skeletal muscle alone does not replicate the phenotype of Sod1KO mice, suggesting an interactive
effect between both muscle and neural tissues. Thus, our objective is to critically test this “two-hit” mechanism
for sarcopenia. We hypothesize that (1) defects in neuronal function arising from altered redox homeostasis,
due to Sod1 deficiency or aging, initiate disruption of NMJs resulting in muscle mitochondrial dysfunction; and
(2) under circumstances of impaired ability of muscles to maintain mitochondrial function, resultant changes in
ROS, calcium, and/or inflammation will feed back to further impair maintenance of the NMJ. We will address
this hypothesis in a set of highly integrated Aims that will determine 1. the impact of altered redox homeostasis
in motor neurons on NMJ formation and function, 2. whether NMJ degeneration and increased ROS generation
by muscle mitochondria (mtROS) are necessary to induce sarcopenia, and 3. the role of muscle mtROS,
calcium, and inflammation in the weakness and muscle fiber loss. We will achieve these Aims through three
synergistic Projects supported by Administrative and Animal Resource Cores that are key to the success of
this interactive P01 that relies on shared animal models, frequent contact, and highly collaborative science.

## Key facts

- **NIH application ID:** 9920073
- **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:** $1,663,511
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9920073

## Citation

> US National Institutes of Health, RePORTER application 9920073, Molecular Mechanisms of Neuromuscular Interactions Underlying Age-Related Atrophy (5P01AG051442-05). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/9920073. Licensed CC0.

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