# BLR&D Research Career Scientist Award Application

> **NIH VA IK6** · OKLAHOMA CITY VA MEDICAL CENTER · 2022 · —

## Abstract

Project Summary/Abstract.
The overall focus of my work as a Senior VA Research Career Scientist has been to study the effect of
oxidative stress and mitochondrial dysfunction in age-related conditions such as sarcopenia and frailty,
and in the neurodegenerative disease, Amyotrophic Lateral Sclerosis (ALS). My research program is highly
relevant to the mission of the VA due to the universal impact of sarcopenia and frailty on older veterans,
and the increased prevalence of ALS in veterans. Sarcopenia is the progressive loss of muscle mass and
function with age characterized by a deterioration of muscle quantity and quality leading to a gradual loss
of activity and a decline in strength and power. Sarcopenia has a critical impact on the aging population
and older Veterans (more than 40% of veterans are over age 65) due to the increased risk of falls and
injuries, leading to excess morbidity and mortality. An understanding of the factors and interactions in the
mechanisms involved in motorneuron health, maintenance and eventual degeneration of the
neuromuscular junction (NMJ), synaptic function and degenerative changes in the muscle tissue itself are
critical to identify potential therapeutic targets to prevent or reduce muscle atrophy during aging and in
neuromuscular degenerative diseases such as ALS. In my most recent completed VA merit review project
“Testing the mechanisms by which NMJ disruption contributes to sarcopenia” we specifically investigated
the role of the neuromuscular junction and loss of innervation in muscle atrophy and weakness. Using
several novel mouse models to target deficits in neurons alone, muscle alone or in both tissues, we tested
whether alterations in the neuromuscular junction play a critical role in sarcopenia by modulating the NMJ
through presynaptic and postsynaptic alterations and measuring the effect on downstream degenerative
pathways in muscle. Key findings from these studies show that changes in the neuron are important, and
likely initiate changes in the muscle, yet deficits in both the neuron and the muscle are required to initiate
a full sarcopenic phenotype. Importantly, we further demonstrated that rescuing neuronal deficits
specifically in neurons in a CuZnSOD (Sod1-/-) knockout mouse that mimics accelerated age related
sarcopenia is sufficient to preserve neuromuscular junction and skeletal muscle structure despite the high
levels of overall oxidative stress in this model. These results suggest that redox homeostasis in motor
neurons plays a key role in initiating sarcopenia during aging and that therapies to reduce muscle atrophy
during aging may be most effective if they target the motor neurons. Another key result from the studies
in the past funding period formed the basis for our new studies that point to maintenance of cytosolic
calcium as a potential regulator of downstream muscle degenerative changes. We found that the loss of
muscle mass and function in the Sod1-/- mouse model could be prevent...

## Key facts

- **NIH application ID:** 10451499
- **Project number:** 5IK6BX005234-03
- **Recipient organization:** OKLAHOMA CITY VA MEDICAL CENTER
- **Principal Investigator:** HOLLY VAN REMMEN
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10451499

## Citation

> US National Institutes of Health, RePORTER application 10451499, BLR&D Research Career Scientist Award Application (5IK6BX005234-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10451499. Licensed CC0.

---

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