# Lipid hydroperoxides in sarcopenia and muscle wasting: mechanisms and intervention

> **NIH VA IK2** · OKLAHOMA CITY VA MEDICAL CENTER · 2022 · —

## Abstract

SIGNIFICANCE TO VETERANS HEALTH: Two-thirds of all veterans are 55 years of age or older. Sarcopenia
is a syndrome that effects approximately 25% of the U.S. population over the age of 70 characterized by
progressive loss of skeletal muscle mass and strength with an increased risk of adverse outcomes such as
physical disability, poor quality of life and even death. Further, the development of sarcopenia may lead to
secondary health conditions such as disuse, malnutrition, falls, fractures and diabetes. In addition to the physical
ailments that accompany patients that suffer from sarcopenia, sarcopenia contributes to over $18.5 billion dollars
of total health care expenditures. The prevalence of sarcopenia is higher in subjects presenting another health
condition than in healthy subjects including mental conditions such as depression that are common among
veterans. There are currently no effective treatments for sarcopenia because underlying mechanisms are not
fully elucidated. OBJECTIVES: The objective of this study is to test if denervation induced generation of lipid
hydroperoxides (LOOHs), through the enzyme 12/15-Lipoxygenase (12/15-Lox) or through direct oxidation of
lipids, leads to neuromuscular junction (NMJ) disruption and mitochondrial dysfunction that initiates muscle
atrophy, muscle protein breakdown, and weakness. RESEARCH PLAN: In Specific Aim 1, I will test the effect
of reducing LOOHs via treatment with the LOOH scavenger liproxstatin-1 on mitochondrial function, NMJ
structure and function, protein turnover, and maintenance of muscle mass and function in aged mice. In Specific
Aim 2, I will test the effect of muscle specific genetic deletion of 12/15-Lox, an enzyme that generates eicosanoids
and oxylipins, on the maintenance of muscle mass and function in aged mice. Finally, in Specific Aim 3, I will
test the effect of muscle specific overexpression of glutathione peroxidase 4 (GPx4), an enzyme that reduces
LOOHs within membranes, on the maintenance of muscle mass and function in aged mice. We will use a
combination of pharmacological approaches, genetic mouse models, and novel research techniques to test the
central hypothesis. ANTICIPATED OUTCOMES: All of my Specific Aims focus on reducing skeletal muscle
LOOHs (either enzymatically generated or direct oxidation of lipids) in response to age-related denervation. I
hypothesize that my interventions will ameliorate skeletal muscle atrophy and dysfunction in hindlimb muscle
from aged mice by reducing lipid peroxidation, improving mitochondrial function, reducing rates of protein
degradation, and maintaining NMJ integrity. My preliminary data clearly shows that LOOH generation is elevated
in aged muscle, and that LOOH generation is strongly correlated to muscle mass loss in models of denervation
atrophy. For skeletal muscle mass loss to occur, rates of protein degradation have to be greater than rates of
protein synthesis. Therefore, my interventions have to reduce rates of protein ...

## Key facts

- **NIH application ID:** 10366483
- **Project number:** 1IK2BX005620-01A1
- **Recipient organization:** OKLAHOMA CITY VA MEDICAL CENTER
- **Principal Investigator:** Jacob Levi Brown
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10366483

## Citation

> US National Institutes of Health, RePORTER application 10366483, Lipid hydroperoxides in sarcopenia and muscle wasting: mechanisms and intervention (1IK2BX005620-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10366483. Licensed CC0.

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