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 ...