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The Role of Nuclear Factor Erythroid 2-related factor 2 in Sarcopenic Obesity

Award Number: R00AG083239
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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The Role of Nuclear Factor Erythroid 2-related factor 2 in Sarcopenic Obesity - PROJECT SUMMARY/ABSTRACT Sarcopenic obesity is a debilitating condition that increases the risk of frailty, loss of autonomy, institutionalization, and death in older adults. Currently, obesity medications and lifestyle/behavioral interventions have limited efficacy for sarcopenia, worsening quality of life, and healthspan. As such, there is a critical need to identify and develop treatment strategies for patients with sarcopenic obesity. Reactive oxygen species (ROS) are linked with several age-related human diseases. Oxidative stress has been implicated as a critical factor contributing to the development of sarcopenic obesity by mediating the decline in muscular fitness. To this end, genetic manipulation of redox systems drives oxidative stress, altering mitochondrial integrity and function in aged skeletal muscle. Oxidative stress also decreases the mitochondrial number and phosphorylation capacity while increasing mitochondrial DNA mutations, ultimately resulting in organelle apoptosis. The nuclear factor erythroid-related 2 (NRF2) is a primary regulator of antioxidant and redox-regulating protein expression that maintains redox balance across the lifespan. In fact, NRF2 expression in older adults is decreased and is associated with increased oxidative stress and damage in skeletal muscle. Therefore, activation of NRF2 is a promising therapeutic approach for several chronic diseases under oxidative stress and impaired mitochondrial quality control, such as sarcopenic obesity. This application will examine the role of NRF2 in sarcopenic obesity. The central hypothesis is that NRF2 dictates the mitochondrial quality control signaling, and its disruption exacerbates muscle loss by impairing mitochondrial turnover and redox balance during sarcopenic obesity. In Aim 1 (K99 phase), I will test whether loss of NRF2 regulates DRP1-induced mitochondrial fragmentation in skeletal muscle. I will conduct a series of in vitro loss of function experiments of NRF2 in primary myotubes to assess mitochondrial fission activation and trafficking. These experiments will contribute to our understanding of whether targeting NRF2 improves muscle function and mass during sarcopenic obesity by regulating mitochondrial fission. For Aim 2 (R00 phase), I will determine whether NRF2 is a master regulator of mitochondrial quality control signaling in skeletal muscle during sarcopenic obesity. Here, we will use aged mice that are normal weight or have obesity with muscle-specific deletion of NRF2 treated with or without a mitophagic flux inhibitor (Chloroquine). These experiments will identify whether loss of NRF2 blunts mitochondrial quality control, exacerbating oxidative stress in the muscle. This MOSAIC-K99/R00 NIH Pathway to Independence Award will provide dedicated time and training to learn classic concepts of mitochondrial biology, skeletal muscle cell culture techniques, and the generation of transgenic mice. These new skills will be combined with my previous muscle biology skills to facilitate the implementation of an independent study during the R00 phase. These studies will position me to achieve my long-term goal of directing an extramurally funded research program that addresses skeletal muscle mitochondrial quality control during aging.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $249,000 )
2026	2026	UNIVERSITY OF OREGON	1776 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Aging Research	000	3	4/9/2026	NON-COMPETING CONTINUATION	$249,000
														Subtotal = $249,000

Issue Date FY: 2025 ( Subtotal = $244,020 )
2025	2025	UNIVERSITY OF OREGON	1776 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Aging Research	000	2	8/19/2025	EXTENSION WITH OR WITHOUT FUNDS	$244,020
														Subtotal = $244,020

Grand Total All Awards = $493,020

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The Role of Nuclear Factor Erythroid 2-related factor 2 in Sarcopenic Obesity

Award Number: R00AG083239

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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