R01AG074535

LOOH-Induced Muscle Atrophy with Age - Project Summary

Maintenance of skeletal muscle mass is essential for healthy aging and plays a significant role in quality of life. Age-induced skeletal muscle atrophy (sarcopenia) not only reduces mobility but also increases the propensity to develop metabolic and cardiovascular diseases.

Although skeletal muscle atrophy has broad clinical impact in the increasingly sedentary and aging population, a pharmacologic therapy for muscle mass loss does not exist. Reactive oxygen species (ROS) likely induce muscle atrophy by accelerating proteolysis and depressing protein synthesis. However, ROS refers to a collection of radical molecules whose cellular signals are vast, and it is unclear which of the downstream consequences of oxidative stress are responsible for the loss of muscle mass and function that occurs with age or disuse.

In this application, we will test our hypothesis that lipid ROS (LOOH) promotes muscle atrophy through accelerating autophagy/lysosome-dependent protein degradation.

1) Cellular LOOH is neutralized by phospholipid hydroperoxidase (GPX4), preventing its accumulation and degradation to form reactive lipid aldehydes. We will determine whether neutralization of LOOH by N-acetylcarnosine treatment (lipid aldehyde scavenger) will suppress age and/or disuse-induced skeletal muscle atrophy.

2) Suppression of polyunsaturated fatty acid (PUFA) incorporation by lysophosphatidylcholine acyltransferase-3 (LPCAT3) inhibition prevents LOOH-induced cell death. We will investigate whether LPCAT3 deletion can protect mice from muscle atrophy, and perform subcellular fluxomics to examine intracellular fate of LPCAT3 product during oxidative stress.

3) GPX4 deletion increases protein degradation by accelerating lysosomal degradation. We will test our hypothesis that LOOH supercharges autophagic machinery by its lipidation with LC3.

University Of Utah

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Utah United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 467% from $532,919 to $3,023,977.