Elucidating the Mechanisms of Translational Approaches to Enhance Recovery of Aged Muscle

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT Muscle atrophy resulting from physical disuse (such as post-surgery, or with extended periods of physical inactivity) increases fall risk and disability in older adults. With a growing aging population, the dysfunctions related to physical disuse will be widespread contributing to large-scale decreases in healthspan, and increases in morbidities and hospitalizations as skeletal muscle health is important for whole body glucose regulation, postural stability/balance, and strength to perform activities of daily living (independence). Unfortunately, physical rehabilitation alone does not always adequately restore muscle size and function in older populations. The use of mechanistic-based, translational therapeutics may provide a much-needed solution to improve muscle recovery in older adults following disuse, however, well designed, translational pre-clinical trials testing therapeutic agents are required. Here, in the F99 phase, I propose a rigorous pre-clinical trial utilizing a metformin and leucine combination treatment (MET+LEU) to promote muscle recovery from disuse in aged mice. My current progress supports that MET+LEU promotes recovery from disuse in aged mice as evidenced by increased strength, satellite cells and reduced muscle fibrosis. Through in vitro and in vivo methods, we aim to test the mechanism of MET+LEU action. The goal of this work is to identify if MET+LEU treatment confers positive benefits in a skeletal muscle cell autonomous fashion, and if the effects of MET+LEU are regulated through the SIRT1-AMPKα-PGC-1α signaling axis, implicated to be targeted by MET+LEU. During the K00 phase, I will work under an expert in muscle aging specifically in extracellular matrix remodeling and fibroblast- satellite cell crosstalk, to further elucidate the effects of MET+LEU and other translational therapeutics on muscle health. In doing so, we will become closer to providing a solution to promote muscle recovery following disuse by furthering our knowledge on how MET+LEU and other translationally relevant therapies influence muscle dysfunction with disuse and aging. Through these two critical phases and the mentoring across two exceptional academic institutions, I will fill current gaps in my skillset using skeletal muscle cell genetic manipulation, genetic mouse models, guidance in utilizing potential translatable pharmaceuticals in pre-clinical research, exposure to related clinical trials, and new knowledge and techniques to investigate cell-to-cell crosstalk in aging muscle. I will additionally gain grant writing and outreach skills to promote diversity in health-related biomedical research. These skills gained will enhance my long-term career goal to become a tenured professor running an independent, NIH-funding laboratory focused on novel, translatable therapeutics to promote muscle health in aging.