Manipulation of the systemic environment to improve skeletal muscle recovery after disuse-induced atrophy

About This Grant

PROJECT SUMMARY / ABSTRACT Aging Veterans have higher incidences of comorbid chronic diseases compared to the general population, resulting in more frequent hospitalizations. An outcome of frequent hospitalizations in aged individuals is prolonged bed rest or immobilization, which accelerates sarcopenia. This period of disuse is compounded by aging, as skeletal muscle mass and function fail to fully recover to the same extent as in younger adults. The failure to recover skeletal muscle mass and function after disuse atrophy has a profound impact on mobility, independence, and quality of life. Therefore, improving the ability of aged skeletal muscle to recover muscle mass and function after periods of disuse would improve clinical outcomes in the lives of aging Veterans. Exercise is polytherapeutic in that it positively affects most tissues and attenuates many of the hallmarks of aging. Exercise releases factors such as peptides, metabolites, and RNAs into the systemic environment (termed exerkines), many of which are transported via extracellular vesicles (EVs). These exerkines act in an autocrine, paracrine, and endocrine manner to improve health outcomes. The current study tests the novel idea that changing the systemic milieu with exercised plasma and exerkine-packaged EVs isolated from plasma will improve skeletal muscle health after disuse atrophy. These data will be the first to explore how the systemic environment could be manipulated to improve muscle recovery after bed rest using exercised plasma and EVs. The overall hypothesis is that exerkines in plasma and EVs can improve the recovery of aged skeletal muscle mass and function after a period of disuse-induced atrophy. To test this hypothesis, we will administer exercised plasma before, during, or after hindlimb unloading (HLU) to determine the effects on skeletal muscle recovery in both sexes. We will also determine the effects of EV-depleted plasma, isolated exercise-induced EVs, and synthetic “exercise-mimicking” EVs on aged skeletal muscle recovery and mitochondrial structure and function after a period of HLU. We will use a battery of approaches to assess functional and molecular changes in skeletal muscle mass and function, as well as how each intervention alters the systemic environment. We will examine plasma and EV cargo using proteomic and miRNA sequencing to determine potential mechanisms of recovery. To delineate potential mechanisms, we will use Support Vector Machine Learning to determine which miRNAs and proteins independently and concomitantly improve aged skeletal muscle recovery. We expect improved muscle recovery following the administration of exerkines in plasma and EVs (endogenous and synthetic EVs), and that these improvements will be associated with increased mitochondrial bioenergetic capacity, redox balance, and anti-inflammatory processes. Furthermore, we will identify which miRNAs and proteins are responsible for these improvements in skeletal muscle mass and function. My short-term goals are to determine if manipulation of the systemic environment with exercise plasma and plasma factors can improve aged skeletal muscle mass and function after disuse atrophy. To achieve these short-term goals, I will receive training in aging, the use of stable isotopes, EVs, bioinformatics, and scientific communication. I will receive this training through a combination of meetings with my mentoring team, conferences, presentations, formal courses, and conducting experiments. The training plan I have outlined will allow me to achieve my long-term goal of becoming an independent VA scientist.