The aging population accounts for nearly 50% Veterans, but only 18% of non-Veterans. This large population of aging Veterans is susceptible to age-related skeletal muscle wasting known as sarcopenia. Importantly, there are no FDA-approved drugs for treating sarcopenia. Consequently, identifying cost-effective interventions to treat sarcopenia is a major public health challenge for Veterans. At the cellular level, one of the important contributors of sarcopenia is dysfunction of the satellite cells or muscle progenitor cells (MPCs), leading to the impaired ability to form new muscle fibers. Physiologically, muscle-derived prostaglandin E2 (PGE2) is an important inducer of myogenesis by activating the expansion of satellite cells and MPCs that precedes muscle formation. However, owing to PGE2's rapid degradation in vivo, one strategy to increase the abundance of PGE2 is to block the negative regulator of PGE2 known as prostaglandin E2 (PGE2)-degrading enzyme (15- PGDH). Through our previous space-based drug screening studies aboard the International Space Station to study muscle formation using engineered muscle tissue, we identified a small molecule inhibitor of 15-PGDH (SW033291) that has profound effect in enhancing muscle formation in vitro. However, successful clinical translation of this drug will require site-specific and sustained delivery of SW03329. Furthermore, since exercise is recommended to combat sarcopenia, the potential synergistic benefits of drug therapy and exercise have yet to be evaluated. Therefore, the objective is to develop a biomaterials-based strategy for site-specific and sustained release of SW033291, and then to test the efficacy of drug delivery with rehabilitative exercise for treating sarcopenia in aged mice. The overarching hypothesis is that biomaterials-based delivery of SW03329 with rehabilitative exercise will improve muscle function and muscle mass in a murine sarcopenia model. Specific Aim 1 is to develop a microsphere-based sustained release system for SW033291, and to validate the efficacy of SW033291 to promote muscle formation and contractility in vitro. We hypothesize that the biocompatible microspheres will support sustained drug release, leading to enhanced muscle formation in MPCs. We will employ an established poly(lactic-co-glycolic acid)-poly(ethylene glycol)-carboxyl (PLGA-PEG-COOH)-based microsphere delivery system to achieve a range of sustained release concentrations. MPCs will be cultured in expansion media for 5 days either in the presence or absence of the drug-laded microspheres. For up to 5 days after exposure to the microspheres, MPCs will be assessed for cell cytotoxicity, and the conditioned media will be assayed for PGE2 levels using a PGE2 enzyme linked immunosorbent assay. To study the efficacy of drug exposure on myotube formation, the cells will be immunofluorescently stained to visualize myotubes using skeletal muscle myosin heavy chain. The degree of myotube contractility in res...