PROJECT SUMMARY: Muscle weakness in VA patients most commonly results from inactivity related to injury, illness, or surgery. Even with aggressive rehabilitation, bouts of enforced skeletal muscle inactivity can lead to atrophy and loss of function that persist long after remobilization. While pharmacotherapies might improve outcomes for many veterans suffering from loss of function secondary to disuse atrophy, none exist. Since age- related loss of muscle function accelerates further loss of function and increases risk of disability, development of a pharmacotherapy that enables full recovery of function would be transformative for veterans and the general population. Effective recovery of atrophied skeletal muscle is dependent upon macrophages. First, macrophage inflammation directs satellite cells to fuse with damaged fibers to facilitate repair. Then, macrophage regenerative factors resolve inflammation and promote muscle growth. Therefore, a pharmacotherapy is needed that can specifically target these cells within the skeletal muscle. We met this challenge by developing polymer particles for localized, extended release of all-trans retinoic acid (ATRA-PLG). ATRA is in broad use clinically for indications other than muscle wasting, but our data indicate delivery of ATRA-PLG to the facia of atrophied muscle restores muscle fiber size, improves mobility, increases IGF-1, and decreases IL-6 in the early phase of recovery. Also, in vitro studies indicate ATRA-PLG induces macrophages to secrete IGF-1. Therefore, our central hypothesis is that administration of ATRA-PLG to atrophied muscle enhances 1) skeletal muscle recovery and 2) the macrophage regenerative response. We will test this hypothesis by inducing muscle atrophy with cast immobilization in mice and then injecting ATRA-PLG with release kinetics that match the time course of muscle recovery when the cast is removed. Specific Aim 1 will determine if ATRA-PLG delivery accelerates functional recovery of skeletal muscle after remobilization. Specific Aim 2 will determine if ATRA-PLG delivery enhances the macrophage regenerative response in skeletal muscle recovering from disuse. The potential of this work for positive impact is high. A pharmacotherapy that enables full functional recovery of atrophied muscle could revolutionize healthcare for veterans and the general population. If we are successful in rodents, the pathway to clinical implementation is clear and straight forward. First, our therapy could be tested in large animals using ultrasound-guided delivery, which is already used in humans for localized musculoskeletal interventions. Second, ATRA is one of the most prescribed medications in the U.S. and PLG is implemented in 19 FDA drug formulations. Thus, if ATRA-PLG is successful, getting this therapy to veterans may be faster and less expensive than developing new drugs. Finally, the delivery system is versatile, able to accommodate new or additional pharmaceutics or multiple admini...