Local injection of particles for retinoic acid drug delivery improves muscle structure and modulates inflammation in mice recovering from cast immobilization

Disuse muscle atrophy secondary to acute illness or injury prolongs recovery and increases risk of permanent disability as a result of reduced muscle strength and myofiber damage upon reambulation. However, there are no pharmacotherapies to support muscle growth and repair following prolonged immobility. We propose that all-trans retinoic acid (ATRA) may support recovery of atrophied muscle via modulation of satellite cells and macrophages. Clinical application of ATRA is hindered by solubility, stability, and the need for high systemic doses. Therefore, in the current study, we developed poly(lactide-co-glycolide) (PLG) particles for local injection and extended release of ATRA (ATRA-PLG) and investigated the impact of ATRA-PLG on muscle recovery from disuse atrophy in adult mice following 10 days of hindlimb cast immobilization. A single administration of ATRA-PLG to the facia surrounding the calf muscle, at the time of cast removal, accelerates recovery of soleus muscle cross-sectional area. This is associated with decreased tissue damage, increased expression of macrophage scavenger receptors CD206 and CD163, and decreased CD68 and IL-6. Meanwhile, markers of muscle repair and growth are weakly impacted by ATRA-PLG. The data suggest that ATRA-PLG modulation of macrophages may limit inflammation and secondary injury to the atrophied muscle during the early stages of recovery, which then requires a lower repair response, and this translates to accelerated recovery of cross-sectional area. Our findings lay the foundation for future investigations of ATRA-PLG in populations that exhibit incomplete recovery from atrophy and dysregulated macrophage function, such as the elderly.<b>NEW & NOTEWORTHY</b> No pharmacotherapies exist to support muscle recovery from disuse. We developed particles for extended release of retinoic acid (ATRA-PLG) and investigated its impact on muscle recovery from cast immobilization. A single administration to the hindlimb, at the time of cast removal, accelerates soleus recovery and promotes macrophage polarization associated with repair. Our work supports ATRA-PLG as a clinical countermeasure to facilitate recovery from disuse and implicates modulation of inflammation as a mechanism of action.