A microparticle delivery system for extended release of all-trans retinoic acid and its impact on macrophage insulin-like growth factor 1 release and myotube formation

Muscle atrophy secondary to disuse, aging, or illness increases the risk of injury, prolonged recovery, and permanent disability. The recovery process involves macrophages and their secretions, such as insulin-like growth factor 1 (IGF-1), which direct muscle to regenerate and grow. Retinoic acid receptor (RAR) activation in macrophages increases IGF-1 expression and can be achieved with all-trans retinoic acid (ATRA). However, poor bioavailability limits its clinical application. Thus, we encapsulated ATRA into poly(lactide-co-glycolide) microparticles (ATRA-PLG) to maintain bioactivity and achieve extended release. ATRA-PLG induces IGF-1 release by RAW 264.7 macrophages, and conditioned media from these cells enhances C2C12 myotube formation through IGF-1. Additionally, ATRA released from ATRA-PLG enhances myotube formation in the absence of macrophages. Toward clinical translation, we envision that ATRA-PLG will be injected in the vicinity of debilitated muscle where it can be taken up by macrophages and induce IGF-1 release over a predetermined therapeutic window. Along these lines, we demonstrate that ATRA-PLG microparticles are readily taken up by bone marrow-derived macrophages and reside within the cytosol for at least 12 days with no toxicity. Interestingly, ATRA-PLG induced IGF-1 secretion by thioglycolate-elicited macrophages, but not bone marrow derived macrophages. We found that the RAR isoforms present in lysate differed between the macrophages studied, which could explain the different IGF-1 responses to ATRA. Given that ATRA-PLG enhances myotube formation directly (through ATRA) and indirectly (through macrophage IGF-1) this study supports the further testing of this promising pharmaceutical using rodent models of muscle regeneration and growth.