Abstract
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.