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Drug Delivery

Drug Delivery - Poster Session E

Poster X13 - Retinoic acid drug delivery accelerates muscle recovery in mice with muscle atrophy

Saturday, October 26, 2024
10:00 AM – 11:00 AM EST
Location: Exhibit Hall E, F & G

Introduction:  Muscle atrophy from disuse (e.g. surgery, illness, injury) is caused by loss of contractile protein, resulting in smaller, weaker fibers. The return to activity post-atrophy can further damage the weakened fibers. Recovery starts with muscle stem cells, or satellite cells. These cells proliferate and differentiate in response to exercise or damage, fusing and repairing existing fibers. In some cases, formation of entirely new fibers may be needed to replace irreparable fibers. The recovery process is additionally modulated by macrophages, an immune cell population that creates a local environment conducive for recovery. All-trans retinoic acid (ATRA) is a metabolite of vitamin A and has been researched as a regenerative agent and is established to exert muscle-supportive effects through macrophages and directly to muscle cells. However, ATRA has poor bioavailability when administered orally or intravenously. Thus, we developed particles for local, extended release. For this study, we hypothesized that when encapsulated into polymer microparticles, ATRA delivery to the fascia of atrophied muscle would accelerate muscle growth after immobilization-induced atrophy in mice

Materials and

Methods:  ATRA particles were fabricated using a single oil-in-water emulsion/solvent evaporation technique using poly(lactide-co-glycolide) as the drug carrier. Particles were characterized by size, drug loading, and release kinetics. Healthy young adult C57Bl/6 male mice were given casts immobilizing the hindlimbs for 10 days. Upon cast removal, particles containing 90, 30, or 9 ng of ATRA or saline were injected into the intermuscular space between the gastrocnemius and tibialis anterior muscles. Mice were allowed to recover for 3, 7, or 14 days, after which mice were euthanized and hindlimb muscles were collected for histological analysis using H&E or immunofluorescence confocal microscopy.

Results, Conclusions, and Discussions: ATRA-PLG treatment enhanced recovery of atrophied muscle when measuring fiber cross sectional area (CSA). CSA, which is positively correlated to functional strength, is larger in the 90 and 30 ng ATRA-PLG groups compared to saline at the 3- and 7-day timepoints. Macrophage inflammation can inhibit muscle growth and, thus, we studied these cells in muscle recovering from casting. Solei immunostainined for macrophage markers CD206, CD68, and CD163 indicate that inflammatory macrophages are decreased with 90 ng ATRA-PLG treatment. In a focused study comprising of only saline- and 90ng-ATRA-PLG treated animals across 14 days of recovery after atrophy, the muscle fiber CSA of saline-treated animals are still significantly smaller compared to ATRA-PLG treated animals. Another histological indicator of regeneration, centralized nuclei, is also decreased in ATRA-PLG treated animals whereas this measurement is elevated in saline-treated animals. These measurements indicate that the ATRA-PLG treated animals have returned to near-recovery whereas saline-treated animals are still recovering at this timepoint.

Taken together, local delivery of ATRA-PLG accelerates recovery after muscle atrophy, shown with CSA and other measurements.

Acknowledgements (Optional):