Date of Award
Fall 2024
Document Type
Open Access Dissertation
Department
Biomedical Engineering
First Advisor
R. Michael Gower
Abstract
Muscle atrophy is the loss of muscle mass and function from disuse, chronic illness, or aging. This condition significantly reduces quality of life, increases the risk of pre- and post-operative complications, and elevates mortality rates. Current treatments (dietary modifications and resistance exercise), though effective in young individuals with mild atrophy, often require prolonged recovery periods of weeks to months and many do not achieve full recovery. All-trans retinoic acid (ATRA), a metabolite of vitamin A, has shown potential as a muscle regenerative agent through macrophage modulation and direct effects on muscle tissue. However, systemic administration of ATRA is limited by poor bioavailability and severe side effects. In this study, we developed biocompatible and biodegradable poly(lactide-co-glycolide) (PLG) microparticles loaded with ATRA (ATRA-PLG) to enhance its bioavailability and enable localized, sustained release. In vitro experiments with macrophages demonstrated that ATRA-PLG retains the immune-modulating properties of ATRA without compromising cell viability, while also promoting the secretion of growth factors in certain macrophage types. Additionally, ATRA-PLG also has the ability to increase myotube formation in an in vitro muscle growth model. Next, we further evaluated ATRA-PLG in a mouse model of muscle atrophy induced by cast immobilization. After ten days of hindlimb casting, ATRA-PLG was administered locally to the hindlegs, followed by reambulation. Confocal microscopy of the soleus muscle revealed that ATRA-PLG modulated macrophage populations towards a regenerative phenotype, reducing the inflammatory population compared to controls. At the 3-day timepoint, ATRA-PLG treated animals exhibited muscle fibers twice the size of those in control animals, which failed to achieve comparable recovery even after two weeks. Notably, by dat 14, ATRA-PLG treated animals displayed histological signs of full muscle recovery, whereas control animals still showed markers of ongoing regeneration. These findings suggest that ATRA-PLG accelerates muscle recovery following atrophy, potentially offering protective benefits during the early phases of reambulation. The ability of ATRA-PLG to modulate macrophages and promote faster muscle regeneration highlights its potential as a novel therapeutic strategy for enhancing recovery in patients with muscle atrophy, especially in populations where traditional interventions are less effective or increase health risks. This approach could significantly reduce recovery times, improve patient outcomes, and mitigate long-term complications associated with muscle atrophy.
Rights
© 2025, Candice Virginia Cheung
Recommended Citation
Cheung, C. V.(2024). A Particle-Based Delivery System for Extended Release of All-Trans Retinoic Acid Accelerates Recovery After Cast-Immobilization Atrophy in Mice.. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/8133