Abstract 14285: Rapamycin Nanoparticles Potently Induce Cardiac Autophagy and Improve Ventricular Function in 18-month Old mdx Mice, The Animal Model of Duchenne Muscular Dystrophy
INTRODUCTION: Autophagy, or “self-eating”, is a cellular process responsible for recycling metabolites and eliminating toxic byproducts. We have shown previously that rapamycin-loaded nanoparticles (R-NP) dramatically increase grip strength in adult mdx mice, through effects on the mTOR pathway that increase autophagic flux, but that conventional oral rapamycin is ineffective, even in pharmacological doses, thereby demonstrating the utility of delivery via NP carriers. Here we hypothesize that cardiac dysfunction in old mdx mice also reflects reduced autophagy that can be augmented by R-NP to improve ventricular function.
METHODS: R-NP (0.275 mol % rapamycin) were formulated using our standard protocols. A total of fourteen 17-month old mdx mice in two groups received R-NP (N=7) or no (N=7) treatment. Treated animals underwent eight IV injections (1.5mL/Kg/dose) over four weeks. At the age of 18-month, all mice were lightly anesthetized for cardiac ultrasonography using a 16 MHz array (Spark, Ardent Sound, Inc.) Both short-axis and long-axis views were acquired to determine the dimensions of left ventricle (LV), which were used to model the LV cavity as an ellipsoid to estimate the LV volume and ejection fraction. LC3 II and P62 protein expression was determined by western blots and normalized by GADPH expression to assess autophagic flux responses.
RESULTS: The presence of R-NP in mdx myocardium was confirmed by standard fluorescent histology of myocardium (Fig.). LV ejection fraction for R-NP treated mice was 57 ± 2.9 %, and approximately 16% higher than that of none-treated mdx mice (49 ± 2.5 %; p<0.03). R-NP treatment increased the expression of LC3 II by 80 % (p<0.01) and reduced P62 by 55 % (p<0.02), both reflecting increased autophagic flux.
CONCLUSION: R-NP treatment of old mdx mice increases autophagic activity with rapid beneficial consequences for improved LV function after only eight doses.
- © 2013 by American Heart Association, Inc.