Abstract P1022: Synthetic Copolymer-Based Membrane Stabilizers Confer Protection To Dystrophin-Deficient Striated Muscle In Vitro And In Vivo

Abstract

Duchenne muscular dystrophy (DMD) is a chronic and progressive muscle wasting disease resulting from the inability to produce the cytoskeletal protein dystrophin. The absence of dystrophin increases the susceptibility of the sarcolemma to mechanical damage and ultimately contributes to muscle degeneration and fibrosis. A growing body of evidence suggests that synthetic membrane stabilizing copolymers can be an effective strategy to limit contraction-induced sarcolemma damage. First-in-class copolymer-based membrane stabilizer Poloxamer 188 (P188) is a linear, amphiphilic triblock copolymer demonstrated to protect dystrophic cardiac and skeletal muscle in a wide variety of in vitro and in vivo models. However, the architectural features of P188 responsible for its membrane protective effects remain to be fully elucidated. Additionally, various other membrane-stabilizing copolymers differing in their size, architecture, and composition have been useful in structure-function studies. Here we sought to elucidate the properties of synthetic copolymers that confer stabilization to the dystrophin-deficient membrane. Using newly developed techniques, we designed and investigated an innovative class of branched “bottlebrush” copolymers at the single skeletal muscle fiber and organismal levels. Our results identify an intriguing, novel bottlebrush copolymer effective at previously unreported nanomolar concentrations in vitro . We also show in preliminary studies that bottlebrush copolymers may further confer protection during isoproterenol-induced cardiac stress testing in dystrophin deficient mice in vivo . These findings will be discussed in terms of copolymer-based membrane-interfacing molecules in the context of stabilizing dystrophin-deficient striated muscle.