Membrane-Stabilizing Copolymers Enhance Dystrophic Skeletal Muscle Function and Confer Protection Against Isoproterenol-Induced Death in the Mdx Mouse
Duchenne muscular dystrophy (DMD) is an X-linked recessive disease affecting 1 in 3,500-5,000 males. DMD is caused by the absence of the cytoskeletal protein dystrophin, which results in a loss of sarcolemma integrity and accentuates the damage to the muscle that occurs during contraction. Synthetic membrane stabilizing copolymers have been shown to limit contraction-induced sarcolemma damage in a wide variety of DMD and non-DMD models. The linear, amphiphilic triblock copolymer Poloxamer 188 (P188) leads this class of copolymer-based membrane stabilizers and has been shown to confer protection to dystrophic cardiac and skeletal muscle. However, the architectural features of P188 responsible for its membrane protective effects are not yet fully understood. Additionally, structure-function studies have shown that manipulating copolymer size, architecture, and composition affects copolymer membrane-stabilizing ability. Here we report our preliminary results on an innovative class of branched “bottlebrush” copolymers. We identify an promising, novel bottlebrush copolymer that improves skeletal muscle contractility at previously unreported nanomolar concentrations in vitro. We also provide initial evidence 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.