Membrane-Sealant Copolymers Confer Protection to Dystrophic Skeletal Muscle in Vitro and in Vivo
2014
Muscle membrane vulnerability is a hallmark of Duchenne Muscular Dystrophy (DMD), an X-linked disease that results in progressive skeletal muscle weakness and cardiomyopathy. Cardiac disease is an increasing cause of death in DMD and there is currently no cure for DMD. One unique therapeutic approach is the use of membrane sealants to protect the fragile dystrophic muscle membranes from mechanical stress. We propose a structure-function strategy in understanding the mechanism by which block copolymers may protect dystrophic cardiac and skeletal muscles. Poloxamer 188 (P188) is a membrane sealant that has been shown by us and others to protect the fragile dystrophic myocardium under physiological stress but appears to have reduced efficacy in affecting the skeletal myopathy. P188 belongs to the tri-block copolymer family, which comprises molecules made of a hydrophobic polypropylene oxide (PPO) core flanked by hydrophilic chains of polyethylene oxide (PEO) moieties. These copolymers exist at various molecular weights and PPO to PEO ratios and it is unknown what structural properties of P188 confer its membrane protecting functionality. Mechanistic knowledge is requisite for a deeper understanding of muscle membrane protection by copolymer sealants to enable therapeutic application. Interestingly, our data shows that P188 is efficacious in isolated dystrophic skeletal myofibers suggesting that poor delivery and low diffusion into the core of dystrophic whole muscle in vivo limits P188 effectiveness. Ultimately, fully effective therapeutic strategies must simultaneously target both cardiac and skeletal muscle tissues. We will present data on copolymer structure-function understanding and discuss how these new data will shed light into the structural requisite for more efficacious and potent membrane sealants for dystrophic skeletal muscle in vivo.
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