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Membrane‐Stabilizing Copolymers Confer Protection to Dystrophic Skeletal Muscle in vitro and in vivo
Author(s) -
Houang Evelyne,
Haman Karen,
Filareto Antonio,
Perlingeiro Rita,
Bates Frank,
Lowe Dawn,
Metzger Joseph
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.1039.3
Subject(s) - in vivo , skeletal muscle , duchenne muscular dystrophy , poloxamer , myocyte , dystrophin , in vitro , membrane , cardiac muscle , muscular dystrophy , chemistry , biophysics , copolymer , pharmacology , microbiology and biotechnology , medicine , biochemistry , biology , organic chemistry , polymer
Muscle membrane instability is a hallmark of Duchenne Muscular Dystrophy, a disease that results in skeletal muscle weakness and cardiomyopathy. Poloxamer 188 (P188) is a membrane stabilizer that has been shown by us and others to protect the dystrophic myocardium under physiological stress but its effects on the skeletal myopathy have been less clear to date. P188 belongs to the tri‐block copolymer family, which comprises molecules made of a hydrophobic polypropylene oxide (PPO) core flanked by linear chains of hydrophilic polyethylene oxide (PEO) moieties. These exist at various sizes and PPO/PEO ratios and it is unclear what structural properties of P188 confer its membrane protecting functionality. Mechanistic knowledge is requisite for a deeper understanding of membrane protection by copolymers. We show that P188 at concentrations protective for dystrophic cardiac myocytes is also efficacious in stabilizing membranes of dystrophic skeletal muscle cells in vitro suggesting that delivery limits P188 efficacy in vivo. We show here that P188′s efficacy in protecting dystrophic mdx mice limb muscle from lengthening injury in vivo is critically dependent on delivery route. We also show that extended tri‐block copolymers can provide increased potency. Systematic optimization of tri‐block copolymer delivery, dosing and structure offers a unique therapeutic strategy to protect both dystrophic cardiac and skeletal muscle in vivo. Funded by MDA, NIH and AHA.