BGP-15 Improves Aspects of the Dystrophic Pathology in mdx and dko Mice with Differing Efficacies in Heart and Skeletal Muscle

• DOI: 10.1016/j.ajpath.2016.08.008
• Publication Date: 2016-10-17T12:58:04Z
• Authors: Tahnee L. Kennedy; Kristy Swiderski; Kate T. Murphy; Stefan M. Gehrig; Claire L. Curl; Chanchal Chandram...; Mark A. Febbraio; Lea M.D. Delbridge; René Koopman; Gordon S. Lynch
• Keywords: Male; Utrophin; Diaphragm; 610; HSP72 Heat-Shock Proteins; Heart; Mice, Mutant Strains; Sarcoplasmic Reticulum Calcium-Transporting ATPases; 3. Good health; Dystrophin; Muscular Dystrophy, Duchenne; Disease Models, Animal; Mice; Piperidines; Oximes; Mice, Inbred mdx; Animals; Humans; Muscle, Skeletal

Duchenne muscular dystrophy is a severe and progressive striated muscle wasting disorder that leads to premature death from respiratory and/or cardiac failure. We have previously shown that treatment of young dystrophic mdx and dystrophin/utrophin null (dko) mice with BGP-15, a coinducer of heat shock protein 72, ameliorated the dystrophic pathology. We therefore tested the hypothesis that later-stage BGP-15 treatment would similarly benefit older mdx and dko mice when the dystrophic pathology was already well established. Later stage treatment of mdx or dko mice with BGP-15 did not improve maximal force of tibialis anterior (TA) muscles (in situ) or diaphragm muscle strips (in vitro). However, collagen deposition (fibrosis) was reduced in TA muscles of BGP-15-treated dko mice but unchanged in TA muscles of treated mdx mice and diaphragm of treated mdx and dko mice. We also examined whether BGP-15 treatment could ameliorate aspects of the cardiac pathology, and in young dko mice it reduced collagen deposition and improved both membrane integrity and systolic function. These results confirm BGP-15's ability to improve aspects of the dystrophic pathology but with differing efficacies in heart and skeletal muscles at different stages of the disease progression. These findings support a role for BGP-15 among a suite of pharmacological therapies for Duchenne muscular dystrophy and related disorders.