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

Abstract

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.

BGP-15 Protects against Oxaliplatin-Induced Skeletal Myopathy and Mitochondrial Reactive Oxygen Species Production in Mice

“…They suggested that BGP-15's efficacy was mediated via membrane lipid therapy mechanisms (Salah et al, 2016), an effect that has also been established in other myopathies (Gehrig et al, 2012). Furthermore, BGP-15 has recently been shown to improve certain myopathological aspects of DMD such as collagen deposition (Kennedy et al, 2016), which is consistent with our data.…”

“…The cumulative OXA dosage used in our study is equivalent to that given to humans, scaled for the metabolic activity of mice according to Reagan-Shaw et al (2008). The concentrations and injection protocol for OXA have been used and published by our collaborators previously (Stojanovska et al, 2015; McQuade et al, 2016b), while the BGP-15 dosage administered has proven efficacious against murine myopathies (Chung et al, 2008; Gehrig et al, 2012; Kennedy et al, 2016). On day 14, mice were housed in the Promethion metabolic system for 24 h and on day 15, scanned again for changes in body composition, prior to being anaesthetized (sodium pentobarbitone, 60 mg/kg).…”

“…Via its action as a modulator of the cytoprotective response to cellular stress, and specifically as a poly (ADP-ribose) polymerase (PARP) inhibitor, heat shock protein-inducer (Sarszegi et al, 2012; U.S. National Institutes of Health, 2014), membrane lipid therapeutic (Salah et al, 2016) and an antioxidant inducer (Henstridge et al, 2014), BGP-15 has previously been shown to protect against skeletal muscle dysfunction, damage and wasting (Sapra et al, 2014; Kennedy et al, 2016; Salah et al, 2016). As such, it is of particular interest to us for protection against chemotherapy-induced skeletal muscle dysfunction due to its capacity to improve myopathic structural changes.…”

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

“…BGP-15 is a hydroxylamine derivative that has been shown to exert cyto-and neuroprotective effects in mammalian models of injury, stress, and disease (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). These improvements in cellular function have been correlated with the activation of several intracellular pathways.…”

“…These improvements in cellular function have been correlated with the activation of several intracellular pathways. For example, the heat-shock response is enhanced by increased levels of the molecular chaperone HSP72 (21,24,26,28,29), possibly mediated by Rac-1 signaling (31, 32). BGP-15 also decreases phospho-JNK (pJNK) and p38 stress signaling (21, 23) and increases AKT and IGFR1 protective signaling (23,25).…”