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

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    Author
    Sorensen, JC; Petersen, AC; Timpani, CA; Campelj, DG; Cook, J; Trewin, AJ; Stojanovska, V; Stewart, M; Hayes, A; Rybalka, E
    Date
    2017-04-10
    Source Title
    Frontiers in Pharmacology
    Publisher
    FRONTIERS MEDIA SA
    University of Melbourne Author/s
    Hayes, Alan
    Affiliation
    Medicine and Radiology
    Metadata
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    Document Type
    Journal Article
    Citations
    Sorensen, J. C., Petersen, A. C., Timpani, C. A., Campelj, D. G., Cook, J., Trewin, A. J., Stojanovska, V., Stewart, M., Hayes, A. & Rybalka, E. (2017). BGP-15 Protects against Oxaliplatin-Induced Skeletal Myopathy and Mitochondrial Reactive Oxygen Species Production in Mice. FRONTIERS IN PHARMACOLOGY, 8 (APR), https://doi.org/10.3389/fphar.2017.00137.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/253636
    DOI
    10.3389/fphar.2017.00137
    Abstract
    Chemotherapy is a leading intervention against cancer. Albeit highly effective, chemotherapy has a multitude of deleterious side-effects including skeletal muscle wasting and fatigue, which considerably reduces patient quality of life and survivability. As such, a defense against chemotherapy-induced skeletal muscle dysfunction is required. Here we investigate the effects of oxaliplatin (OXA) treatment in mice on the skeletal muscle and mitochondria, and the capacity for the Poly ADP-ribose polymerase (PARP) inhibitor, BGP-15, to ameliorate any pathological side-effects induced by OXA. To do so, we investigated the effects of 2 weeks of OXA (3 mg/kg) treatment with and without BGP-15 (15 mg/kg). OXA induced a 15% (p < 0.05) reduction in lean tissue mass without significant changes in food consumption or energy expenditure. OXA treatment also altered the muscle architecture, increasing collagen deposition, neutral lipid and Ca2+ accumulation; all of which were ameliorated with BGP-15 adjunct therapy. Here, we are the first to show that OXA penetrates the mitochondria, and, as a possible consequence of this, increases mtROS production. These data correspond with reduced diameter of isolated FDB fibers and shift in the fiber size distribution frequency of TA to the left. There was a tendency for reduction in intramuscular protein content, albeit apparently not via Murf1 (atrophy)- or p62 (autophagy)- dependent pathways. BGP-15 adjunct therapy protected against increased ROS production and improved mitochondrial viability 4-fold and preserved fiber diameter and number. Our study highlights BGP-15 as a potential adjunct therapy to address chemotherapy-induced skeletal muscle and mitochondrial pathology.

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