trewin-bgp15protectsagainst-2017.pdf (4.36 MB)
BGP-15 protects against oxaliplatin-induced skeletal myopathy and mitochondrial reactive oxygen species production in mice
journal contribution
posted on 2017-04-01, 00:00 authored by James C Sorensen, Aaron C Petersen, Cara A Timpani, Dean G Campelj, Jordan Cook, Adam Trewin, Vanesa Stojanovska, Mathew Stewart, Alan Hayes, Emma RybalkaChemotherapy 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.
History
Journal
Frontiers in pharmacologyVolume
8Article number
137Pagination
1 - 19Publisher
Frontiers MediaLocation
Lausanne, SwitzerlandPublisher DOI
Link to full text
ISSN
1663-9812Language
engPublication classification
C1 Refereed article in a scholarly journalCopyright notice
2017, Sorensen, Petersen, Timpani, Campelj, Cook, Trewin, Stojanovska, Stewart, Hayes and RybalkaUsage metrics
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BGP-15mitochondriamitochondrial reactive oxygen speciesmuscle wastingoxaliplatin chemotherapyprotein synthesisskeletal muscleScience & TechnologyLife Sciences & BiomedicinePharmacology & PharmacyINDUCED OXIDATIVE STRESSISOLATED LIMB PERFUSIONLONG-TERM SURVIVORSMUSCLE ATROPHYCARDIAC MITOCHONDRIAENERGY-METABOLISMDOXORUBICIN ACTSADULT SURVIVORSPHASE-ICANCER
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