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

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-induce...

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Autores principales: Sorensen, James C., Petersen, Aaron C., Timpani, Cara A., Campelj, Dean G., Cook, Jordan, Trewin, Adam J., Stojanovska, Vanesa, Stewart, Mathew, Hayes, Alan, Rybalka, Emma
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385327/
https://www.ncbi.nlm.nih.gov/pubmed/28443020
http://dx.doi.org/10.3389/fphar.2017.00137
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author Sorensen, James C.
Petersen, Aaron C.
Timpani, Cara A.
Campelj, Dean G.
Cook, Jordan
Trewin, Adam J.
Stojanovska, Vanesa
Stewart, Mathew
Hayes, Alan
Rybalka, Emma
author_facet Sorensen, James C.
Petersen, Aaron C.
Timpani, Cara A.
Campelj, Dean G.
Cook, Jordan
Trewin, Adam J.
Stojanovska, Vanesa
Stewart, Mathew
Hayes, Alan
Rybalka, Emma
author_sort Sorensen, James C.
collection PubMed
description 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 Ca(2+) 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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spelling pubmed-53853272017-04-25 BGP-15 Protects against Oxaliplatin-Induced Skeletal Myopathy and Mitochondrial Reactive Oxygen Species Production in Mice Sorensen, James C. Petersen, Aaron C. Timpani, Cara A. Campelj, Dean G. Cook, Jordan Trewin, Adam J. Stojanovska, Vanesa Stewart, Mathew Hayes, Alan Rybalka, Emma Front Pharmacol Pharmacology 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 Ca(2+) 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. Frontiers Media S.A. 2017-04-10 /pmc/articles/PMC5385327/ /pubmed/28443020 http://dx.doi.org/10.3389/fphar.2017.00137 Text en Copyright © 2017 Sorensen, Petersen, Timpani, Campelj, Cook, Trewin, Stojanovska, Stewart, Hayes and Rybalka. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Sorensen, James C.
Petersen, Aaron C.
Timpani, Cara A.
Campelj, Dean G.
Cook, Jordan
Trewin, Adam J.
Stojanovska, Vanesa
Stewart, Mathew
Hayes, Alan
Rybalka, Emma
BGP-15 Protects against Oxaliplatin-Induced Skeletal Myopathy and Mitochondrial Reactive Oxygen Species Production in Mice
title BGP-15 Protects against Oxaliplatin-Induced Skeletal Myopathy and Mitochondrial Reactive Oxygen Species Production in Mice
title_full BGP-15 Protects against Oxaliplatin-Induced Skeletal Myopathy and Mitochondrial Reactive Oxygen Species Production in Mice
title_fullStr BGP-15 Protects against Oxaliplatin-Induced Skeletal Myopathy and Mitochondrial Reactive Oxygen Species Production in Mice
title_full_unstemmed BGP-15 Protects against Oxaliplatin-Induced Skeletal Myopathy and Mitochondrial Reactive Oxygen Species Production in Mice
title_short BGP-15 Protects against Oxaliplatin-Induced Skeletal Myopathy and Mitochondrial Reactive Oxygen Species Production in Mice
title_sort bgp-15 protects against oxaliplatin-induced skeletal myopathy and mitochondrial reactive oxygen species production in mice
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385327/
https://www.ncbi.nlm.nih.gov/pubmed/28443020
http://dx.doi.org/10.3389/fphar.2017.00137
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