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

James C Sorensen,Jordan Cook,Vanesa Stojanovska,Emma Rybalka,Alan Hayes,Cara A Timpani,Dean G Campelj,Adam J Trewin,Mathew Stewart,Aaron C Petersen

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.

Highlights

Cancer is a leading cause of world-wide mortality accounting for 8.2 million deaths in 2012 alone, with this figure predicted to reach 14 million by 2034 (World Health Organisation, 2015)
The loss of lean tissue observed was not associated with changes in hydration status (p > 0.05, Figure 2C), there was a trend for OXA treatment to reduce the fat mass index by 15% (p = 0.075; Figure 2B) with BGP-15 treatment affording no protection against this measure (p > 0.05, Figure 2B)
In this study we demonstrate that OXA chemotherapy: (1) significantly reduces body weight which is underpinned by a decline in lean tissue and liver mass; (2) does not impact voluntary exercise capacity, O2 consumption or energy expenditure in mice; (3) shifts fiber size distribution to favor smaller fibers in the tibialis anterior (TA) whilst increasing collagen, neutral lipid, and Ca2+ accumulation; (4) reduces Flexor Digitorum Brevis (FDB) fiber diameter; (5) penetrates the mitochondria and increases mitochondrial population and superoxide (O−2 ) production in FDB fibers and Succinate Dehydrogenase (SDH) content/capacity in TA; and (6) reduces molecular markers of protein synthesis pathways with the tendency to reduce intramuscular protein content

Summary

Introduction

Cancer is a leading cause of world-wide mortality accounting for 8.2 million deaths in 2012 alone, with this figure predicted to reach 14 million by 2034 (World Health Organisation, 2015). Due to its non-specific and systemic mode of action, chemotherapy elicits effects on healthy tissues causing the classic side-effects attributable to anti-cancer therapy including nausea, vomiting, cardio-toxicity, immune disorders, peripheral and axial neuropathy, hair and weight loss and debilitative fatigue (Greene et al, 1993; Zitvogel et al, 2008; Gilliam and St Clair, 2011; National Cancer Institute, 2012; Ariaans et al, 2015) These side-effects often limit treatment tolerability, efficacy and therapeutic options, sometimes leading to the cessation of treatment all together and reducing patient quality of life and prognosis due to the development of co-morbidities (Gilliam and St Clair, 2011; Scheede-Bergdahl and Jagoe, 2013; Argilés et al, 2015; Cheregi et al, 2015). Since skeletal muscle has a high energy requirement, and a high mitochondrial density, emerging data suggests that skeletal muscle pathology may be underpinned by damage induced to the mitochondrial by chemotherapy administration (Davies and Doroshow, 1986; Doroshow and Davies, 1986; Sarosiek et al, 2013; Tabassum et al, 2015)

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