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

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.

Oxaliplatin induces muscle loss and muscle‐specific molecular changes in Mice

“…Given that mice 8 weeks of age are still growing, reduced weight gain in this population may persist in older mice, and we have observed that body weight gain remains significantly reduced for >60 days in mice treated with the extended regimen (30‐mg/kg oxaliplatin cumulative dose). Although food intake was not measured in this model, a recent publication found that oxaliplatin treatment caused weight loss without a significant reduction in food or water intake in mice, suggesting that muscle loss was independent of chemotherapy‐associated anorexia . Interestingly, Barreto et al .…”

“…One study, using a similar apparatus, showed that oxaliplatin reduces the total distance traveled in mice (representing locomotive behavior) . Other studies suggested that nosepoke (exploratory/escape behavior) was non‐significantly reduced in oxaliplatin‐treated rats and voluntary exploratory behavior in oxaliplatin‐treated mice was unaltered when measured over a 24‐hour period . The voluntary exploratory behavior included interaction with food and water, which was independently significantly increased in oxaliplatin‐treated mice, and this may have confounded aspects of these results.…”

“…However, given the dose concentration and short time frame of this treatment regimen, it is perhaps not surprising that extreme muscle wasting was not detectable. Indeed, another study showed that mice treated with 18‐mg/kg cumulative dose of oxaliplatin had no significant skeletal muscle mass loss at day 15 after first injection . Interestingly, however, in a model of cisplatin‐induced muscle atrophy, mice treated with cisplatin for 4 consecutive days with a cumulative dose concentration of 12 mg/kg had significant hindlimb and quadriceps muscle wasting and reduced myofiber diameters .…”

“…The antineoplastic activity of oxaliplatin derives from its ability to generate platinum–DNA adducts, leading to inhibition of DNA replication, irreversible mitochondrial and cytoskeletal damage, and subsequent cellular apoptosis . A recent study indicated that oxaliplatin‐treated mice have reduced lean and fat tissue mass, altered muscle fiber size, calcium accumulation, collagen deposition, and reduced intramuscular protein, in association with mitotoxicity . In this study, we aimed to further determine whether oxaliplatin independently causes the development of a cachexia‐like response in muscle in non–tumor‐bearing mice and also to identify novel contributing molecular pathways.…”

“…29 A recent study indicated that oxaliplatin-treated mice have reduced lean and fat tissue mass, altered muscle fiber size, calcium accumulation, collagen deposition, and reduced intramuscular protein, in association with mitotoxicity. 30 In this study, we aimed to further determine whether oxaliplatin independently causes the development of a cachexia-like response in muscle in non-tumor-bearing mice and also to identify novel contributing molecular pathways.…”