The Paradoxical Effect of PARP Inhibitor BGP-15 on Irinotecan-Induced Cachexia and Skeletal Muscle Dysfunction.

Abstract

Simple SummaryBoth cancer and the chemotherapy used to treat it are drivers of cachexia, a life-threatening body-wasting condition which complicates cancer treatment. Poly-(ADP-ribose) polymerase (PARP) inhibitors are currently being investigated as a treatment against cancer. Here, we present paradoxical evidence that they might also be useful for mitigating the skeletal muscle specific side-effects of anti-cancer chemotherapy or exacerbate them. BGP-15 is a small molecule PARP inhibitor which protected against irinotecan (IRI)-induced cachexia and loss of skeletal muscle mass and dysfunction in our study. However, peculiarly, BGP-15 adjuvant therapy reduced protein synthesis rates and the expression of key cytoskeletal proteins associated with the dystrophin-associated protein complex and increased matrix metalloproteinase activity, while it increased the propensity for fast-twitch muscles to tear during fatiguing contraction. Our data suggest that both IRI and BGP-15 cause structural remodeling involving proteins associated with the contractile apparatus, cytoskeleton and/or the extracellular matrix which may be only transient and ultimately beneficial or may paradoxically onset a muscular dystrophy phenotype and be detrimental if more permanent.Chemotherapy-induced muscle wasting and dysfunction is a contributing factor to cachexia alongside cancer and increases the risk of morbidity and mortality. Here, we investigate the effects of the chemotherapeutic agent irinotecan (IRI) on skeletal muscle mass and function and whether BGP-15 (a poly-(ADP-ribose) polymerase-1 (PARP-1) inhibitor and heat shock protein co-inducer) adjuvant therapy could protect against IRI-induced skeletal myopathy. Healthy 6-week-old male Balb/C mice (n = 24; 8/group) were treated with six intraperitoneal injections of either vehicle, IRI (30 mg/kg) or BGP-15 adjuvant therapy (IRI+BGP; 15 mg/kg) over two weeks. IRI reduced lean and tibialis anterior mass, which were attenuated by IRI+BGP treatment. Remarkably, IRI reduced muscle protein synthesis, while IRI+BGP reduced protein synthesis further. These changes occurred in the absence of a change in crude markers of mammalian/mechanistic target of rapamycin (mTOR) Complex 1 (mTORC1) signaling and protein degradation. Interestingly, the cytoskeletal protein dystrophin was reduced in both IRI- and IRI+BGP-treated mice, while IRI+BGP treatment also decreased β-dystroglycan, suggesting significant remodeling of the cytoskeleton. IRI reduced absolute force production of the soleus and extensor digitorum longus (EDL) muscles, while IRI+BGP rescued absolute force production of the soleus and strongly trended to rescue force output of the EDL (p = 0.06), which was associated with improvements in mass. During the fatiguing stimulation, IRI+BGP-treated EDL muscles were somewhat susceptible to rupture at the musculotendinous junction, likely due to BGP-15’s capacity to maintain the rate of force development within a weakened environment characterized by significant structural remodeling. Our paradoxical data highlight that BGP-15 has some therapeutic advantage by attenuating IRI-induced skeletal myopathy; however, its effects on the remodeling of the cytoskeleton and extracellular matrix, which appear to make fast-twitch muscles more prone to tearing during contraction, could suggest the induction of muscular dystrophy and, thus, require further characterization.