PTEN-AKT pathway attenuates apoptosis and adverse remodeling in ponatinib-induced skeletal muscle toxicity following BMP-7 treatment.

Abstract

Tyrosine kinase inhibitors (TKIs) including ponatinib are commonly used to treat cancer patients. Unfortunately, TKIs induce cardiac as well as skeletal muscle dysfunction as a side effect. Therefore, detailed mechanistic studies are required to understand its pathogenesis and to develop a therapeutic treatment. The current study was undertaken to examine whether ponatinib induces apoptosis and apoptotic mechanisms both in vitro and in vivo models and furthermore to test the potential of bone morphogenetic protein 7 (BMP-7) as a possible treatment option for its attenuation. Sol8 cells, a mouse myogenic cell line was exposed to ponatinib to generate an apoptotic cell culture model and were subsequently treated with BMP-7 to understand its protective effects. For the in vivo model, C57BL/6J mice were administered with ponatinib to understand apoptosis, cell signaling apoptotic mechanisms, and adverse muscle remodeling and its attenuation with BMP-7. TUNEL staining, immunohistochemistry (IHC), and real-time polymerase chain reaction (RT-PCR) methods were used. Our data show significantly (p < 0.05) increased TUNEL staining, caspase-3, BAX/Bcl2 ratio in the in vitro model. Furthermore, our in vivo muscle data show ponatinib-induced muscle myopathy, and loss in muscle function. The observed muscle myopathy was associated with increased apoptosis, caspase-3 staining, and BAX/Bcl-2 ratio as confirmed with IHC and RT-PCR. Furthermore, our data show a significant (p < 0.05) increase in the involvement of cell signaling apoptotic regulator protein PTEN and a decrease in cell survival protein AKT. These results suggest that increased apoptosis following ponatinib treatment showed an increase in skeletal muscle remodeling, sarcopenia, and fibrosis. Furthermore, BMP-7 treatment significantly (p < 0.05) attenuated ponatinib-induced apoptosis, BAX/Bcl2 ratio, decreased PTEN, and increased cell survival protein AKT, decreased adverse muscle remodeling, and improved muscle function. Overall, we provide evidence that ponatinib-induces apoptosis leading to sarcopenia and muscle myopathy with decreased function which was attenuated by BMP-7.