Chemotherapy agents reduce protein synthesis and ribosomal capacity in myotubes independent of oxidative stress

Chemotherapeutic agents (CAs) are first-line antineoplastic treatments in a wide variety of cancers. These agents can induce oxidative stress and promote muscle loss. CAs trigger local and systemic oxidative stress by increasing mitochondrial reactive oxygen species (ROS) and thereby stimulate protein breakdown. However, whether CAs can directly impact muscle protein synthesis independent of ROS production is currently unknown. To address this problem, first, we identified the mechanism by which oxidative stress impairs myotube protein synthesis. Transient elevations in ROS production resulted in protein synthesis deficits, reduced ribosomal (r)RNA levels and increased rRNA oxidation. We then investigated the effects of CAs on protein synthesis in the absence of detectable elevations in ROS levels (sub-ROS). Paclitaxel (PTX), Doxorubicin (DXR) and Marizomib (Mzb) diminished protein synthesis and ribosomal capacity, and also impaired transcription of the rRNA genes (rDNA). These results indicate that while oxidative stress disrupted protein synthesis by compromising ribosome quantity and quality, CAs at sub-ROS doses also impaired protein synthesis and ribosomal capacity by reducing rDNA transcription. Therefore, CAs can negatively modulate myotube protein synthesis in a ROS-independent manner by altering the capacity for protein synthesis.