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

Am J Physiol Cell Physiol. 2021 Dec 1;321(6):C1000-C1009. doi: 10.1152/ajpcell.00116.2021. Epub 2021 Oct 27.

Abstract

Chemotherapeutic agents (CAs) are first-line antineoplastic treatments against a wide variety of cancers. Despite their effectiveness in halting tumor progression, side effects associated with CAs promote muscle loss by incompletely understood mechanisms. To address this problem, we first identified how oxidative stress impairs protein synthesis in C2C12 myotubes. Transient elevations in reactive oxygen species (ROS) resulted in protein synthesis deficits and reduced ribosomal (r)RNA levels. Oxidative stress did not reduce rRNA gene (rDNA) transcription, but it caused an increase in rRNA and protein oxidation. To determine whether CAs affect protein synthesis independent of oxidative stress, we exposed myotubes to Paclitaxel (PTX), Doxorubicin (DXR), or Marizomib (Mzb) at doses that did result in elevated ROS levels (sub-ROS). Exposure to CAs reduced protein synthesis and rRNA levels, but unlike oxidative stress, sub-ROS exposures impaired rDNA transcription. These results indicate that although oxidative stress disrupts protein synthesis by compromising ribosomal quantity and quality, CAs at sub-ROS doses compromise protein synthesis and ribosomal capacity, at least in part, by reducing rDNA transcription. Therefore, CAs negatively impact protein synthesis by causing oxidative stress in addition to directly reducing the ribosomal capacity of myotubes in a ROS-independent manner.

Keywords: chemotherapy; muscle wasting; oxidative stress; protein synthesis; ribosomal RNA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / toxicity*
  • Cell Line
  • Hydrogen Peroxide / toxicity
  • Mice
  • Muscle Fibers, Skeletal / drug effects*
  • Muscle Fibers, Skeletal / metabolism
  • Oxidative Stress / drug effects*
  • Oxidative Stress / physiology
  • Protein Biosynthesis / drug effects*
  • Protein Biosynthesis / physiology
  • Ribosomes / drug effects*
  • Ribosomes / metabolism

Substances

  • Antineoplastic Agents
  • Hydrogen Peroxide