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

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.

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Work Title Chemotherapy agents reduce protein synthesis and ribosomal capacity in myotubes independent of oxidative stress
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Open Access
Creators
  1. Bin Guo
  2. Devasier Bennet
  3. Daniel J. Belcher
  4. Hyo-Gun Kim
  5. Gustavo A. Nader
Keyword
  1. Chemotherapy
  2. Muscle wasting
  3. Oxidative stress
  4. Protein synthesis
  5. Ribosomal RNA
License In Copyright (Rights Reserved)
Work Type Article
Publisher
  1. American Journal of Physiology-Cell Physiology
Publication Date December 2, 2021
Publisher Identifier (DOI)
  1. https://doi.org/10.1152/ajpcell.00116.2021
Deposited July 21, 2022

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Version 1
published

  • Created
  • Added 2021_Guo_et_al-Chemotherapy_and_rDNA-AJP_Cell.pdf
  • Added Creator Bin Guo
  • Added Creator Devasier Bennet
  • Added Creator Daniel J. Belcher
  • Added Creator Hyo Gun Kim
  • Added Creator Gustavo A. Nader
  • Published
  • Updated Keyword, Publisher, Publication Date Show Changes
    Keyword
    • Chemotherapy, Muscle wasting, Oxidative stress, Protein synthesis, Ribosomal RNA
    Publisher
    • American Journal of Physiology
    • American Journal of Physiology-Cell Physiology
    Publication Date
    • 2021-12-01
    • 2021-12-02
  • Renamed Creator Hyo-Gun Kim Show Changes
    • Hyo Gun Kim
    • Hyo-Gun Kim
  • Updated