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

Abstract

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.

Emerging role of TAK1 in the regulation of skeletal muscle mass

“…Skeletal muscle growth requires a net increase in protein synthesis that is governed by the translation efficiency (amount of protein synthesis per unit RNA) and translation capacity (the total ribosomal content) within muscle fibers. [69][70][71][72] Translation is initiated by binding of eukaryotic initiating factor eIF4E to the 5′ Cap of mRNA strand.…”

“…Skeletal muscle growth requires a net increase in protein synthesis that is governed by the translation efficiency (amount of protein synthesis per unit RNA) and translation capacity (the total ribosomal content) within muscle fibers. [ 69–72 ] Translation is initiated by binding of eukaryotic initiating factor eIF4E to the 5′ Cap of mRNA strand. The interaction between eIF4E and mRNA leads to the recruitment of eIF4G, eIF4A, and eIF4B factors to form eIF4F, the translation preinitiation complex, which recruits the 40S subunit of the ribosome to the mRNA strand.…”

Does the blunted stimulation of skeletal muscle protein synthesis by aging in response to mechanical load result from impaired ribosome biogenesis?

“…Chemotherapeutic agents, which are commonly used to treat cancer and blunt tumor progression, have also a detrimental effect on skeletal muscle mass ( Barreto et al, 2016 ; Damrauer et al, 2018 ). A recent study showed in C2C12 myotubes that exposure to chemotherapeutic agents reduced protein synthesis, rRNA content, and Pol I-mediated rDNA transcription at the initiation step, suggesting that chemotherapy-induced anabolic deficits may partly result from impaired ribosome production ( Guo et al, 2021 ).…”