Chemotherapeutic drugs negatively affect myoblast proliferation and myotube anabolism by reducing rDNA transcription

Cancer cachexia negatively affects quality of life and contributes to increased morbidity and mortality in a wide variety of cancer types. Emerging evidence suggests that, in addition to tumor derived factors, chemotherapeutic drugs may also play a role in muscle wasting. The goal of this study was to determine the cellular mechanisms underpinning skeletal muscle depletion by chemotherapy drugs. Treatment of myoblasts or myotubes with Paclitaxel (PTX) or Doxorubicin (DXR) reduced cell viability in a dose dependent manner with myoblasts displaying more susceptibility than myotubes regardless of the drug. At non‐lethal doses, PTX or DXR induced significant reductions in myoblast proliferation (47%, p<0.01 and 43%, p<0.05 respectively). In myoblasts, PTX and DXR caused a reduction in rDNA transcription of 24% (p<0.0001) and 19% (p<0.0005) relative to control and a concomitant reduction in rRNA of 16% (p<0.0001) and 18% (p<0.0001), respectively. In myotubes, PTX or DXR reduced rDNA transcription by 21% (p<0.0001) and 30% (p<0.0001) compared to control, and consequently rRNA was 20% (p<0.01) and 17% (p<0.05) lower after the respective drug treatments. The reduction in rRNA reduced translational capacity in myotubes as evidenced by lower global protein synthesis of 52% (p<0.001) and 47% (p<0.001) following exposure to PTX or DXR. These results indicate that chemotherapeutic agents may affect muscle mass by impairing the ability of myogenic cells to proliferate, and by reducing the capacity for protein synthesis in myofibers via a reduction in rDNA transcription. Support or Funding Information Supported by NIH grant AR073385