Muscle Wasting in Cancer Involves Suppression of Ribosomal Production and Increased Expression of the Ribophagy Receptor NUFIP1

Abstract

Muscle wasting/cachexia is a major contributor of mortality and morbidity in cancer and is frequently accompanied by functional and metabolic muscle abnormalities. Muscle mass is determined by the balance between protein synthesis and degradation, yet very little is known about the mechanisms controlling the translational capacity (i.e., ribosome biogenesis) of skeletal muscle in cancer cachexia. Muscle ribosome content is mainly regulated by transcription of the ribosomal (r)DNA genes and also by degradation of ribosomes via ribophagy. In this study, we investigated whether muscle wasting in a previously described model for the study of ovarian cancer cachexia is associated with reduced rDNA transcription and ribosomal mass. Nod SCID gamma mice were injected with 1 × 107 ES‐2 human high‐grade serous ovarian cancer cells and observed for fourteen days. Gastrocnemius muscle was collected for qPCR and western blot analysis. Fourteen days of tumor bearing resulted in a 24% (P < 0.0001) loss in gastrocnemius muscle weight. Muscle wasting was associated with ~50% (P = 0.0003) reduction in ribosomal capacity and a significant suppression in rDNA transcription rates (35%, P = 0.0086). This was accounted by a significant reduction in specific rDNA loci. Factors associated with the regulation of rDNA transcription (i.e., Pol1rb, UBF, RRN3, TAF1C, PAF53) were significantly higher than control (1.5 to 4‐fold, P < 0.05). Muscle wasting was also associated with a 4‐fold increased expression (P < 0.0001) of the ribophagy receptor NUFIP1. Our findings indicate that in cancer cachexia, the anabolic capacity of skeletal muscle is diminished due to reduced ribosome production and likely increased ribosome degradation via ribophagy.Support or Funding InformationSupported by NIH grant R56AR‐073385 to GAN, The Pennsylvania State University, and The Huck Institute of the Life Sciences.