Reduced rDNA transcription diminishes skeletal muscle ribosomal capacity and protein synthesis in cancer cachexia
- 2 February 2021
- journal article
- research article
- Published by Wiley in The FASEB Journal
- Vol. 35 (2), e21335
- https://doi.org/10.1096/fj.202002257r
Abstract
Muscle wasting in cancer is associated with deficits in protein synthesis, yet, the mechanisms underlying this anabolic impairment remain poorly understood. The capacity for protein synthesis is mainly determined by the abundance of muscle ribosomes, which is in turn regulated by transcription of the ribosomal (r)RNA genes (rDNA). In this study, we investigated whether muscle loss in a preclinical model of ovarian cancer is associated with a reduction in ribosomal capacity and was a consequence of impaired rDNA transcription. Tumor bearing resulted in a significant loss in gastrocnemius muscle weight and protein synthesis capacity, and was consistent with a significant reduction in rDNA transcription and ribosomal capacity. Despite the induction of the ribophagy receptor NUFIP1 mRNA and the loss of NUFIP1 protein, in vitro studies revealed that while inhibition of autophagy rescued NUFIP1, it did not prevent the loss of rRNA. Electrophoretic analysis of rRNA fragmentation from both in vivo and in vitro models showed no evidence of endonucleolytic cleavage, suggesting that rRNA degradation may not play a major role in modulating muscle ribosome abundance. Our results indicate that in this model of ovarian cancer-induced cachexia, the ability of skeletal muscle to synthesize protein is compromised by a reduction in rDNA transcription and consequently a lower ribosomal capacity. Thus, impaired ribosomal production appears to play a key role in the anabolic deficits associated with muscle wasting in cancer cachexia.Keywords
Funding Information
- American Cancer Society (132013‐RSG‐18‐010‐ 01‐CCG)
- V Foundation for Cancer Research (132013‐RSG‐18‐010‐ 01‐CCG)
- National Institutes of Health (AR073385)
This publication has 61 references indexed in Scilit:
- Definition and classification of cancer cachexia: an international consensusThe Lancet Oncology, 2011
- Pathogenesis of muscle wasting in cancer cachexia: targeted anabolic and anticatabolic therapiesCurrent Opinion in Clinical Nutrition and Metabolic Care, 2010
- Inflammatory burden and amino acid metabolism in cancer cachexiaCurrent Opinion in Clinical Nutrition and Metabolic Care, 2009
- UBF levels determine the number of active ribosomal RNA genes in mammalsThe Journal of cell biology, 2008
- Mouse Ribosomal RNA Genes Contain Multiple Differentially Regulated VariantsPLOS ONE, 2008
- Transcriptional profile of a myotube starvation model of atrophyJournal of Applied Physiology, 2005
- Human rRNA transcription is modulated by the coordinate binding of two factors to an upstream control elementCell, 1986
- Protein synthesis in muscle measured in vivo in cachectic patients with cancer.BMJ, 1984
- Turnover of ribosomal 28S and 18S rRNA during rat liver regenerationBioscience Reports, 1983
- Protein Degradation and the Regulation of Protein Balance in MuscleCiba Foundation symposium, 1980