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Proteasome activity is required for ribosomal DNA transcription and muscle hypertrophy
Author(s) -
Chandler Paige Nicole,
Liu Chang,
Walden Ferdinand,
Nader Gustavo A
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb782
Subject(s) - muscle hypertrophy , transcription (linguistics) , protein turnover , biology , proteasome , myogenesis , medicine , endocrinology , protein biosynthesis , microbiology and biotechnology , skeletal muscle , chemistry , linguistics , philosophy
Skeletal muscle hypertrophy requires enhanced ribosome production, which is mediated by increased transcription of ribosomal DNA (rDNA) genes. Additionally, muscle growth necessitates that protein turnover is finely tuned to ensure a net protein accretion. However, how anabolic and catabolic processes coordinate muscle protein turnover remains to be determined. The objective of this study was to determine the interaction between anabolic and catabolic mechanisms during myotube hypertrophy. Myotubes were stimulated to undergo hypertrophy in the presence of proteolytic inhibitors for the ubiquitin proteasome (UPS, MG‐132), autophagy (ATG, Chloroquine), and caspase systems (CSP, Z‐VAD‐FMK). Inhibition of UPS, but not ATG or CSP, impaired muscle hypertrophy as evidenced by a 68% reduction in protein synthesis rates (p<0.001). Myotube protein content was also impaired by 25%, reflecting the decrease in UPS activity. Because hypertrophy requires increases in rDNA transcription, we considered the possibility that UPS inhibition impaired hypertrophy by disrupting rDNA transcription. Inhibition of UPS by MG‐132 resulted in impaired rDNA transcription, and subsequent analysis revealed that absence of functioning UPS resulted in altered nucleolar morphology in a pattern typical of nucleolar stress. In order to identify potential mediator(s) of nucleolar stress, we determined whether inhibition of the UPS was associated with changes in p53 levels. UPS inhibition caused a significant increase in p53 levels, and direct pharmacological activation of p53 in the presence of a functioning UPS decreased myotube protein content by 25% (p<0.05) and impaired rDNA transcription by 25% (p<0.001). These data indicate that UPS activity impinges in anabolic processes by blocking protein synthesis and rDNA transcription. Furthermore, UPS activity causes nucleolar stress and rDNA transcriptional suppression in a p53‐dependent manner. Support or Funding Information Supported by the Swedish Research Council (Vetenskapsradet VRK2008‐67X‐20797‐01‐04), The Pennsylvania State University, and The Huck Institute of the Life Sciences.