Transcriptional programming of translation by BCL6 controls skeletal muscle proteostasis

Krithika Ramachandran, Christopher R. Futtner, Meredith A. Sommars, Mattia Quattrocelli, Yasuhiro Omura, Ellen Fruzyna, Janice C. Wang, Nathan J. Waldeck, Madhavi D. Senagolage, Carmen G. Telles, Alexis R. Demonbreun, Erin Prendergast, Nicola Lai, Daniel Arango, Ilya R. Bederman, Elizabeth M. McNally, Grant D. Barish*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Skeletal muscle is dynamically controlled by the balance of protein synthesis and degradation. Here we discover an unexpected function for the transcriptional repressor B cell lymphoma 6 (BCL6) in muscle proteostasis and strength in mice. Skeletal muscle-specific Bcl6 ablation in utero or in adult mice results in over 30% decreased muscle mass and force production due to reduced protein synthesis and increased autophagy, while it promotes a shift to a slower myosin heavy chain fibre profile. Ribosome profiling reveals reduced overall translation efficiency in Bcl6-ablated muscles. Mechanistically, tandem chromatin immunoprecipitation, transcriptomic and translational analyses identify direct BCL6 repression of eukaryotic translation initiation factor 4E-binding protein 1 (Eif4ebp1) and activation of insulin-like growth factor 1 (Igf1) and androgen receptor (Ar). Together, these results uncover a bifunctional role for BCL6 in the transcriptional and translational control of muscle proteostasis.

Original languageEnglish (US)
Pages (from-to)304-322
Number of pages19
JournalNature Metabolism
Volume6
Issue number2
DOIs
StatePublished - Feb 2024

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Physiology (medical)
  • Cell Biology

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