Transcriptional programming of translation by BCL6 controls skeletal muscle proteostasis

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

2024-01-01

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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.