Transcriptional programming of translation by BCL6 controls skeletal muscle proteostasis.

in Nature metabolism by 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

TLDR

  • The study investigates how a protein called BCL6 affects the health of muscles in mice. The study finds that BCL6 helps maintain the balance between making new muscle proteins and breaking down old ones. The study also finds that BCL6 affects how muscles use energy and how they grow. The study's findings suggest that BCL6 is important for muscle health and may be a potential target for treatments for muscle-related disorders.

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.

Overview

  • The study investigates the role of B cell lymphoma 6 (BCL6) in skeletal muscle proteostasis and strength in mice. The study uses skeletal muscle-specific Bcl6 ablation in utero or in adult mice to test the hypothesis that BCL6 plays a role in muscle proteostasis and strength. The study finds that Bcl6 ablation 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. The study identifies 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) as the mechanisms behind the observed effects. The primary objective of the study is to understand the role of BCL6 in muscle proteostasis and strength.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions detailed in the study. The study finds that Bcl6 ablation 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. The study identifies 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) as the mechanisms behind the observed effects. The key findings of the study are that BCL6 plays a bifunctional role in the transcriptional and translational control of muscle proteostasis and strength.

Implications and Future Directions

  • The study's findings suggest that BCL6 plays a crucial role in muscle proteostasis and strength. The study identifies 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) as the mechanisms behind the observed effects. The study's findings have significant implications for the field of research and clinical practice, as they suggest that BCL6 may be a potential therapeutic target for muscle-related disorders. Future research directions could explore the role of BCL6 in other tissues and the potential therapeutic applications of targeting BCL6 in muscle-related disorders. Additionally, future research could investigate the role of BCL6 in other proteostasis-related processes, such as neurodegenerative diseases.
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