Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Jesse Brown VA Medical Center, Chicago, IL, USA.
Nat Metab. 2024 Feb;6(2):304-322. doi: 10.1038/s42255-024-00983-3. Epub 2024 Feb 9.
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.
骨骼肌的蛋白质合成和降解平衡是其动态调控的基础。在这里，我们发现转录抑制因子 B 细胞淋巴瘤 6（BCL6）在小鼠肌肉稳态和力量中具有意想不到的功能。胚胎期或成年期骨骼肌特异性 Bcl6 缺失会导致肌肉质量和力量产生减少超过 30%，这是由于蛋白质合成减少和自噬增加所致，同时促进向较慢的肌球蛋白重链纤维表型转变。核糖体谱分析显示，Bcl6 缺失的肌肉中整体翻译效率降低。从机制上讲，串联染色质免疫沉淀、转录组学和翻译分析表明，BCL6 直接抑制真核翻译起始因子 4E 结合蛋白 1（Eif4ebp1），并激活胰岛素样生长因子 1（Igf1）和雄激素受体（Ar）。综上所述，这些结果揭示了 BCL6 在肌肉稳态的转录和翻译控制中的双重功能作用。
