Ribosomal control of muscle mass: Transcriptional and epigenetic mechanisms

项目总结 骨骼肌在整个生命周期的健康维护中起着至关重要的作用。肌肉质量损失 可能会产生长期的有害后果，导致长时间的恢复期和 死亡率。肌肉的生长和维持在很大程度上取决于肌肉的合成能力 蛋白质，这反过来又受肌肉核糖体的调节。核糖体的产生部分受转录控制。 核糖体(R)RNA基因(RDNA)通过RNA聚合酶I，并受转录抑制物调控 Rb和p130。在这项建议中，我们试图了解去除Rb和p130如何导致增强 RRNA基因转录与肌肉肥大。使用一种新的动物模型，我们报告了令人兴奋的初步结果 结果表明，Rb和p130的遗传去除会导致核糖体生产和骨骼的增加 肌肉肥大。使用这一模型和其他支持模型，我们将定义控制rRNA的新机制 研究转录和染色质重塑因子对基因表达的调控作用 在rDNA上的功能。这些研究将极大地推进这一领域，并为 预防肌肉质量和功能丧失的治疗方法的发展。

PROJECT SUMMARY Skeletal muscle plays a fundamental role in health maintenance throughout the lifespan. Loss of muscle mass can have long-lasting deleterious consequences leading to prolonged periods of convalescence and increased mortality. Muscle growth and maintenance are largely determined by the ability of the muscle to synthesize proteins, which in turn is regulated by muscle ribosome. Ribosome production is partly controlled by transcription of ribosomal (r)RNA genes (rDNA) by RNA Polymerase I, and is modulated by the transcriptional suppressors Rb and p130. In this proposal, we seek to understand how the removal Rb and p130 leads to enhanced transcription of rRNA genes and muscle hypertrophy. Using a novel animal model, we report exciting preliminary results indicating that genetic removal of Rb and p130 leads to enhanced ribosome production and skeletal muscle hypertrophy. Using this and other supporting models, we will define novel mechanisms controlling rRNA gene expression by studying the role of transcription and chromatin remodeling factors exerting modulatory functions on rDNA. These studies will significantly advance the field and generate novel targets for the development of therapies to prevent the loss of muscle mass and function.