Ribosomal control of muscle mass: Transcriptional and epigenetic mechanisms

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.