Role of Ribonucleotide Reductase (Rnr) in Skeletal Muscle with Age: the Functionality of Rrm2b in Repair and Regeneration

Aging is the process that appears as a biological limit to lifespan. Previous reports indicated aging is a threat for skeletal muscle in mammals and is associated with a progressive loss of muscle mass, quality and strength. When people are getting older, resulting in severe muscle defects which is termed sarcopenia. Many researchers are devoted to discovering therapeutic methods to improve morbidity and mortality due to muscle sarcopenia. The long-term goal in this project is to gain molecular mechanistic insights into the systemic regulation of aging induced sarcopenia for promoting a healthy lifespan and delaying aging in mammals. Rrm2b, the small subunit of ribonucleotide reductases (RNR), is not only induced by p53 with DNA damage, but also constitutively express in proliferating and non-proliferating cells. In the patients with mitochondrial depletion syndrome, RRM2B is directly correlated with severe muscle mitochondrial DNA depletion. In mouse models, Rrm2b deficiency leads to systemically atrophy in skeletal muscle, while no clear mechanisms have been explored so far. In order to investigate the functionality of Rrm2b on skeletal muscle aging, we will study the following specific aims: (1) To verify whether Rrm2b has a critical function on skeletal muscle repair and regeneration with respect to satellite cells or atypical muscle stem cells such as pericytes and hematopoietic stem cells; (2) To generate the genetically modified mouse models for Rrm2b and characterize the phenotypes of skeletal muscle; (3) To investigate the influence of Rrm2b on satellite cells (or other atypical stem cells) and their niche/microenvironment in mice; and (4) To study whether Rrm2b overexpression can facilitate muscle regeneration in aged mice and further rescue the muscle disorders. We will demonstrate that Rrm2b has a critical function on repair and regeneration of skeletal muscle and provide a chance for establishment of cell therapy in skeletal muscle disorders.