Activation of Bmi1 expression as a tool to increase self-renewal of myogenic satellite cells in ageing and disease

Adult skeletal muscle has remarkable ability to repair itself after injury as a result of its resident stem cell population, the ?satellite cells?. In the uninjured muscle these cells are in a resting state, after injury they are stimulated to begin proliferating, some will then differentiate to help repair the damaged muscle while others will return to the resting state and maintain the pool of satellite cells. However with age and in muscle diseases like Duchenne Muscular Dystrophy (DMD) the satellite cells ability to proliferate has been shown to decline and this results in degenerative changes in the muscles, leading to premature disability and even death. In other stem cell populations the ability to proliferate is regulated by the level of a polycomb group gene Bmi1. The loss of Bmi1 leads to a severely reduced proliferative ability and the overexpression of Bmi1 has been shown to keep cells proliferative. Here we plan to investigate the function of Bmi1 in regulating the biological functions of the satellite cell population. We will study the impact of gain of function of Bmi1 on the regenerative capacity of the satellite cells in vitro and in vivo. A restoration of Bmi1 levels in the satellite cells could potentially provide a mechanism for maintaining the muscle mass of aged muscle and coupled with other therapeutic techniques could be used to treat DMD patients.

Skeletal muscle can respond dynamically to physiological stimuli and injury due mainly to its resident stem cell population the ?satellite cells?. These are normally quiescent and reversibly arrested in G0 and are characterised by high expression of Pax7 transcription factor. Upon stimulation the satellite cells become activated and upon upregulation of expression of the myogenic transcription factor MyoD, re-enter the cell cycle and proliferate. A proportion of these proliferating satellite cells will become terminally differentiated and will fuse with the existing muscle fibres or form bridges across the damaged regions. The remainder of the activated satellite cells will downregulate MyoD expression and return to the quiescent state, thus maintaining the pool of satellite cells. However with age and in muscle diseases such as Duchenne Muscular Dystrophy (DMD) the ability of the satellite cells to re-enter the cell cycle declines and this results in an impaired regenerative capacity and a decline in the muscle mass. This leads to serious disability and in DMD patients can contribute to premature death. The senescent phenotype noted in other stem cell populations is often related to the level of Bmi1, a Polycomb group gene. Our unpublished preliminary data show that Bmi1 is expressed in the satellite cell population of adult skeletal muscle and that loss of Bmi1 impairs the proliferative potential of the satellite cells, whereas the overexpression of Bmi1 leads to increased numbers of satellite cells without affecting the differentiation potential of these cells. Here we plan to investigate further the role of Bmi1 in regulating self renewal of satellite cells and its contribution to muscle regeneration by means of mouse models. Moreover we propose to investigatigate the impact of gain of function of Bmi1 in the satellite cell population by genetically modified animals. Fine tuning of the expression levels of Bmi1 in the satellite cells could potential provide a mechanism for maintaining the muscle mass of aged muscle and could contribute to better regeneration of the dystrophic muscle.