ROLE OF CYCLIN D3 IN SATELLITE CELL FUNCTION AND MUSCLE REGENERATION

Skeletal muscle has a remarkable ability to regenerate in response to injury. The primary cellular constituent of adult muscle that is responsible for this regenerative potential is the satellite cell, a muscle precursor cell residing beneath the basal laminae of mature myofibres. In the dystrophies, there is a gradual failure of the capacity of muscle to regenerate in response to injury, and this is due to depletion of satellite cells and/or to a gradual loss of their ability to respond to damage. The capacity for self-renewal and ability to completely regenerate adult skeletal muscle makes satellite cells a valuable resource for cellular therapies in the treatment of muscular dystrophies. However, a major obstacle in their therapeutic use is our lack of understanding regarding the factors that regulate their proliferation and differentiation. It has been demonstrated that the gene MyoD is key regulator of the balance between self-renewal and differentiation during regeneration. In previous studies we have shown that MyoD induces the expression of the cell-cycle regulatory gene cyclin D3 at the onset of differentiation, and that cyclin D3 is required in the process of myogenic differentiation in vitro. The objective of our project is to define the role cyclin D3 in vivo in the control of satellite cell proliferation and differentiation during muscle regeneration. Therefore, we will assess the ability of cyclin a D3-null mouse model to regenerate muscle in response to acute injury. These studies will be accompanied by analyses of the differentiation properties of satellite cells lacking cyclin D3, and investigations on the molecular mechanism of cyclin D3 action. Our studies will contribute to enhance the understanding of the regulatory mechanisms controlling proliferation, differentiation and self-renewal of myogenic progenitors, which is necessary for their successful use for therapeutic applications.