Grant: Project Grant

Skeletal muscle has a remarkable ability to repair itself after injury or exercise, a feature that can be attributed to resident stem cells called satellite cells. After injury, satellite cells begin to divide to produce daughter cells. Of these, the majority will mature into myocytes that can fuse to one another or to damaged muscle fibers to initiate repair. The remaining daughter cells remain as satellite cells, ensuring that the muscle retains its capacity to repair over the lifespan of the organism. Understanding, on a molecular level, what makes a cell decide to mature or to remain a stem cell can help understand how disease arises in muscle and can help us develop better stem cell-based therapies. My laboratory has discovered that the protein C/EBPbeta regulates entry into myogenesis, promotes stem cell marker expression, and is necessary for maintaining the satellite cell population. In the absence of C/EBPbeta, satellite cells precociously differentiate and don't self-renew, resulting in bigger muscle fibers and a smaller stem cell population that cannot support muscle repair long term. In healthy muscle, C/EBPbeta can be found in satellite cells but once these cells become activated to repair muscle, C/EBPbeta levels drop but reappear at the late stages of new fiber formation. C/EBPbeta is misexpressed in skeletal muscle in cachexia and during aging where muscle wasting occurs. While we know that C/EBPbeta is important to prevent satellite cell maturation, it is unclear how C/EBPbeta regulates self-renewal or what its function is in new myofibers. The proposal will concentrate on answering these questions with the ultimate goal of understanding how C/EBPbeta contributes to muscle disease, and how this can be converted into novel therapies for muscle wasting.