b'10 Carnegie Science|Spring/Summer 2020Muscle and Tendon Repairand RecoveryAmong the studies in Chen-Ming Fans lab are how the components of the musculoskeletal system are repaired after injury and maintained throughout life. Muscles and tendonsThese two micrographs show how treatment with the binding-protein GDNF repairs aged muscle stem cells to support robust muscle regeneration. The image on the left provide the mechanical support for our posture and movement.shows small muscle fibers (red shapes with blue nuclei inside), which were made by Fans lab studies how this system is generated, maintained, andold muscle stem cells. The image on the right shows increased muscle fiber size and recovers from injury.muscle stem cell numbers due to GDNF treatment. Image courtesy Liangji Li, Carnegie Institution for Science Why Old Muscles Repair Slowly. . . removing GAS1 from aged The older we get, the slower our muscles repair. According to a team of current and former Carnegie biologists led by Chen-Mingmuscle stem cells rejuvenated Fan, this age-related decline in recovery from muscle injury can bethem to a youthful state . . .traced to a protein that suppresses the special ability of muscle stem cells to build new muscles. Nature Metabolism published theSkeletal muscles have a capacity to make new muscles from work.special muscle stem cells. These blank cells generate more of themselves. But their amazing abilities diminish with age, resulting in poorer muscle regeneration from muscle trauma. The research teamincluding Carnegies Liangji Li, Michelle Rozo, Sibiao Yue, Xiaobin Zheng, and Frederick Tan, as well as Christoph Lepper formerly of Carnegie now at the Ohio State Universityfigured out that a protein called GAS1 is the culprit for this age-related decline. Encoded by the growth-arrest specific gene, the GAS1 protein lives up to its name, accelerating the functional decline of muscle stem cells, explained lead author Li.The protein is found in only a small number of young muscle stem cells but is present in all aged muscle stem cells, they discovered. Tinkering with muscle stem cells to express GAS1 in the entire young stem cell population resulted in diminished regeneration. By contrast, removing GAS1 from aged muscle stem cells rejuvenated them to a youthful state that supported robust regeneration.They also discovered that GAS1 inhibits another protein, a cell-surface receptor called RET, which they showed is necessary for muscle stem-cell renewal. The more GAS1 protein is present, the more RETs function is reduced. The inhibition of RET by GAS1 could be reversed by a third protein called GDNF, which binds to and activates RET. Indeed, when the researchers injected GDNF directly into the muscles of aged mice, muscle stem cell function and muscle regeneration were restored.With a rapidly aging population, issues like muscle deterioration are an increasing societal challenge, said Fan. Our work couldSUPPORT:reveal a potential pathway forThe U.S. National Institutes of Health, in part, supported therapeutic targeting to combat musclethis work. degeneration in the elderly.Lead author Liangji Li (left) worked with Carnegie staff scientist Chen-Ming Fan (right) and team on this study. Image courtesy Bill Kupiec, Carnegie Institution for Science'