Project Summary Aging-related muscle atrophy (sarcopenia) is a process that affects nearly every person, contributing to debilitations and reductions in quality of life. As people grow older, fast-twitch muscle fibers are selectively atrophied resulting in weakness. Normally, muscle regenerates through a population of stem cells called satellite cells, which differentiate and non-selectively fuse to existing myofibers in order to repair the damaged muscle tissue. However, several recent studies have suggested that the contribution of satellite cells to muscle during homeostasis and aging is minimal. Thus, it’s possible that loss of an alternative muscle precursor that fuses specifically to fast-twitch fibers may be a mechanism by which aging-related muscle atrophy occurs. Through the technique of lineage-tracing (fate-mapping) of the transcription factor Twist2, we have identified a novel muscle progenitor that fuses specifically to type IIb/x (fast-twitch, glycolytic) muscle fibers during both aging and homeostasis conditions. Additionally, loss of Twist2+ cells result in specific atrophy of fast-twitch myofibers. I hypothesize that Twist2 is playing a role in regulating both the fiber type specificity as well as the quiescence of this novel progenitor cell. To test this hypothesis, we propose to study the genes Neuropilin1 and Suv39h1 through mouse models, stripe migration assays, fusion assay, Chip-Seq, and cell culture studies.