Sca-1-expressing nonmyogenic cells contribute to fibrosis in aged skeletal muscle

We report an age-dependent increase in nonimmunohematopoietic cells (CD45^neg) in regenerating muscle characterized by high stem-cell antigen (Sca-1) expression. In aged regenerating muscle, only 14% of these CD45^negSca-1^pos cells express MyoD, whereas 82% of CD45^negSca-1^pos cells are MyoD^pos in young adult muscle. In vitro, CD45^negMyoD^negSca-1^pos cells overexpress fibrosis-promoting genes, potentially controlled by Wnt2. The cells are proliferative, nonmyogenic, and nonadipogenic, and arise in clonally derived myoblast cultures from aged mice. MyoD^neg Sca-1^pos nonmyogenic cells also emerge in C2C12 myoblast cultures at late passage. Both in vitro and in vivo studies suggest that MyoD^negSca-1^pos cells from aged muscle are more susceptible to apoptosis than myoblasts, which may contribute to depletion of the satellite cell pool. Thus, with age, a subset of myoblasts takes on an altered phenotype, which is marked by high Sca-1 expression. These cells do not participate in muscle regeneration, and instead may contribute to muscle fibrosis in aged muscle.