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Sca-1-Expressing Nonmyogenic Cells Contribute to Fibrosis in Aged Skeletal Muscle

¹ College of Health Sciences and Division of Hematology and Oncology
² College of Medicine, University of Kentucky, Lexington.
³ College of Medicine, University of Arkansas for Medical Sciences, Little Rock.

Address correspondence to Charlotte A. Peterson, PhD, College of Health Sciences, University of Kentucky, 900 S. Limestone, CTW 105, Lexington, KY 40536-0200. E-mail: cpete4{at}uky.edu

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.

Key Words: Sca-1 • Skeletal muscle regeneration • Muscle stem cells • Fibrosis • Aging