Sca-1-expressing nonmyogenic cells contribute to fibrosis in aged skeletal muscle.
We report an age-dependent increase in nonimmunohematopoietic cells (CD45neg) in regenerating muscle characterized by high stem-cell antigen (Sca-1) expression. In aged regenerating muscle, only 14% of these CD45negSca-1pos cells express MyoD, whereas 82% of CD45negSca-1(pos) cells are MyoDpos in young adult muscle. In vitro, CD45negMyoDnegSca-1pos 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. MyoDneg Sca-1pos nonmyogenic cells also emerge in C2C12 myoblast cultures at late passage. Both in vitro and in vivo studies suggest that MyoDnegSca-1pos 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.
Hidestrand
Mats
M
College of Health Sciences, University of Kentucky, 900 S. Limestone, CTW 105, Lexington, KY 40536-0200, USA.
Richards-Malcolm
Sonia
S
Gurley
Catherine M
CM
Nolen
Greg
G
Grimes
Barry
B
Waterstrat
Amanda
A
Zant
Gary Van
GV
Peterson
Charlotte A
CA
D000375:Aging / Q000473:pathology*; D000818:Animals; D000950:Antigens, Ly / Q000032:analysis*; D002478:Cells, Cultured; D005260:Female; D005355:Fibrosis; D017493:Leukocyte Common Antigens / Q000032:analysis; D008565:Membrane Proteins / Q000032:analysis*; D051379:Mice; D008811:Mice, Inbred DBA; D018482:Muscle, Skeletal / Q000473:pathology* / Q000502:physiology; D017570:MyoD Protein; D012038:Regeneration / Q000502:physiology
D000950:Antigens, Ly; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D017570:MyoD Protein; D017493:Leukocyte Common Antigens