Increased Wnt Signaling During Aging Alters Muscle Stem Cell Fate and Increases Fibrosis

TLDR

Skeletal muscle regenerative capacity declines with age, accompanied by increased fibrosis. Aged satellite cells shift from a myogenic to a fibrogenic lineage during proliferation, a conversion driven by systemic factors that activate canonical Wnt signaling and can be suppressed by Wnt inhibitors, indicating Wnt’s key role in stem cell aging and fibrosis.

Abstract

The regenerative potential of skeletal muscle declines with age, and this impairment is associated with an increase in tissue fibrosis. We show that muscle stem cells (satellite cells) from aged mice tend to convert from a myogenic to a fibrogenic lineage as they begin to proliferate and that this conversion is mediated by factors in the systemic environment of the old animals. We also show that this lineage conversion is associated with an activation of the canonical Wnt signaling pathway in aged myogenic progenitors and can be suppressed by Wnt inhibitors. Furthermore, components of serum from aged mice that bind to the Frizzled family of proteins, which are Wnt receptors, may account for the elevated Wnt signaling in aged cells. These results indicate that the Wnt signaling pathway may play a critical role in tissue-specific stem cell aging and an increase in tissue fibrosis with age.