Notch-Mediated Restoration of Regenerative Potential to Aged Muscle

TLDR

A hallmark of aging is diminished regenerative potential of tissues, but the mechanism of this decline is unknown. Insufficient up‑regulation of the Notch ligand Delta leads to reduced Notch activation in aged, regenerating muscle. Analysis of injured muscle shows that aged satellite cells have impaired proliferation and myoblast production, and that Notch inhibition hampers regeneration in young muscle while forced Notch activation restores regenerative capacity in old muscle, establishing Notch signaling as a key determinant of age‑related decline in muscle regeneration.

Abstract

A hallmark of aging is diminished regenerative potential of tissues, but the mechanism of this decline is unknown. Analysis of injured muscle revealed that, with age, resident precursor cells (satellite cells) had a markedly impaired propensity to proliferate and to produce myoblasts necessary for muscle regeneration. This was due to insufficient up-regulation of the Notch ligand Delta and, thus, diminished activation of Notch in aged, regenerating muscle. Inhibition of Notch impaired regeneration of young muscle, whereas forced activation of Notch restored regenerative potential to old muscle. Thus, Notch signaling is a key determinant of muscle regenerative potential that declines with age.