Notch-mediated restoration of regenerative potential to aged muscle.
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.
Conboy
Irina M
IM
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305-5235, USA.
Conboy
Michael J
MJ
Smythe
Gayle M
GM
Rando
Thomas A
TA
D000375:Aging / Q000502:physiology*; D000818:Animals; D002135:Calcium-Binding Proteins; D002452:Cell Count; D002454:Cell Differentiation; D002455:Cell Division; D002469:Cell Separation; D046508:Culture Techniques; D006614:Hindlimb; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000166:cytology / Q000293:injuries / Q000502:physiology*; D032446:Myoblasts / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012038:Regeneration; D032496:Satellite Cells, Skeletal Muscle / Q000502:physiology*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D014157:Transcription Factors; D015854:Up-Regulation
D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C497762:Notch1 protein, mouse; C106293:Numb protein, mouse; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D000072099:Serrate-Jagged Proteins; D014157:Transcription Factors; C064045:delta protein