Numb is required to prevent p53-dependent senescence following skeletal muscle injury.
Regeneration relies on coordinated action of multiple cell types to reconstitute the damaged tissue. Here we inactivate the endocytic adaptor protein Numb in skeletal muscle stem cells prior to chronic or severe muscle injury in mice. We observe two types of senescence in regenerating muscle; a transient senescence in non-myogenic cells of control and Numb mutant mice that partly depends on INK4a/ARF activity, and a persistent senescence in myogenic cells lacking Numb. The senescence levels of Numb-deficient muscle is reduced to wild type levels by an anti-oxidant treatment or p53 ablation, resulting in functional rescue of the regenerative potential in Numb mutants. Ex vivo experiments suggest that Numb-deficient senescent cells recruit macrophages to sustain inflammation and drive fibrosis, two hallmarks of the impaired muscle regeneration in Numb mutants. These findings provide insights into previously reported developmental and oncogenic senescence that are also differentially regulated by p53.
Department of Developmental and Stem Cell Biology, Stem Cells and Development, CNRS URA 2578, Institut Pasteur, 25 rue du Dr Roux, Paris 75015, France.
Isabelle
I
Le Roux
Department of Developmental and Stem Cell Biology, Stem Cells and Development, CNRS URA 2578, Institut Pasteur, 25 rue du Dr Roux, Paris 75015, France.
Julie
J
Konge
Molecular Basis of Carcinogenesis, Institut de Recherche en Cancérologie de Montpellier, 208 rue des Apothicaires, Montpellier, cedex 5 34298, France.
Laurent
L
Le Cam
Human Histopathology and Animal Models, Institut Pasteur, 25 rue du Dr Roux, Paris 75015, France.
Patricia
P
Flamant
Department of Developmental and Stem Cell Biology, Stem Cells and Development, CNRS URA 2578, Institut Pasteur, 25 rue du Dr Roux, Paris 75015, France.
Shahragim
S
Tajbakhsh
D000818:Animals; D016922:Cellular Senescence; D005260:Female; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000293:injuries / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C106293:Numb protein, mouse; D016159:Tumor Suppressor Protein p53