Numb is required to prevent p53-dependent senescence following skeletal muscle injury

Isabelle Le Roux (), Julie Konge, Laurent Le Cam, Patricia Flamant and Shahragim Tajbakhsh ()
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Isabelle Le Roux: Stem Cells and Development, CNRS URA 2578, Institut Pasteur
Julie Konge: Stem Cells and Development, CNRS URA 2578, Institut Pasteur
Laurent Le Cam: Molecular Basis of Carcinogenesis, Institut de Recherche en Cancérologie de Montpellier
Patricia Flamant: Human Histopathology and Animal Models, Institut Pasteur
Shahragim Tajbakhsh: Stem Cells and Development, CNRS URA 2578, Institut Pasteur

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms9528

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