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Loss of a single allele for Ku80 leads to progenitor dysfunction and accelerated aging in skeletal muscle

Nathalie Didier, Christophe Hourdé, Helge Amthor, Giovanna Marazzi, David Sassoon

Author Affiliations

  1. Nathalie Didier1,
  2. Christophe Hourdé2,
  3. Helge Amthor2,
  4. Giovanna Marazzi1, and
  5. David Sassoon (david.a.sassoon{at}gmail.com) *,1,
  1. 1Myology Group, UMR S787 INSERM, Université Pierre et Marie Curie Paris VI, Pitié‐Salpétrière, Paris Cedex, France
  2. 2Institut de Myologie, Université Pierre et Marie Curie Paris VI, Unité Mixte de Recherche UPMC‐AIM UM 76, INSERM U 974, CNRS UMR 7215, Paris, France
  1. *Tel: +33 1 40 77 81 31; Fax: +33 1 53 60 08 02
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Abstract

Muscle wasting is a major cause of morbidity in the elderly. Ku80 is required for DNA double strand repair and is implicated in telomere maintenance. Complete loss‐of‐function leads to reduced post‐natal growth and severe progeria in mice. We examined the role of Ku80 in age‐related skeletal muscle atrophy. While complete loss of Ku80 leads to pronounced aging in muscle as expected, accompanied by accumulation of DNA damage, loss of a single allele is sufficient to accelerate aging in skeletal muscle although post‐natal growth is normal. Ku80 heterozygous muscle shows no DNA damage accumulation but undergoes premature telomere shortening that alters stem cell self‐renewal through stress response pathways including p53. These data reveal an unexpected requirement for both Ku80 alleles for optimal progenitor function and prevention of early onset aging in muscle, as well as providing a useful model for therapeutic approaches.

  • Received November 13, 2011.
  • Revision received June 25, 2012.
  • Accepted June 26, 2012.
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This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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