期刊
EMBO MOLECULAR MEDICINE
卷 4, 期 9, 页码 910-923出版社
WILEY
DOI: 10.1002/emmm.201101075
关键词
aging; Ku80; skeletal muscle; stem cells; telomere
资金
- NIH [NCI PO1 CA80058-06]
- French Ministry of Research 'Chaire d'Excellence'
- Muscular Dystrophy Association of America
- Duchenne Parent Project (France)
- Association Monegasque contre les Myopathies
- European Community [Health-F5-2009-223098]
- ENDOSTEM [241440]
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.
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