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Originally published online as doi:10.2353/ajpath.2009.080560 on February 26, 2009

Published online before print February 26, 2009
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(American Journal of Pathology. 2009;174:1435-1442.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080560

Large CTG Repeats Trigger p16-Dependent Premature Senescence in Myotonic Dystrophy Type 1 Muscle Precursor Cells

Anne Bigot*{dagger}, Arnaud F. Klein*{dagger}, Erwan Gasnier*{dagger}, Virginie Jacquemin*{dagger}, Philippe Ravassard{ddagger}, Gillian Butler-Browne*{dagger}, Vincent Mouly*{dagger} and Denis Furling*{dagger}

From the Université Pierre et Marie Curie (UPMC) Paris 6, UMRS 787 and 974,* and INSERM, U787 and 974,{dagger} Institut de Myologie, Paris, France; and the Centre National de la Researche Scientifique (CNRS) and UPMC, LGN UMR 7091,{ddagger} Paris, France

A CTG repeat amplification is responsible for the dominantly inherited neuromuscular disorder, myotonic dystrophy type 1 (DM1), which is characterized by progressive muscle wasting and weakness. The expanded (CTG)n tract not only alters the myogenic differentiation of the DM1 muscle precursor cells but also reduces their proliferative capacity. In this report, we show that these muscle precursor cells containing large CTG expansion sequences have not exhausted their proliferative capacity, but have entered into premature senescence. We demonstrate that an abnormal accumulation of p16 is responsible for this defect because the abolition of p16 activity overcomes early growth arrest and restores an extended proliferative capacity. Our results suggest that the accelerated telomere shortening measured in DM1 cells does not contribute to the aberrant induction of p16. We propose that a cellular stress related to the amplified CTG repeat promotes premature senescence mediated by a p16-dependent pathway in DM1 muscle precursor cells. This mechanism is responsible for the reduced proliferative capacity of the DM1 muscle precursor cells and could participate in both the impaired regeneration and atrophy observed in the DM1 muscles containing large CTG expansions.






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Copyright © 2009 by the American Society for Investigative Pathology.