Large CTG repeats trigger p16-dependent premature senescence in myotonic dystrophy type 1 muscle precursor cells.
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.
Bigot
Anne
A
Université Pierre et Marie Curie Paris 6, UMR 787, Paris, France.
Klein
Arnaud F
AF
Gasnier
Erwan
E
Jacquemin
Virginie
V
Ravassard
Philippe
P
Butler-Browne
Gillian
G
Mouly
Vincent
V
Furling
Denis
D
D015153:Blotting, Western; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005333:Fetus; D006801:Humans; D007150:Immunohistochemistry; D032446:Myoblasts / Q000473:pathology*; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D032496:Satellite Cells, Skeletal Muscle / Q000473:pathology*; D016615:Telomere / Q000378:metabolism; D018911:Trinucleotide Repeats / Q000235:genetics*
D019941:Cyclin-Dependent Kinase Inhibitor p16