Anne Bigot is a post-doc researcher in the group of Gillian Butler-Browne, UMR 974, Institute of Myology, dedicated to remodeling, regeneration and cell therapy of striated muscle. With her colleagues, she just published an article* concerning the effects of the effects of CTG expansions on the proliferative capacity of muscle precursor cells.
In what way does this work shed new light on the symptoms of DM1?
In this study, we focused on the effects of CTG expansions on the proliferative capacity of satellite cells or muscle precursor cells. We demonstrated that muscle precursor cells from DM1 patients with a large number of CTG repeats (n>2000) have a reduced proliferative capacity in comparison with control cells. The in vivo consequence of this defect has not yet been clearly determined, but the premature onset of proliferative senescence may be involved in the inability of these cells to compensate for the progressive atrophy observed in these patients. In your experiments, you induced abolition of p16 activity and thereby observed restoration of the proliferative capacity of muscle precursor cells. Might it therefore be possible to use a similar system in humans to compensate for the consequences of CTG repeats?
We now know that mutant DMPK mRNA containing CUG expansions accumulates inside the cell nucleus in the form of aggregates. These toxic aggregates are involved in the development of the disease. They sequester and modify the activity of maturation factors, leading to splicing defects in certain RNA and are also a cause of cellular stress. Restoring the proliferative capacity of the cells does not eliminate these aggregates and cannot compensate for the other consequences induced by repeats. In treatment terms, research is focusing more on the elimination of mutant RNA. What are the next steps?
In this study, we showed that muscle precursor cells from DM1 patients are prematurely arrested via induction of the p16 pathway and undergo accelerated telomere shortening. While this characterisation has enabled us to define the pathways involved in the premature senescence of DM1 cells, numerous questions still remain unanswered. What is it that triggers the early onset of p16 stress in DM1 cells and why do the telomeres shorten more quickly in these cells? Is there a link between CTG instability and telomere instability?
Various data in the literature suggest that CTG repeats may trigger enhanced sensitivity to oxidative stress. This may cause early induction of the p16 protein and an acceleration of telomere shortening in DM1 cells. We are currently testing the sensitivity of DM1 cells to stress and early results appear to suggest a greater sensitivity to stress of these cells.
In addition, several data lead us to put forward the hypothesis of a possible relationship between CTG repeat instability and telomere instability. CTG instability may cause displacement of the repair factors present in the telomeres. Delocalisation of these factors may lead to loss of protection of the telomeres, reflected by accelerated telomere shortening at each division.
Finally, it is important to confirm whether the accumulation of senescent satellite cells in vivo is involved in the inability of these cells to compensate for progressive atrophy in DM1. In addition, the contribution of this mechanism in other muscle diseases, such as oculopharyngeal muscular dystrophy, is also being examined. April 2009Interview by Anne Berthomier, translation by Racquel N. Cooper * Large CTG repeats trigger p16-dependent premature senescence in myotonic dystrophy type 1 muscle precursor cells.
Bigot A, Klein AF, Gasnier E, Jacquemin V, Ravassard P, Butler-Browne G, Mouly V, Furling D.
Am J Pathol. 2009 Apr;174(4):1435-42. Epub 2009 Feb 26.