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

Bigot, Anne; Klein, Arnaud; Gasnier, E.; Jacquemin, Virginie; Ravassard, Philippe; Butler-Browne, Gillian; Mouly, Vincent; Furling, Denis

doi:10.2353/ajpath.2009.080560

Cited by 90 publications

(94 citation statements)

References 37 publications

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“…Myoblasts derived from congenital forms of DM1 have alteration in various cell-cycle modulators, including p21 and cyclin D1 (Timchenko et al, 2001b;Timchenko et al, 2004). They also exhibit premature senescence through a p16-dependent mechanism and defect in p38MAPK and ERK MEK (Bigot et al, 2009), leading to defective proliferation and differentiation (Beffy et al, 2010;Bigot et al, 2009;Timchenko et al, 2001b;Timchenko et al, 2004). In addition, the induction of autophagy has been recently observed in myoblasts derived from congenital DM1 patients; a link to a p53-dependent inhibition of mTOR pathway in response to metabolic stress has been hypothesized (Beffy et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…At the skeletal muscle level, three main molecular events can be described: (1) formation of nuclear foci that are composed at least of mutant DMPK mRNA and recruited RNA-binding proteins, such as splicing regulators and transcription factors (Ebralidze et al, 2004;Mankodi et al, 2001;Timchenko and Caskey, 1996); (2) disturbance of specific gene expression (Mankodi et al, 2002;Savkur et al, 2001;Yadava et al, 2008); and (3) impairment of cell proliferation and differentiation (Bigot et al, 2009;Furling et al, 2001;Timchenko et al, 2001a). Although DM1 has long been considered mainly as a muscle disorder, there is extensive evidence for the involvement of the central nervous system.…”

Section: Introductionmentioning

confidence: 99%

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mTOR-dependent proliferation defect in human ES-derived neural stem cells affected by Myotonic Dystrophy Type1

Denis

Gauthier

Rachdi

et al. 2013

Journal of Cell Science

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SummaryPatients with myotonic dystrophy type 1 exhibit a diversity of symptoms that affect many different organs. Among these are cognitive dysfunctions, the origin of which has remained elusive, partly because of the difficulty in accessing neural cells. Here, we have taken advantage of pluripotent stem cell lines derived from embryos identified during a pre-implantation genetic diagnosis for mutant-gene carriers, to produce early neuronal cells. Functional characterization of these cells revealed reduced proliferative capacity and increased autophagy linked to mTOR signaling pathway alterations. Interestingly, loss of function of MBNL1, an RNA-binding protein whose function is defective in DM1 patients, resulted in alteration of mTOR signaling, whereas gain-of-function experiments rescued the phenotype. Collectively, these results provide a mechanism by which DM1 mutation might affect a major signaling pathway and highlight the pertinence of using pluripotent stem cells to study neuronal defects.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mTOR-dependent proliferation defect in human ES-derived neural stem cells affected by Myotonic Dystrophy Type1

Denis

Gauthier

Rachdi

et al. 2013

Journal of Cell Science

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“…myoblasts from human cDM1 patients that survived after the neonatal period versus myoblasts from aborted cDM1 fetuses) or by a difference in the age of the satellite cells, which may also influence myogenesis 44 because of the recently reported implication of the p16 premature senescence of DM1 myoblasts. 45,46 Catabolic pathways and a novel pathogenetic mechanism. During differentiation, myoblasts undergo sequential events, ending with fusion into syncytial cells, a cell type more resistant to sublethal damage than proliferating myoblasts, which go on to generate muscle fibers.…”

Section: Discussionmentioning

confidence: 99%

Normal myogenesis and increased apoptosis in myotonic dystrophy type-1 muscle cells

et al. 2010

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Myotonic dystrophy (DM) is caused by a (CTG) n expansion in the 3 0 -untranslated region of DMPK gene. Mutant transcripts are retained in nuclear RNA foci, which sequester RNA binding proteins thereby misregulating the alternative splicing. Controversy still surrounds the pathogenesis of the DM1 muscle distress, characterized by myotonia, weakness and wasting with distal muscle atrophy. Eight primary human cell lines from adult-onset (DM1) and congenital (cDM1) patients, (CTG) n range 90-1800, were successfully differentiated into aneural-immature and contracting-innervated-mature myotubes. Morphological, immunohistochemical, RT-PCR and western blotting analyses of several markers of myogenesis indicated that in vitro differentiation-maturation of DM1 myotubes was comparable to age-matched controls. In all pathological muscle cells, (CTG) n expansions were confirmed by long PCR and RNA fluorescence in situ hybridization. Moreover, the DM1 myotubes showed the splicing alteration of insulin receptor and muscleblind-like 1 (MBNL1) genes associated with the DM1 phenotype. Considerable myotube loss and atrophy of 15-day-differentiated DM1 myotubes indicated activated catabolic pathways, as confirmed by the presence of apoptotic (caspase-3 activation, cytochrome c release, chromatin fragmentation) and autophagic (P62/LC3) markers. Z-VAD treatment significantly reduced the decrease in myonuclei number and in average width in 15-day-differentiated DM1 myotubes. We thus propose that the muscle wasting typical in DM1 is due to impairment of muscle mass maintenanceregeneration, through premature apoptotic-autophagic activation, rather than altered myogenesis. Myotonic dystrophy (DM) is a multi-systemic disorder caused by two different microsatellite expansions in non-coding regions. Together, these two mutations affect 1 out of 8000 individuals and represent the most common form of muscular dystrophy in adults. DM1 and DM2 have common symptoms such as myotonia, muscle weakness and early cataract development. 1,2 Although DM1 and DM2 initially affect different muscles (distal versus proximal), histological analysis of the muscular tissues shows common aspects such as central nucleation. The classic form of DM1 is characterized by muscle distress with myotonia, progressive muscle weakness and wasting. Atrophy has also been reported, occurring preferentially in type-1 fibers in DM1 and in type-2 in DM2. 3 DM1 but not DM2 also presents a congenital form (cDM1), characterized by a high neonatal mortality and symptoms such as hypotonia, mental retardation and respiratory distress. 4,5 DM1 is associated with an unstable (CTG) n trinucleotide expansion located in the 3 0 -untranslated (3 0 -UTR) region of the DM protein kinase (DMPK) gene on chromosome 19q13.3. The mutant DMPK transcript, containing the expanded (CTG) n sequence, accumulates in discrete nuclear foci able to sequester various nuclear factors such as RNAbinding proteins or splicing regulators, causing different and highly variable downstream deleterious effects. 2,6...

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“…It has been noted that in DM-affected muscle tissue there is a decreased muscle regeneration in response to the ongoing muscle loss and dystrophy (Harper 2001), and it has been hypothesised that a reduced repair response may result from impaired myogenesis in adult DM muscle (e.g. Timchenko et al 2001Timchenko et al , 2004Kim and Sharpless 2006;Salisbury et al 2008;Bigot et al 2009). However, the accumulation of splicing and cleavage factors found in the present study in myonuclei of both DM1 and DM2 patients strongly suggests an overall impairment of post-transcriptional pre-mRNA pathways ): actually, hnRNPs and snRNPs are essential factors for the co-transcriptional splicing of pre-mRNAs (Lührmann et al 1990;Madhani and Guthrie 1994), while CStF is involved in the maturation of 3 0 ends (Wahle and Rüegsegger 1999).…”

Section: Discussionmentioning

confidence: 99%

RNA processing is altered in skeletal muscle nuclei of patients affected by myotonic dystrophy

Malatesta

Giagnacovo

Cardani

et al. 2011

Histochem Cell Biol

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Myotonic dystrophies (DMs) are characterised by highly variable clinical manifestations consisting of muscle weakness and atrophy, and a wide spectrum of extramuscular manifestations. In both DM1 and DM2 forms, expanded nucleotide sequences cause the accumulation of mutant transcripts in the nucleus, thus deregulating the function of some RNA-binding proteins and providing a plausible explanation for the multifactorial phenotype of DM patients. However, at the skeletal muscle level, no mechanistic explanation for the muscle wasting has so far been proposed. We therefore performed a study in situ by immunoelectron microscopy on biceps brachii biopsies from DM1, DM2 and healthy subjects, providing the first ultrastructural evidence on the distribution of some nuclear ribonucleoprotein (RNP)-containing structures and molecular factors involved in pre-mRNA transcription and maturation in dystrophic myonuclei. Our results demonstrated an accumulation of splicing and cleavage factors in myonuclei of both DM1 and DM2 patients, suggesting an impairment of post-transcriptional pre-mRNA pathways. The transcription of the expanded sequences in DM myonuclei would therefore hamper functionality of the whole splicing machinery, slowing down the intranuclear molecular trafficking; this would reduce the capability of myonuclei to respond to anabolic stimuli thus contributing to muscle wasting.

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

Cited by 90 publications

References 37 publications

mTOR-dependent proliferation defect in human ES-derived neural stem cells affected by Myotonic Dystrophy Type1

mTOR-dependent proliferation defect in human ES-derived neural stem cells affected by Myotonic Dystrophy Type1

Normal myogenesis and increased apoptosis in myotonic dystrophy type-1 muscle cells

RNA processing is altered in skeletal muscle nuclei of patients affected by myotonic dystrophy

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