Satellite cell dysfunction contributes to the progressive muscle atrophy in myotonic dystrophy type 1

Thornell, Lars‐Eric; Lindstöm, Mona; Renault, Valérie; Klein, Arnaud; Mouly, Vincent; Ansved, Tor; Butler-Browne, Gillian; Furling, Denis

doi:10.1111/j.1365-2990.2009.01014.x

Cited by 74 publications

(78 citation statements)

References 29 publications

(34 reference statements)

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“…SCs are adult muscle precursor cells, and impaired function and/or number of SCs lead to reduced myogenesis and muscular atrophy [27]. In Smad3-null mice, there is a significant reduction in the SC number ( Figure 2E and 2F), and data presented here suggest that this could be due to reduced self-renewal of SCs ( Figure 2B and 2D).…”

Section: Smad3 Signaling Is Required For Proper Function Of Scsmentioning

confidence: 55%

Smad3 signaling is required for satellite cell function and myogenic differentiation of myoblasts

McFarlane

Vajjala

et al. 2011

Cell Res

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TGF-β and myostatin are the two most important regulators of muscle growth. Both growth factors have been shown to signal through a Smad3-dependent pathway. However to date, the role of Smad3 in muscle growth and differentiation is not investigated. Here, we demonstrate that Smad3-null mice have decreased muscle mass and pronounced skeletal muscle atrophy. Consistent with this, we also find increased protein ubiquitination and elevated levels of the ubiquitin E3 ligase MuRF1 in muscle tissue isolated from Smad3-null mice. Loss of Smad3 also led to defective satellite cell (SC) functionality. Smad3-null SCs showed reduced propensity for self-renewal, which may lead to a progressive loss of SC number. Indeed, decreased SC number was observed in skeletal muscle from Smad3-null mice showing signs of severe muscle wasting. Further in vitro analysis of primary myoblast cultures identified that Smad3-null myoblasts exhibit impaired proliferation, differentiation and fusion, resulting in the formation of atrophied myotubes. A search for the molecular mechanism revealed that loss of Smad3 results in increased myostatin expression in Smad3-null muscle and myoblasts. Given that myostatin is a negative regulator, we hypothesize that increased myostatin levels are responsible for the atrophic phenotype in Smad3-null mice. Consistent with this theory, inactivation of myostatin in Smad3-null mice rescues the muscle atrophy phenotype.

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Section: Smad3 Signaling Is Required For Proper Function Of Scsmentioning

confidence: 55%

Smad3 signaling is required for satellite cell function and myogenic differentiation of myoblasts

McFarlane

Vajjala

et al. 2011

Cell Res

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“…This essentially recapitulates the cell cycle effect of CUG200, suggesting that Celf1 mediates the acceleration of cell cycling in RNA toxicity myoblasts. It was reported that the muscles from DM1 patients had increased satellite cell number but without proper terminal differentiation and muscle regeneration, especially in congenital cases [27,28]. The effect of Celf1 on cell cycle control may explain such a baffling phenomenon, and supporting that Celf1 upregulation resulted from RNA toxicity may contribute to the pathogenesis of congenital DM1.…”

Section: Discussionmentioning

confidence: 94%

Celf1 regulates cell cycle and is partially responsible for defective myoblast differentiation in myotonic dystrophy RNA toxicity

Peng

Shen

Chen

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Myotonic dystrophy is a neuromuscular disease of RNA toxicity. The disease gene DMPK harbors expanded CTG trinucleotide repeats on its 3'-UTR. The transcripts of this mutant DMPK led to misregulation of RNA-binding proteins including MBNL1 and Celf1. In myoblasts, CUG-expansion impaired terminal differentiation. In this study, we formally tested how the abundance of Celf1 regulates normal myocyte differentiation, and how Celf1 expression level mediates CUG-expansion RNA toxicity-triggered impairment of myocyte differentiation. As the results, overexpression of Celf1 largely recapitulated the defects of myocytes with CUG-expansion, by increasing myocyte cycling. Knockdown of endogenous Celf1 level led to precocious myotube formation, supporting a negative connection between Celf1 abundance and myocyte terminal differentiation. Finally, knockdown of Celf1 in myocyte with CUG-expansion led to partial rescue, by promoting cell cycle exit. Our results suggest that Celf1 plays a distinctive and negative role in terminal myocyte differentiation, which partially contribute to DM1 RNA toxicity. Targeting Celf1 may be a valid strategy in correcting DM1 muscle phenotypes, especially for congenital cases.

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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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Satellite cell dysfunction contributes to the progressive muscle atrophy in myotonic dystrophy type 1

Cited by 74 publications

References 29 publications

Smad3 signaling is required for satellite cell function and myogenic differentiation of myoblasts

Smad3 signaling is required for satellite cell function and myogenic differentiation of myoblasts

Celf1 regulates cell cycle and is partially responsible for defective myoblast differentiation in myotonic dystrophy RNA toxicity

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

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