Facioscapulohumeral muscular dystrophy (FSHD) myoblasts demonstrate increased susceptibility to oxidative stress

Winokur, Sara T.; Barrett, Kathy; Martı́n, Jorge; Forrester, James; Simon, Mariella; Tawil, Rabi; Chung, Seung-Ah; Masny, Peter S.; Figlewicz, Denise A.

doi:10.1016/s0960-8966(02)00284-5

Cited by 130 publications

(154 citation statements)

References 27 publications

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“…12,26 The reasons behind these discrepancies remain to be determined, but the very low level of FRG2 expression and different qPCR assays might contribute. Also unlike previous studies, 14,16 we found no difference between FSHD and unaffected cells in responses to paraquat or hydrogen peroxide. Our results, however, are consistent with previous work 12 which found no significant differences between FSHD and unaffected myogenic cells in expression of FRG1 or other 4q genes such as PDLIM3.…”

Section: Discussioncontrasting

confidence: 99%

“…6,[8][9][10][11][12][13][14][15] Some of these studies have suggested possible FSHD-specific phenotypes, including increased sensitivity to oxidative stress, 14,16 altered myotube morphology, 14 and altered expression of FRG1 18 or FRG2. 12 We found that proliferating and differentiating cultures of both FSHD and unaffected cells expressed similar patterns of FRG2 mRNA, and a recent study also found FRG2 mRNA in unaffected myoblasts and myotubes.…”

Section: Discussionmentioning

confidence: 99%

“…14,16 In particular, we examined the effects on cell viability of four types of stressors: (i) buthionine sulphoximine (BSO), which decreases intracellular glutathione by inhibition of gammaglutamylcysteine synthetase; 24 (ii) staurosporine, a kinase inhibitor that induces apoptotic cell death; 25 (iii) paraquat, a superoxide generator; and (iv) hydrogen peroxide. Each stressor was tested at a range of doses and times as used in previous studies 14,16,24,25 for the effect on cell viability (Supplementary Methods).…”

Section: Stressor Responses In Cultures Of Fshd and Unaffected Contromentioning

confidence: 99%

“…7 Many studies have, therefore, used primary myogenic cell cultures derived from FSHD subject biopsies to examine potential pathogenic mechanisms and therapeutic strategies. [8][9][10][11][12][13][14][15] Such studies have suggested several possible FSHD-specific phenotypes, including increased sensitivity to oxidative stress 14,16 and altered gene expression, [17][18][19][20] as well as expression of the long form of DUX4. 5,6 These findings have, however, sometimes not been consistent among laboratories.…”

Section: Introductionmentioning

confidence: 99%

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A unique library of myogenic cells from facioscapulohumeral muscular dystrophy subjects and unaffected relatives: family, disease and cell function

et al. 2011

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To explore possible mechanisms of pathology in facioscapulohumeral muscular dystrophy (FSHD), we generated a novel library of myogenic cells composed of paired cultures derived from FSHD subjects and unaffected first-degree relatives. We prepared cells from biopsies of both biceps and deltoid muscles obtained from each of 10 FSHD and 9 unaffected donors. We used this new collection to determine how family background and disease affected patterns of growth and differentiation, expression of a panel of candidate, and muscle-specific genes, and responses to exogenous stressors. We found that FSHD and unaffected cells had, on average, indistinguishable patterns of differentiation, gene expression, and dose-response curves to staurosporine, paraquat, hydrogen peroxide, and glutathione depletion. Differentiated FSHD and unaffected cultures were both more sensitive to glutathione depletion than proliferating cultures, but showed similar responses to paraquat, staurosporine, and peroxide. For stress responses, the sample size was sufficient to detect a 10% change in effect at the observed variability with a power of 499%. In contrast, for each of these properties, we found significant differences among cells from different cohorts, and these differences were independent of disease status, gender, or muscle biopsied. Thus, though none of the properties we examined could be used to reliably distinguish between FSHD and unaffected cells, family of origin was an important contributor to gene-expression patterns and stressor responses in cultures of both FSHD and unaffected myogenic cells.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Stressor Responses In Cultures Of Fshd and Unaffected Contromentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A unique library of myogenic cells from facioscapulohumeral muscular dystrophy subjects and unaffected relatives: family, disease and cell function

et al. 2011

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“…This finding contrasts with a previous report on FSHD myoblasts carrying three to six D4Z4 repeats, showing a 'vacuolar-necrotic phenotype'. 50 We cannot conclude about this discrepancy because many variables could be involved as, for example, the anatomical location of muscle biopsy, the degree of muscular dystrophy and the cell culture parameters. It may also be due to differences in the genetic status of FSHD patients, since our patients had larger (six to 10) D4Z4 repeats.…”

Section: Discussionmentioning

confidence: 99%

Normal growth and regenerating ability of myoblasts from unaffected muscles of facioscapulohumeral muscular dystrophy patients

Vilquin

Sacconi

et al. 2005

Gene Ther

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Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disease characterized by a typical regional distribution, featuring composed patterns of clinically affected and unaffected muscles. No treatment is available for this condition, in which the pathophysiological mechanism is still unknown. Autologous transfer of myoblasts from unaffected to affected territories could be considered as a potential strategy to delay or stop muscle degeneration. To evaluate the feasibility of this concept, we explored and compared the growth and differentiation characteristics of myoblasts prepared from phenotypically unaffected muscles of five FSHD patients and 10 control donors. According to a clinically approved procedure, 10 9 cells of a high degree of purity were obtained within 16-23 days. More than 80% of these cells were myoblasts, as demonstrated by labeling of the muscle markers CD56 and desmin. FSHD myoblasts presented a doubling time equivalent to that of control cells; they kept high proliferation ability and did not show early telomere shortening. In vitro, these cells were able to differentiate and to express muscle-specific antigens. In vivo, they participated to muscle structures when injected into immunodeficient mice. These data suggest that myoblasts expanded from unaffected FSHD muscles may be suitable tools in view of autologous cell transplantation clinical trials.

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DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53‐dependent myopathy in vivo

Wallace

Garwick

Mei

et al. 2010

Annals of Neurology

220

262

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Objective Facioscapulohumeral muscular dystrophy (FSHD) is associated with D4Z4 repeat contraction on human chromosome 4q35. This genetic lesion does not result in complete loss or mutation of any gene. Consequently, the pathogenic mechanisms underlying FSHD have been difficult to discern. In leading FSHD pathogenesis models, D4Z4 contractions are proposed to cause epigenetic changes, which ultimately increase expression of genes with myopathic potential. Although no gene has been conclusively linked to FSHD development, recent evidence supports a role for the D4Z4-encoded DUX4 gene in FSHD. In this study, our objective was to test the in vivo myopathic potential of DUX4. Methods We delivered DUX4 to zebrafish and mouse muscle by transposon-mediated transgenesis and adeno-associated viral vectors, respectively. Results Overexpression of DUX4, which encodes a transcription factor, caused abnormalities associated with muscular dystrophy in zebrafish and mice. This toxicity required DNA binding, because a DUX4 DNA binding domain mutant produced no abnormalities. Importantly, we found the myopathic effects of DUX4 were p53 dependent, as p53 inhibition mitigated DUX4 toxicity in vitro, and muscles from p53 null mice were resistant to DUX4-induced damage. Interpretation Our work demonstrates the myopathic potential of DUX4 in animal muscle. Considering previous studies showed DUX4 was elevated in FSHD patient muscles, our data support the hypothesis that DUX4 overexpression contributes to FSHD development. Moreover, we provide a p53-dependent mechanism for DUX4 toxicity that is consistent with previous studies showing p53 pathway activation in FSHD muscles. Our work justifies further investigation of DUX4 and the p53 pathway in FSHD pathogenesis.

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Facioscapulohumeral muscular dystrophy (FSHD) myoblasts demonstrate increased susceptibility to oxidative stress

Cited by 130 publications

References 27 publications

A unique library of myogenic cells from facioscapulohumeral muscular dystrophy subjects and unaffected relatives: family, disease and cell function

A unique library of myogenic cells from facioscapulohumeral muscular dystrophy subjects and unaffected relatives: family, disease and cell function

Normal growth and regenerating ability of myoblasts from unaffected muscles of facioscapulohumeral muscular dystrophy patients

DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53‐dependent myopathy in vivo

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