Altered production of extra-cellular matrix components by muscle-derived Duchenne muscular dystrophy fibroblasts before and after TGF-β1 treatment

Zanotti, Simona; Gibertini, Sara; Mora, Marina

doi:10.1007/s00441-009-0889-4

Cited by 52 publications

(40 citation statements)

References 60 publications

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“…However, in chronic diseases such as muscular dystrophy, fibrosis becomes self-perpetuating and excessive, inhibiting regeneration of myofibers. Several studies have suggested that dystrophic muscle fibroblasts have an increased proliferation rate and increased collagen production compared to muscle fibroblasts from normal muscle of mice and humans (Mezzano et al, 2007;Pernitsky and Anderson, 1996;Zanotti et al, 2010). Recently, we have reported that normal skeletal muscle fibroblasts express myostatin and its putative receptor, ActRIIB .…”

Section: Discussionmentioning

confidence: 93%

Inhibiting myostatin reverses muscle fibrosis through apoptosis

Zhang

Wagner

2012

Journal of Cell Science

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SummarySkeletal muscle fibrosis is a defining feature of the muscular dystrophies in which contractile myofibers are replaced by fibroblasts, adipocytes and extracellular matrix. This maladaptive response of muscle to repetitive injury is progressive, self-perpetuating and thus far, has been considered irreversible. We have previously shown that myostatin, a known endogenous modulator of muscle growth, stimulates normal muscle fibroblasts to proliferate. Here, we demonstrate that myostatin also regulates the proliferation of dystrophic muscle fibroblasts, and increases resistance of fibroblasts to apoptosis through Smad and MAPK signaling. Inhibition of myostatin signaling pathways with a soluble activin IIB receptor (ActRIIB.Fc) reduces resistance of muscle fibroblasts to apoptosis in vitro. Systemic administration of ActRIIB.Fc in senescent mdx mice, a model of muscular dystrophy, significantly increases the number of muscle fibroblasts undergoing apoptosis. This leads to the reversal of pre-existing muscle fibrosis as determined by histological, biochemical and radiographical criteria. These results demonstrate that skeletal muscle fibrosis can be pharmacologically reversed through induction of fibroblast apoptosis.

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Section: Discussionmentioning

confidence: 93%

Inhibiting myostatin reverses muscle fibrosis through apoptosis

Zhang

Wagner

2012

Journal of Cell Science

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“…Our previous study showed that primary fibroblasts derived from DMD muscles have a pro-fibrotic phenotype probably due to intrinsic memory of their native environment, which is altered by the primary genetic defect [54,55]. We have also shown that transcript expression and protein modulation of several ECM components are altered in DMD myotubes [58].…”

Section: Introductionmentioning

confidence: 90%

“…Control and DMD fibroblasts and myoblasts were treated with 10 ng/ml h-recombinant TGF-β1 (Peprotech EC, London, UK) for 48 h, as described previously [55].…”

Section: Muscle Biopsies and Cell Culturesmentioning

confidence: 99%

“…We also examined the PAI-1/plasmin system in fibroblasts since we have previously shown that muscle-derived fibroblasts from DMD patients are fibrogenic [54,55] and the system is involved in ECM remodelling and regulation of miR-21 biogenesis [3]. Finally, to assess the therapeutic potential of miR-21 inhibition, we treated mdx mice with antagomiR-21.…”

Section: Introductionmentioning

confidence: 98%

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Opposing roles of miR-21 and miR-29 in the progression of fibrosis in Duchenne muscular dystrophy

Zanotti¹,

Gibertini²,

Curcio³

et al. 2015

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

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Excessive extracellular matrix deposition progressively replacing muscle fibres is the endpoint of most severe muscle diseases. Recent data indicate major involvement of microRNAs in regulating pro- and anti-fibrotic genes. To investigate the roles of miR-21 and miR-29 in muscle fibrosis in Duchenne muscle dystrophy, we evaluated their expression in muscle biopsies from 14 patients, and in muscle-derived fibroblasts and myoblasts. In Duchenne muscle biopsies, miR-21 expression was significantly increased, and correlated directly with COL1A1 and COL6A1 transcript levels. MiR-21 expression was also significantly increased in Duchenne fibroblasts, more so after TGF-β1 treatment. In Duchenne fibroblasts the expression of miR-21 target transcripts PTEN (phosphatase and tensin homolog deleted on chromosome 10) and SPRY-1 (Sprouty homolog 1) was significantly reduced; while collagen I and VI transcript levels and soluble collagen production were significantly increased. MiR-29a and miR-29c were significantly reduced in Duchenne muscle and myoblasts, and miR-29 target transcripts, COL3A1, FBN1 and YY1, significantly increased. MiR-21 silencing in mdx mice reduced fibrosis in the diaphragm muscle and in both Duchenne fibroblasts and mdx mice restored PTEN and SPRY-1 expression, and significantly reduced collagen I and VI expression; while miR-29 mimicking in Duchenne myoblasts significantly decreased miR-29 target transcripts. These findings indicate that miR-21 and miR-29 play opposing roles in Duchenne muscle fibrosis and suggest that pharmacological modulation of their expression has therapeutic potential for reducing fibrosis in this condition.

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“…TGF- is known to modulate the ability of cells to synthesize various ECM components and was shown to modify the protein pattern produced by DMD fibroblasts upon their transformation to myofibroblasts. It increased MMP-7 thought to contribute to fibrosis (Fadic et al, 2006;Simona Zanotti et al, 2010;S. Zanotti et al, 2007).…”

Section: Matrix Metalloproteinases In Dystrophic Musclesmentioning

confidence: 99%