Temporal and spatial mRNA expression patterns of TGF-β1, 2, 3 and TβRI, II, III in skeletal muscles of mdx mice

Zhou, Lan; Porter, John D.; Cheng, Georgina; Gong, Bolin; Hatala, Denise A.; Merriam, Anita P.; Zhou, Xiaohua; Rafael, Jill A.; Kaminski, Henry J.

doi:10.1016/j.nmd.2005.09.009

Cited by 90 publications

(109 citation statements)

References 33 publications

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“…Enhanced TGF-␤1 expression has been shown in humans who suffer from MD (51, 62, 63) and mouse models of MDs (48,50,64,65). In line with these findings, in the present study, we observed elevated levels of TGF-␤1 in diaphragm muscle from mdm mouse.…”

Section: Volume 290 • Number 41 • October 9 2015supporting

confidence: 92%

Genome-wide Mechanosensitive MicroRNA (MechanomiR) Screen Uncovers Dysregulation of Their Regulatory Networks in the mdm Mouse Model of Muscular Dystrophy

Mohamed

Hajira

Lopez

et al. 2015

Journal of Biological Chemistry

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Section: Volume 290 • Number 41 • October 9 2015supporting

confidence: 92%

Genome-wide Mechanosensitive MicroRNA (MechanomiR) Screen Uncovers Dysregulation of Their Regulatory Networks in the mdm Mouse Model of Muscular Dystrophy

Mohamed

Hajira

Lopez

et al. 2015

Journal of Biological Chemistry

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“…Since inflammatory cells are a critical source of TGF␤ in mdx diaphragm (Zhou et al 2006), the influence of fibrin/ogen on the local inflammatory response was next analyzed. We found that the number of macrophages was reduced in fibrin/ogen depleted mdx diaphragm (Supplemental Fig.…”

Section: Resultsmentioning

confidence: 99%

Fibrinogen drives dystrophic muscle fibrosis via a TGFβ/alternative macrophage activation pathway

Vidal¹,

Serrano²,

Tjwa³

et al. 2008

Genes Dev.

235

260

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In the fatal degenerative Duchenne muscular dystrophy (DMD), skeletal muscle is progressively replaced by fibrotic tissue. Here, we show that fibrinogen accumulates in dystrophic muscles of DMD patients and mdx mice. Genetic loss or pharmacological depletion of fibrinogen in these mice reduced fibrosis and dystrophy progression. Our results demonstrate that fibrinogen-Mac-1 receptor binding, through induction of IL-1␤, drives the synthesis of transforming growth factor-␤ (TGF␤) by mdx macrophages, which in turn induces collagen production in mdx fibroblasts. Fibrinogen-produced TGF␤ further amplifies collagen accumulation through activation of profibrotic alternatively activated macrophages. Fibrinogen, by engaging its ␣v␤3 receptor on fibroblasts, also directly promotes collagen synthesis. These data unveil a profibrotic role of fibrinogen deposition in muscle dystrophy.Supplemental material is available at http://www.genesdev.org.Received November 30, 2007; revised version accepted April 28, 2008. Duchenne muscular dystrophy (DMD) results from mutations in the gene coding for the protein dystrophin, which localizes at the inner face of the sarcolemma (Campbell 1995). Besides progressive muscle degeneration and inflammation, fibrotic transition of muscle tissue is critical in DMD as it progressively deteriorates locomotor capacity, posture maintenance, and the vital function of cardiac and respiratory muscles. Indeed, DMD individuals have a high degree of fibrosis increasing with age, which is reproduced in the diaphragm muscle of mdx mice (the mouse model of DMD) (Stedman et al. 1991). Importantly, the underlying mechanisms of fibrosis development within dystrophic muscle remain largely unknown.Fibrinogen is a soluble acute phase protein, which is released into the blood in response to stress. Apart from its key role in controlling blood loss following vascular injury, fibrinogen also extravasates at sites of inflammation or increased vascular permeability where it is immobilized and/or converted to fibrin (Rybarczyk et al. 2003) (from hereon we refer to both by the term "fibrin/ ogen"). We showed previously that mice with defective fibrinolysis exhibited impaired muscle regeneration after experimental injury (Suelves et al. 2002). In this study, we investigated the role of fibrin/ogen deposition in the development of fibrosis in dystrophic muscle. Results and DiscussionWe first analyzed fibrin/ogen deposition in muscles of DMD patients and its correlation with disease course. Compared with muscles of healthy individuals or of fibromyalgia patients, DMD muscles showed significant fibrin/ogen accumulation (Fig. 1A). Similarly, in mdx mice muscles, fibrin/ogen deposits were readily detectable after disease onset, while absent before disease onset (Fig. 1B,C). Thus, fibrin/ogen deposition is associated with muscle dystrophinopathy.Collagen deposition (fibrosis) was prominent in DMD muscles and particularly found in the same areas occupied by fibrin/ogen (Fig. 1D). To investigate the relationship between the e...

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“…Bernasconi et al reported a correlation between higher TGF-b expression and skeletal muscle fibrosis in DMD patients (Bernasconi et al, 1995). Zhou and colleagues showed that TGF-b1, -b2 and -b3 and their receptors are upregulated in mdx mice (Zhou et al, 2006). Therefore, TGF-b isoforms and their signal pathways are a potent therapeutic target for DMD and other fibrotic diseases.…”

Section: Roles Of Tgf-b and Pdgf Signalingmentioning

confidence: 99%

Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle

Uezumi

Ito

Morikawa

et al. 2011

Journal of Cell Science

554

580

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SummaryAccumulation of adipocytes and collagen type-I-producing cells (fibrosis) is observed in muscular dystrophies. The origin of these cells had been largely unknown, but recently we identified mesenchymal progenitors positive for platelet-derived growth factor receptor alpha (PDGFRa) as the origin of adipocytes in skeletal muscle. However, the origin of muscle fibrosis remains largely unknown. In this study, clonal analyses show that PDGFRa + cells also differentiate into collagen type-I-producing cells. In fact, PDGFRa + cells accumulated in fibrotic areas of the diaphragm in the mdx mouse, a model of Duchenne muscular dystrophy. Furthermore, mRNA of fibrosis markers was expressed exclusively in the PDGFRa + cell fraction in the mdx diaphragm. Importantly, TGF-b isoforms, known as potent profibrotic cytokines, induced expression of markers of fibrosis in PDGFRa + cells but not in myogenic cells. Transplantation studies revealed that fibrogenic PDGFRa + cells mainly derived from pre-existing PDGFRa + cells and that the contribution of PDGFRa 2 cells and circulating cells was limited. These results indicate that mesenchymal progenitors are the main origin of not only fat accumulation but also fibrosis in skeletal muscle.

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Temporal and spatial mRNA expression patterns of TGF-β1, 2, 3 and TβRI, II, III in skeletal muscles of mdx mice

Cited by 90 publications

References 33 publications

Genome-wide Mechanosensitive MicroRNA (MechanomiR) Screen Uncovers Dysregulation of Their Regulatory Networks in the mdm Mouse Model of Muscular Dystrophy

Genome-wide Mechanosensitive MicroRNA (MechanomiR) Screen Uncovers Dysregulation of Their Regulatory Networks in the mdm Mouse Model of Muscular Dystrophy

Fibrinogen drives dystrophic muscle fibrosis via a TGFβ/alternative macrophage activation pathway

Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle

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