Immunomodulation of TGF-beta1 in mdx mouse inhibits connective tissue proliferation in diaphragm but increases inflammatory response: Implications for antifibrotic therapy

Andreetta, Francesca; Bernasconi, Pia; Baggi, Fulvio; Ferro, Paolo; Oliva, Laura; Arnoldi, Elisa; Cornelio, F.; Mantegazza, Renato; Confalonieri, Paolo

doi:10.1016/j.jneuroim.2006.03.005

Cited by 113 publications

(131 citation statements)

References 33 publications

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“…TGF-␤ signaling also plays a significant role in muscle fibrosis. TGF-␤ 1 expression parallels development of fibrosis and neutralizing antibodies to TGF-␤ 1 reduce fibrosis in mdx diaphragms (37). Similarly, TGF-␤ 1 expression correlates with fibrosis in dystrophic patient muscle (38).…”

Section: Discussionmentioning

confidence: 98%

Myostatin Directly Regulates Skeletal Muscle Fibrosis

Kollias

Wagner

2008

Journal of Biological Chemistry

221

183

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Skeletal muscle fibrosis is a major pathological hallmark of chronic myopathies in which myofibers are replaced by progressive deposition of collagen and other extracellular matrix proteins produced by muscle fibroblasts. Recent studies have shown that in the absence of the endogenous muscle growth regulator myostatin, regeneration of muscle is enhanced, and muscle fibrosis is correspondingly reduced. We now demonstrate that myostatin not only regulates the growth of myocytes but also directly regulates muscle fibroblasts. Our results show that myostatin stimulates the proliferation of muscle fibroblasts and the production of extracellular matrix proteins both in vitro and in vivo. Further, muscle fibroblasts express myostatin and its putative receptor activin receptor IIB. Proliferation of muscle fibroblasts, induced by myostatin, involves the activation of Smad, p38 MAPK and Akt pathways. These results expand our understanding of the function of myostatin in muscle tissue and provide a potential target for anti-fibrotic therapies.Fibroblasts play an important role in the repair response of tissues to injury by secreting extracellular matrix proteins including collagen and growth factors. However, in a variety of disease states, continued fibrosis contributes to the pathological process. In chronic myopathies and muscular dystrophies, fibrosis is considered to be associated with decreased strength and elasticity of muscle and may inhibit the diffusion of nutrients to myofibers (1-3). Identification of factors that regulate fibrosis is an important goal not only in understanding the pathogenesis of muscular dystrophies but also in developing novel therapies to treat these disorders. Several potential future therapies for the muscular dystrophies, including those involving gene and myoblast transfer, may be hampered by significant fibrosis.Myostatin is a highly conserved transforming growth factor-␤ (TGF-␤) 2 family member that is expressed in skeletal muscle, which is also the primary target tissue (4). Deletion of the myostatin gene (MSTN) in mice leads to muscle hypertrophy and hyperplasia with an approximate doubling of muscle mass (4). This function of myostatin, as an endogenous inhibitor of muscle growth, is also conserved in humans, as demonstrated by the identification of a hypermuscular child with a loss-of-function mutation in the myostatin gene (5). One mechanism by which myostatin regulates muscle growth in adult animals appears to be direct inhibition of the proliferation and differentiation of resident muscle precursor cells (6 -8).The potential effect of myostatin inhibition on muscle degenerative diseases has been explored in various animal models. In the absence of myostatin, muscle regenerates more quickly and completely following acute and chronic injury (8, 9). In the mdx mouse, a model of Duchenne and Becker muscular dystrophy, myostatin deletion, or postnatal inhibition increases muscle mass and strength (10 -12). An early observation of mdx/mstn null mice was that the diaphragm muscle of t...

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Section: Discussionmentioning

confidence: 98%

Myostatin Directly Regulates Skeletal Muscle Fibrosis

Kollias

Wagner

2008

Journal of Biological Chemistry

221

183

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“…In recent years, studies on TGF-β1 showed that it is an effective factor in inducing tissue fibrosis, and plays an important role in the process of fibrosis in the kidney, liver, lung, and heart (Lijnen et al 2000;Hersh et al 2006;Lan 2011). Its functions in muscle fibrosis are also significant Li et al 2004;Andreetta et al 2006). In addition, activated TGF-β1 can eventually lead to fibrosis (Gressner and Weiskirchen 2006).…”

Section: Discussionmentioning

confidence: 99%

Expression of TGF-<i>β</i>1 and CTGF Is Associated with Fibrosis of Denervated Sternocleidomastoid Muscles in Mice

Liu

Tang

Chen

et al. 2016

Tohoku J. Exp. Med.

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Injury to the recurrent laryngeal nerve often leads to permanent vocal cord paralysis, which has a significant negative impact on the quality of life. Long-term denervation can induce laryngeal muscle fibrosis，which obstructs the muscle recovery after laryngeal reinnervation. However, the mechanisms of fibrosis remain unclear. In this study, we aimed to analyze the changes in the expression of fibrosis-related factors, including transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), and α-smooth muscle actin (α-SMA) in denervated skeletal muscles using a mouse model of accessory nerve transection. Because of the small size, we used sternocleidomastoid muscles instead of laryngeal muscles for denervation experiments. Masson's trichrome staining showed that the grade of atrophy and fibrosis of muscles became more severe with time, but showed a plateau at 4 weeks after denervation, followed by a slow decrease. Quantitative assessment and immunohistochemistry showed that TGF-β1 expression peaked at 1 week after denervation (p < 0.05) and was maintained at its high level until 4 weeks. CTGFand α-SMA-positive muscle cells were detected at 1 week after denervation, peaked at 2 weeks (p < 0.05), and remained at high levels with a subsequent slight decrease for 3-4 weeks. These results suggest that TGF-β1 and CTGF may be involved in the process of denervated skeletal muscle fibrosis. They may induce the differentiation of myoblasts into myofibroblasts, as characterized by the activation of α-SMA. These findings may provide insights on key pathological processes in denervated skeletal muscle fibrosis and develop novel therapeutic strategies.

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“…The key cytokine responsible for this aberrant regeneration is TGF-b, which activates fibroblasts to produce ECM components and ECM-remodeling factors, including the autocrine production of TGF-b, collagen, fibronectin, serine proteases (such as uPA/plasmin), metalloproteinases, and tissue inhibitor of metalloproteinases (27). TGF-b protein and connective tissue proteins, including hydroxyproline and procollagen, are significantly upregulated in mdx mice compared with the C57BL/6 controls (1,20). The serum TGF-b1 concentration, evaluated by ELISA, was significantly downregulated by losartan treatment; the Los group had a lower level than that of the Con group, and the ASC + Los group had a lower level than that of the ASC group (Fig.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Effects of Mouse Adipose-Derived Stem Cells and Losartan in the Skeletal Muscle of Injured Mdx Mice

et al. 2015

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Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder caused by mutations in the dystrophin gene. Adipose-derived stem cells (ASCs) are an attractive source of cells for stem cell therapy. Losartan has been reported to improve ASC transplantation in injured mouse muscles. In the present study, we investigated whether the combined treatment of losartan and ASCs in the injured muscles of mdx mice improves regeneration. The combined treatment of ASCs and losartan remarkably improved muscle regeneration and induced muscle hypertrophy. In addition, ASCs and losartan treatment downregulated transforming growth factor-b and inhibited muscle fibrosis. We observed cells coexpressing green fluorescent protein (GFP) and dystrophin in the muscle samples of mice transplanted with GFP-positive ASCs. In the coculture in vitro experiment, we also observed that the GFP ASCs differentiated into dystrophin-expressing myotubes. The present study shows that the combination of transplanted ASCs and treatment with losartan ameliorated muscle fibrosis and improved muscle regeneration in injured mdx mice. Thus, we suggest that combined treatment with losartan and ASCs could help to improve muscle regeneration in the muscles of injured patients, including DMD patients.

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Immunomodulation of TGF-beta1 in mdx mouse inhibits connective tissue proliferation in diaphragm but increases inflammatory response: Implications for antifibrotic therapy

Cited by 113 publications

References 33 publications

Myostatin Directly Regulates Skeletal Muscle Fibrosis

Myostatin Directly Regulates Skeletal Muscle Fibrosis

Expression of TGF-<i>β</i>1 and CTGF Is Associated with Fibrosis of Denervated Sternocleidomastoid Muscles in Mice

Therapeutic Effects of Mouse Adipose-Derived Stem Cells and Losartan in the Skeletal Muscle of Injured Mdx Mice

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