TAK1 inhibition improves myoblast differentiation and alleviates fibrosis in a mouse model of Duchenne muscular dystrophy

Xu, Dengqiu; Li, Sijia; Wang, Lu; Jiang, Jingwei; Zhao, Lei; Huang, Xiaofei; Sun, Zeren; Li, Chunjie; Sun, Lixin; Li, Xihua; Jiang, Zhenzhou; Zhang, Luyong

doi:10.1002/jcsm.12650

Cited by 17 publications

(25 citation statements)

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“…A recent report showed that TAK1 is activated in skeletal muscle of DMD patients and in dystrophic muscle of mdx mice. Moreover, authors reported that inhibition of TAK1 ameliorates dystrophic phenotype in mdx mice (36) . However, in contrast to the published report, we found that muscle-specific inactivation/deletion of TAK1 reduces grip strength and muscle contractile function in mdx mice ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Forced activation of TAK1 in skeletal muscle causes myofiber hypertrophy and also attenuates the loss of muscle mass in response to functional denervation (35) . A recent study has demonstrated that TAK1 is activated in skeletal muscle of DMD patients and dystrophic-deficient mdx mice (36) . However, the muscle-specific role of TAK1 in disease progression and the mechanisms by which TAK1 regulates dystrophic phenotype in mdx mice remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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Temporal regulation of TAK1 to counteract muscular dystrophy

Roy

Koike

Joshi

et al. 2022

Preprint

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Muscular dystrophy is a group of genetic neuromuscular disorders that involves severe muscle wasting. Transforming growth factor β-activated kinase 1 (TAK1) is an important signaling protein that regulates cell survival, growth, and inflammation. TAK1 has been recently found to promote myofiber growth in skeletal muscle of adult mice. However, the role of TAK1 in muscle disorders remains poorly understood. In the present study, we have investigated how TAK1 affects progression of dystrophic phenotype in the mdx mouse model of Duchnne muscular dystrophy (DMD). TAK1 is highly activated during peak necrotic phase in mdx mice. Targeted inducible inactivation of TAK1 inhibits muscle injury, necroptosis, and accumulation of macrophages in dystrophic muscle of mdx mice. Additionally, targeted inactivation of TAK1 leads to the activation of autophagy and Notch and Wnt signaling in the dystrophic muscle. However, inactivation of TAK1 significantly reduces myofiber size and muscle contractile function in both young and adult mdx mice. Forced activation of TAK1 in skeletal muscle after peak necrotic phase induces myofiber growth and improves muscle histopathology in mdx mice. Our results suggest that targeted activation of TAK1 can ameliorate disease progression and improve muscle growth in DMD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Temporal regulation of TAK1 to counteract muscular dystrophy

Roy

Koike

Joshi

et al. 2022

Preprint

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“…The TGFb-TAK1 pathway is a shared molecular pathway regulating TyrK, BRD and p38 MAPK signaling. Growing evidence supports the role of TAK1 as a significant regulator of TGFb signaling through the regulation of the profibrotic response in several systems [43][44][45][83][84][85][86][87]. Very recently, it has been shown that the action of Catalpol (an anti-inflammatory and antioxidant drug from Chinese medicinal herb Rehmannia) on DMD histopathology was due to its binding to TAK1 [88,89].…”

Section: Members Of Thementioning

confidence: 97%

Targeting fibrosis in the Duchenne Muscular Dystrophy mice model: an uphill battle

Théret¹,

M²,

Rempel³

et al. 2021

Preprint

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AimFibrosis is the most common complication from chronic diseases, and yet no therapy capable of mitigating its effects is available. Our goal is to unveil specific signallings regulating the fibrogenic process and to identify potential small molecule candidates that block fibrogenic differentiation of fibro/adipogenic progenitors.MethodWe performed a large-scale drug screen using muscle-resident fibro/adipogenic progenitors from a mouse model expressing EGFP under the Collagen1a1 promotor. We first confirmed that the EGFP was expressed in response to TGFβ1 stimulation in vitro. Then we treated cells with TGFβ1 alone or with drugs from two libraries of known compounds. The drugs ability to block the fibrogenic differentiation was quantified by imaging and flow cytometry. From a two-rounds screening, positive hits were tested in vivo in the mice model for the Duchenne muscular dystrophy (mdx mice). The histopathology of the muscles was assessed with picrosirius red (fibrosis) and laminin staining (myofiber size).Key findingsFrom the in vitro drug screening, we identified 21 drugs and tested 3 in vivo on the mdx mice. None of the three drugs significantly improved muscle histopathology.SignificanceThe in vitro drug screen identified various efficient compounds, none of them strongly inhibited fibrosis in skeletal muscle of mdx mice. To explain these observations, we hypothesize that in Duchenne Muscular Dystrophy, in which fibrosis is a secondary event due to chronic degeneration and inflammation, the drugs tested could have adverse effect on regeneration or inflammation, balancing off any positive effects and leading to the absence of significant results.

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“…Some basal phosphorylation seemed to be present in the absence of LPS stimulation with both antibodies. All three antibodies -the single phospho-specific as well as the double phosphospecific ones -have repeatedly been used in the literature [38][39][40]. This issue will be followed up in the discussion section.…”

Section: Lps-mediated Signalling In Mmscsmentioning

confidence: 99%

The inflammatory signalling mediator TAK1 mediates lymphocyte recruitment to lipopolysaccharide-activated murine mesenchymal stem cells through interleukin-6

et al. 2021

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As a response to pro-inflammatory signals mesenchymal stem cells (MSCs) secrete agents and factors leading to lymphocyte recruitment, counteracting inflammation, and stimulating immunosuppression. On a molecular level, the signalling mediator TGF-β-activated kinase 1 (TAK1) is activated by many pro-inflammatory signals, plays a critical role in inflammation and regulates innate and adaptive immune responses as well. While the role of TAK1 as a signalling factor promoting inflammation is well documented, we also considered a role for TAK1 in anti-inflammatory actions exerted by activated MSCs. We, therefore, investigated the capacity of lipopolysaccharide (LPS)-treated murine MSCs with lentivirally modulated TAK1 expression levels to recruit lymphocytes. TAK1 downregulated by lentiviral vectors expressing TAK1 shRNA in murine MSCs interfered with the capacity of murine MSCs to chemoattract lymphocytes, indeed. Analysing a pool of 84 secreted factors we found that among 26 secreted cytokines/factors TAK1 regulated expression of one cytokine in LPS-activated murine MSCs in particular: interleukin-6 (IL-6). IL-6 in LPS-treated MSCs was responsible for lymphocyte recruitment as substantiated by neutralizing antibodies. Our studies, therefore, suggest that in LPS-treated murine MSCs the inflammatory signalling mediator TAK1 may exert anti-inflammatory properties via IL-6.

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TAK1 inhibition improves myoblast differentiation and alleviates fibrosis in a mouse model of Duchenne muscular dystrophy

Cited by 17 publications

References 50 publications

Temporal regulation of TAK1 to counteract muscular dystrophy

Temporal regulation of TAK1 to counteract muscular dystrophy

Targeting fibrosis in the Duchenne Muscular Dystrophy mice model: an uphill battle

The inflammatory signalling mediator TAK1 mediates lymphocyte recruitment to lipopolysaccharide-activated murine mesenchymal stem cells through interleukin-6

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