MyD88 promotes myoblast fusion in a cell-autonomous manner

Hindi, Sajedah M.; Shin, Jeon-Soo; Gallot, Yann S.; Straughn, Alex R.; Simionescu-Bankston, Adriana; Hindi, Lubna; Xiong, Guangyan; Friedland, Robert P.; Kumar, Ashok

doi:10.1038/s41467-017-01866-w

Cited by 48 publications

(78 citation statements)

References 69 publications

(111 reference statements)

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“…We also found that the preservation of fat mass was more variable and less substantial than that observed for lean mass. This may in part reflect the direct impact of MyD88‐dependent signalling in muscle . However, our prior work demonstrated that muscle‐specific deletion of MyD88 did not attenuate muscle catabolism in response to acute inflammatory challenges .…”

Section: Discussionmentioning

confidence: 88%

MyD88 signalling is critical in the development of pancreatic cancer cachexia

Zhu

Burfeind

Michaelis

et al. 2019

J cachexia sarcopenia muscle

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Background Up to 80% of pancreatic cancer patients suffer from cachexia, a devastating condition that exacerbates underlying disease, reduces quality of life, and increases treatment complications and mortality. Tumour‐induced inflammation is linked to this multifactorial wasting syndrome, but mechanisms and effective treatments remain elusive. Myeloid differentiation factor (MyD88), a key component of the innate immune system, plays a pivotal role in directing the inflammatory response to various insults. In this study, we tested whether MyD88 signalling is essential in the development of pancreatic cancer cachexia using a robust mouse tumour model. Methods Sex, age, and body weight‐matched wide type (WT) and MyD88 knockout (MyD88 KO) mice were orthotopically or intraperitoneally implanted with a pancreatic tumour cell line from a syngeneic C57BL/6 KRAS G12D/+ P53 R172H/+ Pdx‐Cre (KPC) mouse. We observed the effects of MyD88 signalling during pancreatic ductal adenocarcinoma progression and the cachexia development through behavioural, histological, molecular, and survival aspects. Results Blocking MyD88 signalling greatly ameliorated pancreatic ductal adenocarcinoma‐associated anorexia and fatigue, attenuated lean mass loss, reduced muscle catabolism and atrophy, diminished systemic and central nervous system inflammation, and ultimately improved survival. Our data demonstrate that MyD88 signalling plays a critical role in mediating pancreatic cancer‐induced inflammation that triggers cachexia development and therefore represents a promising therapeutic target. Conclusions MyD88‐dependent inflammation is crucial in the pathophysiology of pancreatic cancer progression and contributes to high mortality. Our findings implicate the importance of innate immune signalling pathways in pancreatic cancer cachexia and a novel therapeutic target.

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Section: Discussionmentioning

confidence: 88%

MyD88 signalling is critical in the development of pancreatic cancer cachexia

Zhu

Burfeind

Michaelis

et al. 2019

J cachexia sarcopenia muscle

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“…We found that GB significantly enhanced the expression of key proteins in the Wnt/β‐catenin pathway and the expression of target genes were also promoted. The TOPFlash experiment further confirmed the activation of the Wnt/β‐catenin signalling pathway in GB‐mediated osteoblast differentiation . Nuclear accumulation of β‐catenin is an important step for activation of target genes of the Wnt/β‐catenin signalling pathway .…”

Section: Discussionmentioning

confidence: 63%

Ginkgolide B promotes osteoblast differentiation via activation of canonical Wnt signalling and alleviates osteoporosis through a bone anabolic way

Zhu

Xue

Zhang

et al. 2019

J Cellular Molecular Medi

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Osteoporosis has become a worldwide problem as the population ages. Although many advances have been made in the treatment of osteoporosis in the past few years, the outcome are sometimes disturbing because of the adverse effects of these treatments. Further studies are still needed to identify novel alternate agents to improve the therapeutic effect. Ginkgolide B (GB), a derivative of Ginkgo biloba leaves, has numerous pharmacological effects, including anticancer and anti‐inflammation activities. However, the effect of GB on the regulation of osteoblast activity and bone formation effect has not yet been investigated. In this study, we showed the in vitro and in vivo effects of GB on osteoblast differentiation and bone formation. We found that GB promotes osteoblast differentiation of Bone Mesenchymal Stem Cells (BMSCs) and MC3T3‐E1 cells in vitro in a Wnt/β‐catenin‐dependent manner. In an in vivo study, we constructed a cranial defect model in rats and treated with GB. Histomorphometric and histological analyses confirmed that the usage of GB significantly promotes bone formation. Further study on ovariectomy (OVX) rats demonstrated that GB is capable of alleviating ovariectomy‐induced bone loss by enhancing osteoblast activity. Our findings indicate that GB is a potential therapeutic agent of osteoporosis through an anabolic way in bone.

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“…To investigate the role of MyD88 in cancer cachexia, we used the Myod1-Cre line, which features deletions of the target gene in both myoblasts and differentiated skeletal muscle. Specifically, floxed MyD88 (MyD88 f/f ) mice were crossed with the Myod1-Cre line to generate littermate muscle-specific MyD88knockout (MyD88 myoKO ) and control (MyD88 f/f ) mice as previously described (14). We have previously reported that the levels of MyD88 are drastically reduced in skeletal muscle of MyD88 myoKO mice compared with littermate MyD88 f/f mice (14).…”

Section: Resultsmentioning

confidence: 99%

“…Specifically, floxed MyD88 (MyD88 f/f ) mice were crossed with the Myod1-Cre line to generate littermate muscle-specific MyD88knockout (MyD88 myoKO ) and control (MyD88 f/f ) mice as previously described (14). We have previously reported that the levels of MyD88 are drastically reduced in skeletal muscle of MyD88 myoKO mice compared with littermate MyD88 f/f mice (14). By performing immunoblotting, we confirmed that MyD88 levels were depleted in GA muscle of MyD88 myoKO mice compared with littermate MyD88 f/f mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

The Toll-Like Receptor/MyD88/XBP1 Signaling Axis Mediates Skeletal Muscle Wasting during Cancer Cachexia

Bohnert

Goli

Roy

et al. 2019

Molecular and Cellular Biology

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Skeletal muscle wasting causes both morbidity and mortality of cancer patients. Accumulating evidence suggests that the markers of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) pathways are increased in skeletal muscle under multiple catabolic conditions, including cancer. However, the signaling mechanisms and the role of individual arms of the UPR in the regulation of skeletal muscle mass remain largely unknown. In the present study, we demonstrated that gene expression of Toll-like receptors (TLRs) and myeloid differentiation primary response gene 88 (MyD88) was increased in skeletal muscle in a Lewis lung carcinoma (LLC) model of cancer cachexia. Targeted ablation of MyD88 inhibits the loss of skeletal muscle mass and strength in LLC tumor-bearing mice. Inhibition of MyD88 attenuates the LLC-induced activation of the UPR in skeletal muscle of mice. Moreover, muscle-specific deletion of X-box binding protein 1 (XBP1), a major downstream target of IRE1␣ arm of the UPR, ameliorates muscle wasting in LLC tumor-bearing mice. Our results also demonstrate that overexpression of an active form of XBP1 caused atrophy in cultured myotubes. In contrast, knockdown of XBP1 inhibits myotube atrophy in response to LLC or C26 adenocarcinoma cell conditioned medium. Collectively, our results demonstrate that TLR/MyD88-mediated activation of XBP1 causes skeletal muscle wasting in LLC tumor-bearing mice.

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MyD88 promotes myoblast fusion in a cell-autonomous manner

Cited by 48 publications

References 69 publications

MyD88 signalling is critical in the development of pancreatic cancer cachexia

MyD88 signalling is critical in the development of pancreatic cancer cachexia

Ginkgolide B promotes osteoblast differentiation via activation of canonical Wnt signalling and alleviates osteoporosis through a bone anabolic way

The Toll-Like Receptor/MyD88/XBP1 Signaling Axis Mediates Skeletal Muscle Wasting during Cancer Cachexia

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