Reference - Detail
| RRC ID | 58719 |
|---|---|
| Author | Ono Y, Maejima Y, Saito M, Sakamoto K, Horita S, Shimomura K, Inoue S, Kotani J. |
| Title | TAK-242, a specific inhibitor of Toll-like receptor 4 signalling, prevents endotoxemia-induced skeletal muscle wasting in mice. |
| Journal | Sci Rep |
| Abstract |
Circulating lipopolysaccharide (LPS) concentrations are often elevated in patients with sepsis or various endogenous diseases related to bacterial translocation from the gut. Systemic inflammatory responses induced by endotoxemia induce severe involuntary loss of skeletal muscle, termed muscle wasting, which adversely affects the survival and functional outcomes of these patients. Currently, no drugs are available for the treatment of endotoxemia-induced skeletal muscle wasting. Here, we tested the effects of TAK-242, a Toll-like receptor 4 (TLR4)-specific signalling inhibitor, on myotube atrophy in vitro and muscle wasting in vivo induced by endotoxin. LPS treatment of murine C2C12 myotubes induced an inflammatory response (increased nuclear factor-κB activity and interleukin-6 and tumour necrosis factor-α expression) and activated the ubiquitin-proteasome and autophagy proteolytic pathways (increased atrogin-1/MAFbx, MuRF1, and LC-II expression), resulting in myotube atrophy. In mice, LPS injection increased the same inflammatory and proteolytic pathways in skeletal muscle and induced atrophy, resulting in reduced grip strength. Notably, pretreatment of cells or mice with TAK-242 reduced or reversed all the detrimental effects of LPS in vitro and in vivo. Collectively, our results indicate that pharmacological inhibition of TLR4 signalling may be a novel therapeutic intervention for endotoxemia-induced muscle wasting. |
| Volume | 10(1) |
| Pages | 694 |
| Published | 2020-1-20 |
| DOI | 10.1038/s41598-020-57714-3 |
| PII | 10.1038/s41598-020-57714-3 |
| PMID | 31959927 |
| PMC | PMC6970997 |
| MeSH | Animals Cell Line Disease Models, Animal Endotoxemia / complications* Endotoxemia / metabolism Interleukin-6 / metabolism Lipopolysaccharides / adverse effects Male Mice Muscle Fibers, Skeletal / cytology* Muscle Fibers, Skeletal / drug effects Muscle Fibers, Skeletal / metabolism Muscular Atrophy / etiology Muscular Atrophy / metabolism Muscular Atrophy / prevention & control* NF-kappa B / metabolism Signal Transduction / drug effects Sulfonamides / administration & dosage* Sulfonamides / pharmacology Tumor Necrosis Factor-alpha / metabolism |
| IF | 3.998 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | Patent(IFI CLAIMS) |
| Total number of mentions | 1 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | C2C12(RCB0987) |