Using C2C12 myotubes in vitro and a mouse model of endotoxemia in vivo, we found that TAK-242, a selective inhibitor of TLR4-mediated signalling, blocked systemic and skeletal muscle inflammatory reactions, inhibited the activation of various proteolytic pathways, and ameliorated skeletal muscle wasting induced by LPS. Here, TLR4 is linked to serum lipopolysaccharide activity.