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Toll‐like receptor 4 mediates lipopolysaccharide‐induced muscle catabolism via coordinate activation of ubiquitin‐proteasome and autophagy‐lysosome pathways
Author(s) -
Doyle Alexander,
Zhang Guohua,
Fattah Elmoataz A. Abdel,
Eissa N. Tony,
Li YiPing
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.10-164152
Subject(s) - autophagy , tlr4 , ubiquitin ligase , microbiology and biotechnology , proteasome , muscle atrophy , lysosome , ubiquitin , catabolism , p38 mitogen activated protein kinases , autophagosome , chemistry , biology , mapk/erk pathway , signal transduction , biochemistry , skeletal muscle , endocrinology , metabolism , enzyme , apoptosis , gene
Cachectic muscle wasting is a frequent complication of many inflammatory conditions, due primarily to excessive muscle catabolism. However, the pathogenesis and intervention strategies against it remain to be established. Here, we tested the hypothesis that Toll‐like receptor 4 (TLR4) is a master regulator of inflammatory muscle catabolism. We demonstrate that TLR4 activation by lipopolysac‐charide (LPS) induces C2C12 myotube atrophy via up‐regulating autophagosome formation and the expression of ubiquitin ligase atrogin‐1/MAFbx and MuRF1. TLR4‐mediated activation of p38 MAPK is necessary and sufficient for the up‐regulation of atrogin1/MAFbx and autophagosomes, resulting in myotube atrophy. Similarly, LPS up‐regulates muscle autophagosome formation and ubiquitin ligase expression in mice. Importantly, autophagy inhibitor 3‐methyladenine completely abolishes LPS‐induced muscle proteolysis, while proteasome inhibitor lacta‐cystin partially blocks it. Furthermore, TLR4 knockout or p38 MAPK inhibition abolishes LPS‐induced muscle proteolysis. Thus, TLR4 mediates LPS‐induced muscle catabolism via coordinate activation of the ubiq‐uitin‐proteasome and the autophagy‐lysosomal pathways.—Doyle, A., Zhang, G., Abdel Fattah, E. A., Eissa, N. T., Li, Y.‐P. Toll‐like receptor 4 mediates lipopolysac‐charide‐induced muscle catabolism via coordinate activation of ubiquitin‐proteasome and autophagy‐lysosome pathways. FASEB J. 25, 99–110 (2011). www.fasebj.org