Abstract
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 lipopolysaccharide (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 lactacystin 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 ubiquitin-proteasome and the autophagy-lysosomal pathways.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Autophagy / drug effects
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Blotting, Western
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Cell Line
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Enzyme Inhibitors / pharmacology
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Imidazoles / pharmacology
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Lipopolysaccharides / pharmacology*
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Lysosomes / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Muscle Fibers, Skeletal / drug effects
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Muscle Fibers, Skeletal / metabolism
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Muscle Proteins / genetics
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Muscle Proteins / metabolism
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Muscles / drug effects*
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Muscles / metabolism
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Muscular Atrophy / genetics
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Muscular Atrophy / metabolism
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Phagosomes / drug effects
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Phagosomes / metabolism
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Proteasome Endopeptidase Complex / metabolism
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Pyridines / pharmacology
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RNA Interference
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SKP Cullin F-Box Protein Ligases / genetics
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SKP Cullin F-Box Protein Ligases / metabolism
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Signal Transduction / drug effects*
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / metabolism*
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Ubiquitin / metabolism
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Enzyme Inhibitors
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Imidazoles
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Lipopolysaccharides
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Muscle Proteins
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Pyridines
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Toll-Like Receptor 4
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Ubiquitin
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Fbxo32 protein, mouse
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SKP Cullin F-Box Protein Ligases
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p38 Mitogen-Activated Protein Kinases
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Proteasome Endopeptidase Complex
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4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole