Article

Toll-like receptor 4 mediates lipopolysaccharide-induced muscle catabolism via coordinate activation of ubiquitin-proteasome and autophagy-lysosome pathways

Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX 77030, USA.
The FASEB Journal (Impact Factor: 5.04). 01/2011; 25(1):99-110. DOI: 10.1096/fj.10-164152
Source: PubMed

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.

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Available from: Guohua Zhang, Sep 08, 2014
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    • "An example of such interplay is the LPS/TLR4/muscle wasting pathway. Doyle and colleagues demonstrated that lipopolysaccharides (LPS), which are proinflammatory compounds of bacterial origin, induce muscle catabolism through the toll-like receptor (TLR) 4[30]. If LPS is increased in the serum of cancer patients with cachexia is currently unknown. "
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    • "We also assessed the conversion of light chain 3 B (LC3B)-I to LC3B-II, a process involving lipidation that is required for formation of autophagic vesicles. Consistent with prior work, mice treated with LPS demonstrate a significant increase in the 14 kD LC3B-II isoform (Figure S1) [28]. However, chemotherapy failed to induce a significant conversion of LC3B-I to LC3B-II in either genotype of mice, consistent with the relatively weak induction of autophagy genes relative to LPS treatment [4]. "
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    • "Another possibility is the participation of p38MAPK that is has been recently described to be involved in the transcriptional upregulation of Mas in dorsal root ganglia neurons (Cao et al. 2013). Interestingly, p38 MAPK has been found to be a key player in skeletal muscle atrophy induced by immobilization, AngII treatment and LPS (Doyle et al. 2011; Eley et al. 2008; Kim et al. 2009). Thus, we can speculate that p38MAPK could participate of the Mas upregulation in the atrophic models used for us. "
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