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


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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    ABSTRACT: Cachexia is a multifactorial syndrome that includes muscle wasting and inflammation, and that is associated with chronic underlying diseases, such as cancer, chronic heart failure and chronic kidney disease. Since gut microbes influence host immunity and metabolism, we hypothesized a few years ago that the gut microbiota could be a potential therapeutic target to tackle cancer-related cachexia. In this review, we present evidence from animal and human studies suggesting that the gut microbiota and its crosstalk with the intestine might constitute unexpected targets in the therapeutic management of cancer and related cachexia. Finally, we discuss future research directions and hypotheses to progress in this new promising field, i.e. the role of the gut microbiota in cancer cachexia.
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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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    ABSTRACT: Cancer cachexia is a syndrome of weight loss that results from the selective depletion of skeletal muscle mass and contributes significantly to cancer morbidity and mortality. The driver of skeletal muscle atrophy in cancer cachexia is systemic inflammation arising from both the cancer and cancer treatment. While the importance of tumor derived inflammation is well described, the mechanism by which cytotoxic chemotherapy contributes to cancer cachexia is relatively unexplored. We found that the administration of chemotherapy to mice produces a rapid inflammatory response. This drives activation of the hypothalamic-pituitary-adrenal axis, which increases the circulating level of corticosterone, the predominant endogenous glucocorticoid in rodents. Additionally, chemotherapy administration results in a significant loss of skeletal muscle mass 18 hours after administration with a concurrent induction of genes involved with the ubiquitin proteasome and autophagy lysosome systems. However, in mice lacking glucocorticoid receptor expression in skeletal muscle, chemotherapy-induced muscle atrophy is completely blocked. This demonstrates that cytotoxic chemotherapy elicits significant muscle atrophy driven by the production of endogenous glucocorticoids. Further, it argues that pharmacotherapy targeting the glucocorticoid receptor, given in concert with chemotherapy, is a viable therapeutic strategy in the treatment of cancer cachexia.
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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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