Toll-like receptor 4 mediates Lewis lung carcinoma-induced muscle wasting via coordinate activation of protein degradation pathways

Abstract

Cancer-induced cachexia, characterized by muscle wasting, is a lethal metabolic syndrome with undefined etiology. Current consensus is that multiple factors contribute to cancer-induced muscle wasting, and therefore therapy requires combinational strategies. Here, we show that Toll-like receptor 4 (TLR4) mediates cancer-induced muscle wasting by directly activating muscle catabolism as well as stimulating an innate immune response in mice bearing Lewis lung carcinoma (LLC), and targeting TLR4 alone effectively abrogate muscle wasting. Utilizing specific siRNAs we observed that LLC cell-conditioned medium (LCM)-treated C2C12 myotubes underwent a rapid catabolic response in a TLR4-dependent manner, including activation of the p38 MAPK−C/EBPβ signaling pathway as well as the ubiquitin-proteasome and autophagy-lysosome pathways, resulting in myotube atrophy. Utilizing a reporter cell-line it was confirmed that LCM activated TLR4. These results suggest that LLC-released cachexins directly activate muscle catabolism via activating TLR4 on muscle cells independent of immune responses. Critically, LLC tumor-bearing TLR4−/− mice were spared from muscle wasting due to a blockade in muscle catabolic pathways. Further, tumor-induced elevation of circulating TNFα and interleukin-6 (IL-6) was abolished in TLR4−/− mice. These data suggest that TLR4 is a central mediator and therapeutic target of cancer-induced muscle wasting.

Uncoupling protein 1 expression in adipocytes derived from skeletal muscle fibro/adipogenic progenitors is under genetic and hormonal control

“…It would be also important to assess intramuscular Ucp1 expression in other models of atrophy. This will, however, likely require experiments with additional animal species because fatty infiltration is generally not observed during denervation atrophy [66][67][68][69] or cancer cachexia 65,[70][71][72] in mice.…”

Toll-Like Receptor-4 Disruption Suppresses Adipose Tissue Remodeling and Increases Survival During Cancer Cachexia Syndrome

“…Thus, in addition to the anti-inflammatory and protective effects of skeletal muscle mass as previously demonstrated 10 , we have shown that TLR4 activation is "directly" involved in metabolic disorders in AT such as triglyceride (TG) turnover and browning phenotype, both parameters relevant to the remodeling and dysfunction of AT induced by cachexia. Therefore, the results obtained with the ATOR treatment and TLR4 -/mice during the development of cachexia suggests that the TLR4 pathway plays a fundamental role in maintenance of AT during cachexia syndrome and is a strong candidate for novel anti-cachectic therapy development.…”

“…In a cancer cachexia animal model, genetic ablation of TLR4 elicited a less severe cachexia with an accompanying lower body weight loss, greater lean body and fat mass, and clinical evidence of reduced wasting compared with the age and weightmatched WT mice 11 . More recently, an elegant study showed that TLR4 is a crucial mediator of cancer-induced muscle wasting due to its integration of catabolic signaling by directly activating muscle protein degradation and indirectly increasing cytokine release 10 . Thus, TLR4 may be a critical therapeutic target for cancer cachexia.…”

“…In the present study, the major inflammatory cytokines were abrogated in the same way, both TLR4 -/and pharmacological inhibition of TLR4 in TB mice. In fact, systemic activation of TLR4 increases cytokine synthesis and release from various host cells as an innate immune response 10 . Moreover, a recent study showed the presence of elevated levels of TNF-α and IL-6 in animals bearing-LLC tumor, which was attenuated in TLR4 -/mice in the same experimental condition (cachexia) 10 , corroborating the findings of our study.…”

The Toll-Like Receptor/MyD88/XBP1 Signaling Axis Mediates Skeletal Muscle Wasting during Cancer Cachexia

“…These proteins are packed in extracellular vesicles and delivered to skeletal muscle, where they bind to TLR4 to activate catabolic signaling pathways and production of inflammatory cytokines (8). A recent study has also shown that skeletal muscle wasting is partially rescued in whole-body TLR4-KO mice in response to growth of LLC tumors (9). However, how gene expression of other TLRs as well as MyD88 is regulated and their potential role and mechanisms of action in cancer-associated skeletal muscle wasting remained largely unknown.…”