ABSTRACT Background Cachexia, characterized by severe weight loss and muscle atrophy, frequently occurs in chronic conditions such as sepsis, cancer and chemotherapy, with limited effective treatments. Despite similar clinical manifestations, the underlying mechanisms across different disease contexts remain unclear. Identifying common pathways could lead to novel therapies. This study examines the role of Toll‐like receptor 4 (TLR4), which is upregulated in various cachexia models, and assesses the therapeutic potential of the TLR4‐inhibiting peptide OH‐CATH30 in mitigating muscle atrophy. Methods In vivo models using 8‐week‐old mice treated with lipopolysaccharide (LPS), 4T1 tumour cells and cisplatin were used to investigate common pathways in cachexia. In vitro models were established by treating C2C12 myotubes with TNF‐α, 4T1 culture supernatants and cisplatin. OH‐CATH30's effects on muscle atrophy were assessed by measuring myotube diameter, grip strength, muscle weight and muscle fibre cross‐sectional area (CSA) via H&E staining. RNA‐seq, qPCR, ELISA and Western blotting were performed to explore pathways in cachexia‐induced muscle atrophy and OH‐CATH30's action mechanism. Results Transcriptomic analysis showed significant enrichment of inflammation and protein degradation pathways in skeletal muscle in LPS‐induced sepsis, 4T1 tumour‐induced cancer cachexia and cisplatin‐induced cachexia models, with upregulated expression of TLR4 pathway genes such as Cd14 , Tlr4 and Irak4 ( p 0.05). Conclusions Our findings underscore the critical role of TLR4 signalling in cachexia‐associated muscle wasting across different disease contexts and demonstrate the efficacy of OH‐CATH30, a TLR4 inhibitor, in alleviating muscle atrophy in various cachexia models.
Wang et al. (Thu,) studied this question.