Peptide OH-CATH30 Mitigates Cachexia-Induced Muscle Atrophy via Modulation of TLR4-Associated Inflammation

Area of Science:

• Biomedical Sciences
• Molecular Biology
• Pathology

Background:

• Cachexia, a severe condition marked by weight loss and muscle atrophy, complicates chronic diseases like sepsis and cancer, lacking effective treatments.
• The underlying molecular mechanisms of cachexia across diverse conditions are not fully understood, hindering therapeutic development.
• Toll-like receptor 4 (TLR4) is implicated in cachexia, presenting a potential therapeutic target.

Purpose of the Study:

• To investigate the role of Toll-like receptor 4 (TLR4) signaling in common cachexia pathways.
• To evaluate the therapeutic efficacy of the TLR4-inhibiting peptide OH-CATH30 in mitigating muscle atrophy in various cachexia models.

Main Methods:

• Established in vivo (LPS, 4T1 tumor, cisplatin) and in vitro (TNF-α, 4T1 supernatant, cisplatin) cachexia models.
• Assessed OH-CATH30's effects on muscle atrophy using myotube diameter, grip strength, muscle weight, and cross-sectional area (CSA).
• Employed transcriptomic analysis (RNA-seq), qPCR, ELISA, and Western blotting to elucidate molecular mechanisms.

Main Results:

• Transcriptomic analysis revealed enriched inflammation and protein degradation pathways in skeletal muscle across all cachexia models, with upregulated TLR4 pathway genes.
• OH-CATH30 treatment significantly improved muscle mass, strength, and CSA in vivo and increased myotube diameter and MyHC protein levels in vitro.
• OH-CATH30 downregulated key inflammatory and muscle-degrading genes (e.g., Il6, Mstn, Trim63, Fbxo32) and reduced serum IL-6 levels, confirming TLR4 inhibition's efficacy.

Conclusions:

• TLR4 signaling is a critical common pathway driving muscle wasting in diverse cachexia contexts.
• The TLR4 inhibitor OH-CATH30 demonstrates significant therapeutic potential in alleviating muscle atrophy associated with cachexia.