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

Area of Science:

• Molecular Biology
• Cancer Biology
• Physiology

Background:

• Skeletal muscle wasting (cancer cachexia) significantly impacts cancer patient morbidity and mortality.
• Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) pathways are implicated in muscle loss during catabolic conditions.
• The specific signaling mechanisms and roles of UPR arms in regulating muscle mass are not fully understood.

Purpose of the Study:

• To investigate the role of Toll-like receptors (TLRs) and MyD88 in cancer-induced skeletal muscle wasting.
• To elucidate the involvement of the UPR, particularly the IRE1α-XBP1 pathway, in muscle atrophy during cancer cachexia.

Main Methods:

• Utilized a Lewis lung carcinoma (LLC) mouse model of cancer cachexia.
• Examined gene expression of TLRs and MyD88 in skeletal muscle.
• Employed targeted gene ablation (MyD88) and muscle-specific gene deletion (XBP1) in mice.
• Investigated the effects of XBP1 manipulation in cultured myotubes.

Main Results:

• Increased gene expression of TLRs and MyD88 was observed in skeletal muscle of LLC tumor-bearing mice.
• Ablation of MyD88 prevented muscle mass and strength loss and attenuated UPR activation in LLC mice.
• Muscle-specific deletion of X-box binding protein 1 (XBP1) ameliorated muscle wasting.
• Overexpression of active XBP1 induced myotube atrophy, while XBP1 knockdown inhibited it.

Conclusions:

• Toll-like receptor/MyD88 signaling mediates the activation of X-box binding protein 1 (XBP1) in skeletal muscle.
• This TLR/MyD88-XBP1 axis is a key driver of skeletal muscle wasting in cancer cachexia.