The canonical ER stress IRE1α/XBP1 pathway mediates skeletal muscle wasting during pancreatic cancer cachexia.

Cancer-driven cachexia is a deleterious syndrome which involves progressive loss of skeletal muscle mass with or without fat loss, fatigue, and weakness that cannot be reversed by nutritional intake. Recent studies have shown deregulation of endoplasmic reticulum (ER)-induced unfolded protein response (UPR) pathways in skeletal muscle in various catabolic conditions, including cancer growth. However, the role of individual arms of the UPR in the regulation of muscle mass remains poorly understood. Here, we demonstrate that the IRE1α/XBP1 arm of the UPR stimulates the activation of ubiquitin-proteasome system, autophagy, JAK-STAT3 signaling, and fatty acid metabolism in skeletal muscle of the KPC mouse model of pancreatic cancer cachexia. Furthermore, our results show that IRE1α/XBP1 pathway is a key contributor to cachexia as targeted ablation of XBP1 transcription factor in mouse skeletal muscle inhibits KPC tumor-induced muscle wasting. Transcriptionally active XBP1 protein binds to the promoter region of multiple genes, such as Map1lc3b, Fbxo32, and Il6, whose products are involved in skeletal muscle wasting. Treatment of KPC tumor-bearing mice with 4μ8C, a small molecule IRE1α inhibitor, reverses cachexia-induced molecular changes and improves skeletal muscle mass and strength. Altogether, our study highlights that the IRE1α/XBP1 signaling axis mediates pancreatic cancer-induced muscle wasting and inhibition of this pathway could be a potential approach to mitigate muscle wasting in pancreatic cancer patients.