Molecular pathways driving skeletal muscle wasting in cancer cachexia

Cancer cachexia is a debilitating syndrome characterized by the progressive loss of skeletal muscle mass with or without fat loss. Recent studies have implicated dysregulation of the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) pathways in skeletal muscle under various conditions, including cancer. However, the role of individual arms of the UPR in regulation of cancer-induced cachexia remains poorly understood. In this study, we demonstrate that the inositol-requiring protein 1 (IRE1)/ X-box protein 1 (XBP1) branch of the UPR promotes the activation of proteolytic systems ubiquitin-proteasome system and autophagy, stimulates JAK-STAT3 signaling, and augment fatty acid oxidation in the skeletal muscle of the KPC mouse model of pancreatic cancer cachexia. Moreover, we show that the IRE1/XBP1 pathway is a key contributor to muscle wasting. Skeletal muscle-specific deletion of the XBP1 transcription factor significantly attenuates tumor-induced muscle wasting. Mechanistically, transcriptionally active XBP1 binds to the promoter regions of various genes, which encode proteins known to drive muscle proteolysis. Pharmacological inhibition of IRE1 using a small molecule attenuates cachexia-associated molecular changes and improves muscle mass and strength in KPC tumor-bearing mice. Collectively, our findings suggest that targeting IRE1/XBP1 pathway may offer a therapeutic strategy to counteract muscle wasting during pancreatic cancer-induced cachexia.