Skeletal muscle mass, contractile properties, and metabolic function are regulated through the coordinated activation of multiple intracellular signaling pathways and genetic reprogramming. The endoplasmic reticulum (ER) plays a pivotal role in protein folding and calcium homeostasis in many cell types, including skeletal muscle. Disruption of calcium levels or accumulation of misfolded proteins in the ER lumen leads to stress, which results in the activation of a signaling network called the

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... folded protein response (UPR). Further, recent studies have suggested that in certain conditions, UPR pathways can be activated independent of ER stress. However, the role of ER stress and the UPR in the regulation of skeletal muscle mass and function had not been previously investigated. This dissertation demonstrates that the markers of ER stress are increased in skeletal muscle of mouse models of cancer cachexia. Chronic administration of 4phenylbutyrate (4-PBA), a molecular chaperon and an inhibitor of ER stress, leads to the loss of skeletal muscle mass and function in naïve conditions and in Lewis lung carcinoma (LLC) tumor-bearing mice. 4-PBA also causes atrophy in cultured primary myotubes. Further, our results demonstrate that the targeted deletion of X-box binding vi protein (XBP1), a downstream target of the inositol-requiring enzyme 1α (IRE1α) arm of the UPR, attenuates the loss of skeletal muscle mass in LLC tumor-bearing mice. Overexpression of a spliced form of XBP1 causes atrophy and induces the gene expression of several proinflammatory cytokines and the components of ubiquitin proteasome system and autophagy in cultured myotubes. Our results also demonstrate that toll-like receptors-mediated signaling is responsible, at least in part, for the activation of the UPR in skeletal muscle of LLC tumor-bearing mice.