Date on Master's Thesis/Doctoral Dissertation
Anatomical Sciences and Neurobiology
Anatomical Sciences and Neurobiology, PhD
Moore, J. Patrick
skeletal muscle; cancer cachexia; atrophy; ER stress; XBP1
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 unfolded 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 4-phenylbutyrate (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 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. Finally, the role of the XBP1 in skeletal muscle growth and regeneration was also investigated. Results showed XBP1 mediates overload-induced myofiber hypertrophy and skeletal muscle regeneration potentially through augmenting the proliferation of satellite cells in a non-cell-autonomous manner. Altogether, this dissertation provides initial evidence that while basal levels of ER stress/UPR is essential for the maintenance of skeletal muscle mass and strength, supra-physiological activation of the UPR, especially the IRE1/XBP1 arm, causes skeletal muscle wasting.
Bohnert, Kyle R., "Unfolded protein response pathways in skeletal muscle homeostasis." (2018). Electronic Theses and Dissertations. Paper 3033.
Retrieved from https://ir.library.louisville.edu/etd/3033