Date of Award


Document Type

Open Access Dissertation


Exercise Science

First Advisor

James A Carson


Cachexia affects nearly 70% of all cancer patients depending on the cancer, and decreases cancer survival. Cachexia is associated with muscle mass loss that is accompanied by a loss in muscle oxidative capacity, a decrease in protein synthesis and an increase in protein degradation. While progress has been made in understanding some of the mechanisms underlying the cachectic condition, there are currently no approved pharmaceutical interventions to slow or stop cachexia progression. The purpose this study was to determine the role of skeletal muscle gp130 and STAT3 signaling in the regulation of cachexia induced muscle atrophy and mitochondrial loss. Specific aim 1 examined the regulation of cachexia-induced mitochondrial loss by IL-6 trans signaling, systemic STAT3 signaling and muscle specific gp130 signaling. Inhibition of systemic inflammatory signaling attenuated muscle and body weight loss; while, muscle gp130 inhibition did not. Inhibition of inflammatory signaling at all levels attenuated skeletal muscle mitochondrial loss and while systemic STAT3 and muscle gp130 inhibition relieved cachexia-suppression of mitochondrial fusion, only inhibition of trans IL-6 signaling blocked cachexia-induction of mitochondrial fission protein. Specific aim 2 examined the regulation of muscle protein turnover by skeletal muscle gp130/STAT3 during cancer cachexia. Inhibition of muscle gp130 attenuated muscle loss during LLC-induced cachexia. This was associated with suppression of protein degradation pathways without relieving the inhibition of muscle protein synthesis. The third specific aim was to determine if acute contraction could activate mitochondrial biogenesis in severely cachectic muscle. Contraction alone was unable to up regulate muscle mTOR signaling and mitochondrial proteins in cachectic muscle; however, STAT/NFκB inhibition relieved cachexia-suppression of contraction-induced mTOR signaling and up-regulated markers of mitochondrial biogenesis. In summary, inflammatory signaling through STAT3 and muscle gp130 regulate the suppression mitochondrial content and the induction of muscle protein degradation; however, it does not mediate the cachexia suppression of muscle protein synthesis. These findings provide insight of potential targets for pharmacological therapies for the treatment of cancer cachexia. Additionally, combination therapies involving inflammation inhibition with exercise may be most beneficial for the treatment of cancer cachexia.