Date of Award

2017

Document Type

Open Access Dissertation

Department

Exercise Science

First Advisor

James A. Carson

Abstract

Cancer-related cachexia is a complex metabolic syndrome that involves the unintentional loss of skeletal muscle mass that cannot be reversed by standard nutritional intervention. Skeletal muscle mass depletion directly impacts patient survival and life quality, and therefore treatments that preserve muscle mass and function may have significant implications for cancer patient treatment and survival. Systemic and muscle inflammation has been implicated in the regulation of skeletal muscle homeostasis, and the cytokine interleukin-6 (IL-6) and muscle gp130 receptor signaling have established roles in cancer-induced muscle wasting. Resistance exercise is a nonpharmacological treatment that can improve physical function and metabolic health in many disease conditions, and has proven beneficial outcomes during cancer patient treatment and survival. Unfortunately, no studies to date have examined the effects of exercise in the cachectic cancer patient, and significant gaps remain in our understanding of the interaction between exercise and the systemic cachectic environment during cancer. Therefore, the purpose of this dissertation was to determine how cancer-induced inflammation affects wasting muscles ability to respond to eccentric contractions (ECC). We hypothesized that chronic muscle inflammatory signaling would attenuate the anabolic response to acute ECC. In experiment 1, we determined if muscle inflammatory signaling regulated the cachectic muscle’s acute anabolic response to ECC. We found that muscle inflammatory signaling regulated basal and ECC-induced protein synthesis. In experiment 2, we determined if systemic IL-6 and muscle gp130 signaling regulated basal and ECC- induced protein

synthesis and mTORC1 signaling. We found that systemic IL-6 signaling regulated basal and ECC-induced protein synthesis. In addition, muscle gp130 could regulate ECC-induced protein synthesis. In experiment 3, we determined if altering muscle inflammatory signaling by training improved basal and ECC-induced protein synthesis and mTORC1 signaling. We found that training could improve basal and ECC-induced protein synthesis. These findings provide initial evidence that cachectic muscle is responsive to acute responses and training adaptations induced by exercise. Additionally, we provide evidence for a potential interaction between muscle inflammation, protein synthesis, and oxidative metabolism, which can be influenced by exercise during cancer cachexia.

Available for download on Friday, July 17, 2020

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