Dennis K. Fix

Date of Award

Summer 2019

Document Type

Open Access Dissertation


Exercise Science

First Advisor

Mark A. Sarzynski


Cancer-induced cachexia is a debilitating disease that diminishes quality of life due to severe loss of skeletal muscle mass and function. Skeletal muscle proteostasis fluctuates diurnally depending on different fasting and feeding durations as well as in response to activity and exercise stimuli. Nutrient availability is key in the net loss and gain of skeletal muscle protein. The adenosine monophosphate protein kinase (AMPK) is a nutrient sensitive kinase that has long been established as a critical regulator of both protein synthesis and protein degradation. AMPK is capable of being activated by many different stimuli as well as diseases such as cancer cachexia. During severe cancer cachexia, skeletal muscle AMPK is dysregulated which could have dire consequences regarding muscle proteostasis. When activated, AMPK will phosphorylate tuberous sclerosis protein 2 (TSC2) and Raptor which inhibit mTORC1 activity. In addition to suppressing protein synthesis, AMPK controls degradation through the activation of its direct downstream targets ULK-1 and FOXO3a. While the chronic activation of AMPK and its potential role in anabolic suppression has been examined in detail, the role of this signaling axis in the regulation of protein turnover (synthesis and degradation through UPS and autophagy) is poorly understood in the skeletal muscle of cachectic mice. Moreover, given the sensitivity of this pathway to nutrient availability, further investigation is warranted to elucidate if the physiological fasting and feeding regulation of AMPK signaling is disrupted in the cancer environment. The purpose of this study was to determine if cachexia associated aberrant AMPK signaling is responsive to fasting, feeding, and increased wheel running activity to regulate skeletal muscle proteostasis. We hypothesized that cancer cachexia induces the disruption mitochondrial quality control which disrupts the regulation of AMPK by fasting and feeding leading to muscle mass loss. We also hypothesized that increased physical activity will improve mitochondrial quality control and thus improve the regulation of AMPK to fasting and feeding thus improving protein turnover and attenuating wasting. Our results suggest that skeletal muscle AMPK is necessary for the regulation of protein turnover during cancer cachexia. Furthermore, cachectic mice exhibit an accelerated AMPK signaling response to fasting, which may serve to exacerbate muscle wasting. We also report that cachectic Min mice exhibit an increased sensitivity to nutrients or feeding following a short term fast, suggesting that fasting increases skeletal muscle sensitivity to feeding. Finally, we demonstrate that increased physical activity via wheel running is capable of attenuating or improving the cachectic skeletal muscle AMPK response to fasting.