Date of Award

1-1-2011

Document Type

Campus Access Dissertation

Department

Exercise Science

First Advisor

James A Carson

Abstract

Cancer cachexia is a complex wasting condition associated with the loss of skeletal muscle and fat mass. Muscle wasting exhibits an imbalance in the rate at which proteins are synthesized and degraded, referred to as protein turnover. Our laboratory has shown the ApcMin/+ mouse, a model of colorectal cancer is an excellent model to study the progression of cachexia due to the gradual decline in body weight and dependency on circulating IL-6 levels, as seen in human cachexia. The primary purpose of this study was to determine if muscle protein turnover is differentially regulated during the progression of cachexia in ApcMin/+mice. Specific aim1 examined muscle protein synthesis regulation during the progression of cachexia. During the initial stages of cachexia muscle protein synthesis and insulin-like growth factor-1 (IGF-1) signaling were suppressed. Late stage cachexia showed a further reduction in protein synthesis associated with a further reduction in IGF-1 and possible inhibition related to 5`-adenosine monophosphate-activated protein kinase (AMPK) activation. Specific aim 2 examined the regulation of protein degradation during the progression of cancer cachexia. Proteasomal regulated protein degradation was induced during initial stages of cachexia. Degradation increased further during late stage cachexia through the activation of autophagy proteolytic pathways. The third specific aim was to determine if the regulation of muscle oxidative metabolism was altered during the progression of cachexia. The loss in muscle mitochondrial content was reduced only during late stage cachexia. However, the regulation of mitochondrial biogenesis and dynamics were suppressed with initial cachexia. In summary, mechanisms regulating muscle protein turnover demonstrate a sequential activation related to the extent of body and muscle mass loss throughout the progression of cachexia. This concept is critical for targeting pharmacological therapies to treat patients with varying extent of weight loss.

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