Date of Award

Spring 1-1-2011

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Greg Odorizzi

Second Advisor

Leslie A. Leinwand

Third Advisor

Mark Winey

Fourth Advisor

Russell Moore

Fifth Advisor

Joaquin Espinosa

Abstract

Approximately one-third of cancer deaths are caused by cachexia, a severe form of skeletal muscle and adipose tissue wasting that affects men more than women. The heart also undergoes atrophy in cancer patients but the extent, functional consequences, mechanisms and sex differences have not been elucidated. In a mouse colon-adenocarcinoma model, cancer causes a loss of cardiac mass due to a decrease in cardiac myocyte size that is associated with reduced levels of all sarcomeric proteins. I provide evidence that published reports showing a selective decrease in myosin heavy chain (MyHC) during cancer cachexia are likely an artifact resulting from muscle lysis methods which do not solubilize myosin out of myofibrils. I show that MyHC decreases in parallel with other myofibrillar proteins in cachectic cardiac and skeletal muscle. Unlike skeletal muscle, atrophic hearts do not upregulate the ubiquitin-proteasome system (UPS) or its activity but increase autophagy. Thus, cancer causes cardiac atrophy by a mechanism distinct from that in skeletal muscle. This murine model recapitulates the sexual dimorphism associated with cachexia in human patients. I demonstrate that male tumor-bearing mice have a more severe phenotype than females, including greater cardiac mass loss and mortality. In females, estrogen protects against cancer-induced cardiac atrophy and body weight loss by signaling through its receptor. I also examined the effect of dietary phytoestrogens on cancer cachexia. A soy diet worsens cachexia in both sexes, while a casein-based diet decreases the extent of skeletal and cardiac muscle mass loss in males yet increases cancer mortality in both sexes. Finally, I established an in vitro model of cardiac atrophy. Interferon-γ (IFN), a pro-inflammatory cytokine commonly increased in the serum of cancer patients and in the myocardium of patients suffering from Chagas' disease, causes cardiac myocyte atrophy, but unlike the mechanism in vivo, IFN activates the UPS and causes the specific degradation of MyHC in a proteasome-dependent manner. Together, these studies provide mechanistic insight into cardiac atrophy due to cancer and inflammatory cytokines, and demonstrate that cardiac and skeletal muscle cachexia are modulated by both sex and diet.

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