Publication Date

2010-05-21

Availability

Open access

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Molecular Cell and Developmental Biology (Medicine)

Date of Defense

April 2010

First Committee Member

Dr. Theodore J. Lampidis - Committee Chair

Second Committee Member

Dr. Leonidas G. Koniaris - Committee Member

Third Committee Member

Dr. Teresa A. Zimmers - Mentor

Fourth Committee Member

Dr. Enrique A. Mesri - Outside Committee Member

Abstract

Cachexia is a highly complex syndrome identified by metabolic, hormonal and cytokine-related abnormalities, but can be shortly characterized as accelerated skeletal muscle and adipose tissue loss in the context of a chronic inflammatory response. Cachexia is a debilitating complication of several diseases such as AIDS, sepsis, diabetes, renal failure, burn injury and cancer. Cachexia is responsible for 25-30% of cancer patient deaths. One of the most obvious outcomes of cancer cachexia is the redistribution of the total protein content, namely the depletion of skeletal muscle protein levels and increase in the acute phase response protein levels as a response to tissue injury. Although the plasticity of muscle mass and utility of skeletal muscle as a protein source are known facts, there have not been many studies concerning the mechanism of conversion of skeletal muscle proteins to other protein forms, for which the organism has greater need. IL-6 and activation of the acute phase response have been linked to cancer cachexia. However, IL-6 is generally not thought to signal directly on skeletal muscle and to date no studies have manipulated the STAT3 pathway for regulating skeletal muscle mass. Our data demonstrate direct action of IL-6 on activation of the STAT3 and acute phase response pathway at the skeletal muscle. In addition, our observations that STAT3 is broadly activated in cachexia and that STAT3 activation is sufficient and necesssary to induce muscle wasting are also novel. Thus, these studies define a new pathway leading to muscle wasting, which can be a potential target for reversing muscle wasting in cancer cachexia. Successful inhibition of skeletal muscle wasting and other metabolic derangements of cachexia will increase quality of life and survival of a significant fraction of cancer patients.

Keywords

Cachexia; Skeletal Muscle; APR; STAT3

Share

COinS