Date of Award

6-2015

Degree Name

Doctor of Philosophy

Department

Biological Sciences

First Advisor

Dr. John M. Spitsbergen

Second Advisor

Dr. Christine Byrd-Jacobs

Third Advisor

Dr. Cindy Linn

Fourth Advisor

Dr. Damon A. Miller

Abstract

Glia cell line-derived neurotrophic factor (GDNF) is a survival factor for subpopulations of neurons, including somatic and autonomic motor neurons. These neurons depend, in part, on GDNF that is synthesized and secreted by their target tissues. It has been shown that a number of tissues in the periphery express GDNF and these target tissues differ in their composition, function, and in the case of different muscle cell types, their contractile characteristics. Whether the processes regulating GDNF production in these different tissues is similar or different is poorly understood. The broad goal of this study is to examine factors that normally regulate GDNF expression in skeletal and cardiac muscles, with an emphasis on comparing the similarities and differences in these voluntary and involuntary muscles in relation to GDNF production. Previous studies with nervemuscle co-cultures in our laboratory have shown that GDNF protein levels are reduced when skeletal muscle is in contact with cholinergic nerves. Thus, the hypothesis being tested is that cellular activation by neural cells, via neurotransmitter effects, regulates GDNF expression in voluntary and involuntary muscles. Some cultures were electrically stimulated (30min to 48h) to determine whether electrical activity is an important regulator of neurotrophic factor production. Samples of culture medium and cells were collected between 0h and 48h. The results show that acetylcholine inhibits GDNF secretion in both cell types, while electrical stimulation has opposing effects on GDNF production, where GDNF levels increase with long-term electrical stimulation in skeletal muscle and decrease with long-term electrical stimulation in cardiac muscle. When cardiac muscle cells were tested alone, norepinephrine was found to stimulate production of GDNF but inhibit production of nerve growth factor (NGF). Electrical stimulation had a similar effect on NGF and GDNF production in cardiac muscle cells. This work suggests that GDNF expression may be regulated differently in cardiac and skeletal muscle. Understanding the regulation of GDNF production in these tissues will provide a better understanding of how these processes may be modulated therapeutically.

Access Setting

Dissertation-Open Access

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