Off-campus WSU users: To download campus access dissertations, please use the following link to log into our proxy server with your WSU access ID and password, then click the "Off-campus Download" button below.
Non-WSU users: Please talk to your librarian about requesting this dissertation through interlibrary loan.
Access Type
WSU Access
Date of Award
January 2022
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Physiology
First Advisor
Robert Lasley
Second Advisor
Sokol V. Todi
Abstract
Deciphering mechanisms by which exercise promotes health is of wide-ranging biomedical importance. The prevalence of cancers and cardiovascular, metabolic, and neurodegenerative diseases has increased dramatically. The negative impact of these ailments and their complications take a huge toll on the overall health of the population and the economy. While regular exercise remains the most powerful intervention known, we understand very little about the underlying molecular mechanisms. This knowledge gap has limited development of effective strategies to prevent and treat these diseases. We developed a protocol for inducing endurance training in Drosophila. The system relies on a machine that induces a behavioral instinct to respond to a sudden drop by running upward (negative geotaxis). This training machine, known as the Power Tower, can induce continuous running in several hundred vials of flies simultaneously. Flies continue to respond for as long as the machine is activated. We have defined a gradual, ramped endurance program that induces several responses that are similar to the physiological changes that occur in exercised vertebrates. These changes include increased mitochondrial activity, increased time to fatigue, increased running speed, increased cardiac stress resistance, improved oxidative metabolism and increased cardiac contractile strength. We have identified the PGC1 homolog spargel, the stress-response protein Sestrin, and the invertebrate orthologue of norepinephrine, octopamine, as requirements for maximal exercise benefits, supporting a conserved adaptation mechanism. We use this model to quantitatively evaluate training outcomes during both normal aging and age-related disease. Furthermore, we have leveraged our exercise model and the discovery of these conserved factors to investigate the potential impact of exercise on loss of mobility and early mortality in Drosophila melanogaster models of three polyQ disorders, SCA2, SCA3 and SCA6. Excitingly, we find that daily exercise differentially affects these SCAs, increasing motility and reducing early mortality in SCA2 model flies, and conferring modest improvement in SCA6. In addition, we find that exercise reduces disease protein in SCA2 model flies, and that these benefits can be replicated with Sestrin overexpression, even in flies that do not undergo training. This work provides the foundation for further investigations that will explore the protective role of exercise during physiological aging and across the spectrum of polyQ diseases, opening the door for the development of targeted therapeutics.
Recommended Citation
Sujkowski, Alyson Louise, "Conserved Exercise Pathways In Drosophila Melanogaster" (2022). Wayne State University Dissertations. 3608.
https://digitalcommons.wayne.edu/oa_dissertations/3608