In partial fulfillment of the requirements for the degree of

Master of Science in Biology

in the

School of Biological Sciences

Utku Ergün

Will defend his thesis

“The Role of Cu, Zn Superoxide Dismutase (SOD1) in Muscle Stem Cell Function”

Wednesday, April 21st, 2021

2:00 PM

https://bluejeans.com/694041968

Meeting ID: 694 041 968

Thesis Advisor:

Dr. Young C. Jang

School of Biological Sciences

Georgia Institute of Technology

Committee Members:

Dr. Shuyi Nie

School of Biological Sciences

Georgia Institute of Technology

 Dr. Amit Reddi

School of Chemistry and Biochemistry

Georgia Institute of Technology

Abstract:

      Age-related loss of muscle mass and function often referred to as sarcopenia, dramatically affects the quality of life in the elderly population and predisposes them to an increased risk of morbidity, disability, and mortality. The etiology of sarcopenia is a multi-factorial process that involves both intrinsic and extrinsic factors. However, mounting evidence from both animal and human studies suggests that uncontrolled production of reactive oxygen species (ROS) and subsequent oxidative stress and oxidative modifications to key macromolecules such as DNA, RNA, proteins, and lipids are key underlying mechanisms that exacerbate sarcopenia. Cu, Zn superoxide dismutase (SOD1) is one of the essential antioxidant enzymes that are indispensable for redox homeostasis and prevention of oxidative damage.

      To maintain skeletal muscle homeostasis and repair damaged muscle, a population of dedicated muscle stem cells (MuSC), called satellite cells, activate, express myogenic transcription factors, migrate, proliferate, and fuse with existing myofibers or form de novo myofibers to complete regeneration. However, increased oxidative stress in muscle stem cells may harm the muscle regeneration process by impairing the interactions between existing myofibers with newly regenerated myoblasts and muscle stem cells. Previous studies showed that the whole body-deletion of Sod1 increases the age‐associated sarcopenia in mice; however, effects of deletion of Sod1 specifically in muscle stem cells and how it affects the muscle regeneration processes are still not known. We aimed to fill this gap by investigating the change in myogenesis and muscle regeneration of muscle stem cell-specific Sod1 knock-out (MuSC-Sod1KO) mice.

      Our in-vivo results revealed that the muscle regeneration and MuSC function are severely compromised in the MuSC-Sod1KO mice. Furthermore, our in-vitro studies show that the proliferation, differentiation, and fusion were impaired in the Sod1KO due to the increased number of apoptotic death in the myogenic progenies.

      In summary, we provide direct evidence that oxidative stress in muscle stem cells deteriorates and impairs muscle stem cell function by increasing the apoptotic response in muscle stem cells. We hope our study will open the path for better understanding the redox regulation in stem cells and aid in developing strategies to enhance stem cell-based therapies against muscle-wasting conditions, such as sarcopenia.