Access Type
Open Access Embargo
Date of Award
January 2023
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Biological Sciences
First Advisor
Miriam L. Greenberg
Abstract
The mitochondrial phospholipid cardiolipin (CL) is critical for numerous essential biological processes, including mitochondrial dynamics and energy metabolism. Mutations in the CL remodeling enzyme TAFAZZIN cause Barth syndrome (BTHS), a life-threatening genetic disorder that results in severe physiological defects, including cardiomyopathy, skeletal myopathy, and neutropenia. Although fatigue is among the most debilitating self-reported symptoms of BTHS patients, the mechanistic links whereby CL deficiencies lead to skeletal myopathy and defective muscle formation are not known. In this thesis, using the TAFAZZIN-knockout (TAZ-KO) mouse myoblast C2C12 model, I aimed to elucidate the mechanism of muscle differentiation defect in these cells. We carried out a transcriptomic analysis of the TAZ-KO myoblasts and found that cardiac and muscle development pathways are highly decreased in these cells. Interestingly, the muscle transcription factor myoblast determination protein 1 (MyoD1) is significantly repressed in TAZ-KO cells and TAZ-KO mouse hearts. We also show that exogenous expression of MyoD1 rescued the myogenesis defects previously observed in TAZ-KO cells, suggesting a new regulatory role for CL in muscle development. Our data also show that MyoD1 repression is caused by up-regulation of the MyoD1 negative regulator, homeobox protein Mohawk (MKX), and decreased Wnt signaling. We also observed a decrease in oxygen consumption rate (OCR) in TAZ-KO cells before and after five days of differentiation induction. Together, these data suggest that decreased Wnt signaling and mitochondrial metabolism may be responsible for MyoD1 repression in the absence of TAFAZZIN. In summary, this thesis expands our understanding of the regulatory roles of CL in muscle development through the muscle transcription factor MyoD1 and Wnt signaling.
Recommended Citation
Vo, Linh, "Cardiolipin Metabolism Regulates Expression Of Muscle Transcription Factor Myod1 And Muscle Development" (2023). Wayne State University Dissertations. 3896.
https://digitalcommons.wayne.edu/oa_dissertations/3896