Publication Date

2023

Document Type

Dissertation

Committee Members

Hongmei Ren, Ph.D. (Advisor); Andrew Voss, Ph.D. (Committee Member); Weiwen Long, Ph.D. (Committee Member); Nicholas Reo, Ph.D. (Committee Member); Mauricio Di Fulvio, Ph.D. (Committee Member)

Degree Name

Doctor of Philosophy (PhD)

Abstract

Duchenne muscular dystrophy (DMD) is a severe disease characterized by a progressive muscle fiber loss. DMD affects approximately 1 in 3500 male births worldwide. Patients die at early ages due to failure of respiratory and cardiac functions. DMD is caused by mutations in dystrophin gene. Loss of dystrophin leads to disruption of the membrane integrity and necroptosis in skeletal muscles of DMD patients contributing to muscle fiber loss. Currently, effective therapies for DMD have not been established. The goal of this project is to find mechanisms that may improve muscle function/structure despite dystrophin deficiency. Our data show that the expression lipin1 was significantly downregulated in the muscle of mouse model of DMD (mdx mice). Lipin1 is an enzyme that generates diacylglycerol (DAG) via phosphatidic acid phosphatase (PAP) activity and acts as a transcriptional co-activator for PPARs in the nucleus. Based on our recent work indicating that lipin1 stabilizes the integrity of the sarcolemma, we forced lipin1 expression in the gastrocnemius muscle of mdx mice by using an adeno-associated virus (AAV) vector to test the hypothesis that lipin1 could stabilize plasma membrane. We found that increasing lipin1 levels in the gastrocnemius muscle of mdx mice lessened muscle fiber degeneration, improved muscle mass, reduced muscle necroptosis, and increased force production. In addition, lipin1 rescued the deficiency of DAG and phosphatidylcholine species in the gastrocnemius muscle of mdx mice. By using lipin1 catalytic activity dead (PAP) mutant, we showed that lipin1 PAP activity is required to enhance membrane integrity and elevate specific force production in mdx mice. Our data collectively suggest that lipin1 plays a major role in inhibiting muscle degeneration by improving membrane integrity in mdx mice. Further research is required to investigate how lipin1 contributes to improving the integrity, and function of myofibers

Page Count

110

Department or Program

Biomedical Sciences

Year Degree Awarded

2023


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