Publication Date

2023

Document Type

Dissertation

Committee Members

Hongmei Ren, Ph.D. (Advisor); Weiwen Long, Ph.D. (Committee Member); Shulin Ju, Ph.D. (Committee Member); Mark Rich, Ph.D. (Committee Member); Michael Leffak, Ph.D. (Committee Member)

Degree Name

Doctor of Philosophy (PhD)

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder that affects 1 in 3500 male births worldwide. It is characterized by mutations in the dystrophin gene that results in the loss of functional dystrophin. Dystrophin deficiency leads to instability of the sarcolemma alongside increased inflammation, necrosis and fibrosis resulting in membrane rupture and eventual muscle fiber death. There are currently no effective treatments for DMD. Here we show that Lipin1 expression is significantly downregulated at the mRNA and protein levels in gastrocnemius muscle of mdx mice, the DMD mouse model. Lipin1 has a dual function as a phosphatidic acid phosphatase (PAP) regulating phospholipids and triacylglycerol biosynthesis, but also as a transcriptional cofactor. In this study, we evaluated the role of lipin1 in dystrophic muscle by characterizing two mouse models, Dystrophin/Lipin1-DKO mice and MDX:Lipin1Tg/0 transgenic mice. Further depletion of Lipin1 in our Dystrophin/Lipin1-DKO model showed worsened disease phenotype through increased inflammation, fibrosis, and necroptosis. In contrast, restoration of Lipin1 in our MDX:Lipin1Tg/0 model showed a significant improvement in skeletal muscle health through reduced inflammation, fibrosis, and necroptosis through improved membrane integrity. Altogether, our study showed that Lipin1 could be a potential therapeutic target for DMD.

Page Count

131

Department or Program

Biomedical Sciences

Year Degree Awarded

2023


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