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
Copyright
Copyright 2023, some rights reserved. My ETD may be copied and distributed only for non-commercial purposes and may not be modified. All use must give me credit as the original author.
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.