Publication Date
2022
Document Type
Thesis
Committee Members
Hongmei Ren, Ph.D. (Advisor); Weiwen Long, Ph.D. (Committee Member); Michael Leffak, Ph.D. (Committee Member)
Degree Name
Master of Science (MS)
Abstract
Duchenne Muscular Dystrophy (DMD) is an X-linked recessive disorder that is characterized by severe and progressive muscle wasting (Venugopal & Pavlakis, 2021). This disease is caused by a mutation in the largest known human gene which encodes the protein, dystrophin (Gao & McNally, 2015). Dystrophin connects the inner cytoskeleton to the extracellular matrix and is critical for maintaining the structural stability of muscle cells during contraction (Venugopal & Pavlakis, 2021). Mutations to the dystrophin gene result in myocyte membrane instability, contributing to the structural deterioration of the muscle tissue (Venugopal & Pavlakis, 2021). Progressive muscle degeneration and the replacement of muscle fibers with fibrotic tissue negatively impacts muscle contractility and is particularly detrimental to health when essential muscles such as the diaphragm are affected (Mann et al., 2011). Respiratory failure is a hallmark of DMD and is one of the leading causes of mortality associated with this disease (Venugopal & Pavlakis, 2021). Currently there is no cure for Duchenne Muscular Dystrophy, and gene therapy approaches are limited by the sheer size of the dystrophin gene which spans across 2,200 kb of DNA (Gao & McNally, 2015). Previous data generated from the laboratory has shown that the mdx mouse (used to model DMD) displays reduced expression of lipin1 (Unpublished data). Additionally, other works have shown that skeletal muscle specific lipin1 knockout mice present muscle membrane instability (Sattiraju et al., 2020). Collectively, these findings suggest the potential for lipin1 to serve as an alternative therapeutic target in the dystrophic diaphragm. Within the membrane of the endoplasmic reticulum, lipin1 functions as a phosphatidic acid phosphatase (PAP), which catalyzes the conversion of phosphatidic acid (PA) to diacylglycerol (DAG), a reaction important for membrane phospholipid and triacylglycerol synthesis (Chen et al., 2014). Current data suggests further knockdown of lipin1 in the dystrophic diaphragm leads to increased necroptosis and fibrosis, as well as reduced muscle regeneration. Restoration of lipin1 expression in the dystrophic diaphragm results in reduced inflammation, fibrosis, and degeneration/regeneration cycling of muscle fibers. Additionally, respiratory functionality assays have shown decreased respiratory function when lipin1 is further knocked down but improved respiratory function when lipin1 expression is restored in the dystrophic diaphragm. Continued investigation is required to better understand the mechanisms behind these findings, and to determine the role of lipin1 in maintaining muscle membrane stability.
Page Count
99
Department or Program
Department of Biochemistry and Molecular Biology
Year Degree Awarded
2022
Copyright
Copyright 2022, all rights reserved. My ETD will be available under the "Fair Use" terms of copyright law.
ORCID ID
0000-0001-5035-0322
