Hongmei Ren, Ph.D. (Advisor); Weiwen Long, Ph.D. (Committee Member); Michael Markey, Ph.D. (Committee Member)
Master of Science (MS)
Mutations in lipin1 are suggested to be a common cause of massive rhabdomyolysis episodes in children, however, the molecular mechanism involved in the regulation of myofiber death by lipin1 is not known. In this study, we utilized the skeletal muscle from cell-type-specific lipin1 knockout (Lipin1Myf5cKO) mice to define cell death pathways involved in lipin1 deficient muscles. We observed a significant increase in centrally nucleated fibers and embryonic myosin heavy chain (EMyHC)-positive regenerating fibers in Lipin1Myf5cKO mice compared to wild-type (WT) mice, indicating an increased cycle of degeneration and regeneration in lipin1 deficient muscles. Lipin1 deficient muscles had significantly elevated pro-apoptotic factors (Bax, Bak, and cleaved caspase 9) and necroptotic proteins such as RIPK1, RIPK3, and MLKL compared with WT mice. Moreover, loss of membrane integrity is considered as a hallmark of cell death and we found that Lipin1Myf5cKO mice had significantly higher membrane disruptions as evidenced by increased IgG staining and elevated uptake of Evans Blue Dye (EBD) in muscle fibers. EBD-positive fibers were strongly colocalized with apoptotic or necrotic myofibers, suggesting an association between compromised plasma membrane integrity and cell death pathways. We further show that the absence of lipin1 leads to a significant decrease in the absolute and specific muscle force (normalized to muscle mass). Our work indicates that apoptosis and necroptosis are associated with a loss of membrane integrity in muscle lacking lipin1 and myofiber death may induce an expected decrease in contractile force and a defect in muscle function.
Department or Program
Department of Biochemistry and Molecular Biology
Year Degree Awarded
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