Hongmei Ren (Advisor), Nicholas Reo (Committee Member), Kwang-Jin Cho (Committee Member)
Master of Science (MS)
Our previous characterization of global lipin1-deficient (fld) mice demonstrated that lipin1 played a novel role in skeletal muscle (SM) regeneration. The clinical relevance of lipin1 has been observed in patients with lipin1 null mutations where they exhibited severe rhabdomyolysis with aggregated and dysfunctional mitochondria. Lipin1 is a key gene that plays an important role in lipid biosynthesis and metabolism. It has dual functions as it contains a phosphatase activity that converts phosphatidic acid (PA) to diacylglycerol (DAG), the penultimate step in triglycerides (TAG) biosynthesis as well as transcriptional co-activator function. In the cytosol and ER, lipin1 carries out its lipid and phospholipid biosynthesis whereas in the nucleus it co-regulates the transcriptional co-activation of genes involved in adipogenesis and fatty acid oxidation. In this study, using cell-type specific Myf5-cre;Lipin1fl/fl conditional knockout mice (Lipin1Myf5cKO) we showed that lipin1 is a major determinant of SM development, termed myogenesis. Lipin1 deficiency induced reduced muscle mass. Results from lipin1-deficient myoblasts suggested that lipin1 regulated myoblast differentiation through the protein kinase C (PKC)/histone deacetylase 5 (HDAC5)/Myocyte-specific enhancer factor 2C (MEF2c):MyoD-mediated pathway. Lipin1 deficiency leads to the suppression of PKC isoform activities, as well as the inhibition of their downstream target, class II deacetylase HDAC5 nuclear export, and consequently, the inhibition of MEF2c and MyoD expression in the SM of Lipin1Myf5cKO mice. Inhibition of MyoD induced Pax7 accumulation, which may lead to an increased propensity for satellite cell self-renewal rather than progression through myogenic differentiation. Our findings provide insights into the signaling circuitry that regulates SM development, and have important implications for developing therapies aimed at treating rhabdomyolysis and muscular dystrophies.
Department or Program
Department of Biochemistry and Molecular Biology
Year Degree Awarded
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