Differential expression of choline kinase isoforms in skeletal muscle explains the phenotypic variability in the rostrocaudal muscular dystrophy mouse |
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Authors: | Gengshu Wu Roger B Sher Gregory A Cox Dennis E Vance |
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Institution: | 1. Group on the Molecular and Cell Biology of Lipids and Department of Biochemistry, University of Alberta, Edmonton, Alberta Canada T6G 2S2;2. The Jackson Laboratory, Bar Harbor, Maine 04609, USA |
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Abstract: | Choline kinase in mammals is encoded by two genes, Chka and Chkb. Disruption of murine Chka leads to embryonic lethality, whereas a spontaneous genomic deletion in murine Chkb results in neonatal forelimb bone deformity and hindlimb muscular dystrophy. Surprisingly, muscular dystrophy isn't significantly developed in the forelimb. We have investigated the mechanism by which a lack of choline kinase β, encoded by Chkb, results in minimal muscular dystrophy in forelimbs. We have found that choline kinase β is the major isoform in hindlimb muscle and contributes more to choline kinase activity, while choline kinase α is predominant in forelimb muscle and contributes more to choline kinase activity. Although choline kinase activity is decreased in forelimb muscles of Chkb−/− mice, the activity of CTP:phosphocholine cytidylyltransferase is increased, resulting in enhanced phosphatidylcholine biosynthesis. The activity of phosphatidylcholine phospholipase C is up-regulated while the activity of phospholipase A2 in forelimb muscle is not altered. Regeneration of forelimb muscles of Chkb−/− mice is normal when challenged with cardiotoxin. In contrast to hindlimb muscle, mega-mitochondria are not significantly formed in forelimb muscle of Chkb−/− mice. We conclude that the relative lack of muscle degeneration in forelimbs of Chkb−/− mice is due to abundant choline kinase α and the stable homeostasis of phosphatidylcholine. |
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Keywords: | CK choline kinase CT CTP:phosphocholine cytidylyltransferase PC phosphatidylcholine PE phosphatidylethanolamine PLC phospholipase C PLA2 phospholipase A2 VLDL very low density lipoproteins |
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