title: Understanding the muscular dystrophy caused by deletion of choline kinase beta in mice.
abstract: Choline kinase in mice is encoded by two genes, Chka and Chkb. Disruption of murine Chka leads to embryonic lethality, whereas a spontaneously occurring genomic deletion in murine Chkb results in neonatal bone deformity and hindlimb muscular dystrophy. We have investigated the mechanism by which a lack of choline kinase beta, encoded by Chkb, causes hindlimb muscular dystrophy. The biosynthesis of phosphatidylcholine (PC) is impaired in the hindlimbs of Chkb -/- mice, with an accumulation of choline and decreased amount of phosphocholine. The activity of CTP: phosphocholine cytidylyltransferase is also decreased in the hindlimb muscle of mutant mice. Concomitantly, the activities of PC phospholipase C and phospholipase A2 are increased. The mitochondria in Chkb -/- mice are abnormally large and exhibit decreased inner membrane potential. Despite the muscular dystrophy in Chkb -/- mice, we observed increased expression of insulin like growth factor 1 and proliferating cell nuclear antigen. However, regeneration of hindlimb muscles of Chkb -/- mice was impaired when challenged with cardiotoxin. Injection of CDP-choline increased PC content of hindlimb muscle and decreased creatine kinase activity in plasma of Chkb -/- mice. We conclude that the hindlimb muscular dystrophy in Chkb -/- mice is due to attenuated PC biosynthesis and enhanced catabolism of PC.
authors.affiliation: Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
authors.forename: Gengshu
authors.initials: G
authors.lastname: Wu
authors.forename: Roger B
authors.initials: RB
authors.lastname: Sher
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Cox
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Vance
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002797:Choline Kinase / Q000097:blood / Q000172:deficiency* / Q000378:metabolism; D003402:Creatine Kinase / Q000097:blood; D003566:Cytidine Diphosphate Choline / Q000494:pharmacology; D017353:Gene Deletion; D006614:Hindlimb / Q000201:enzymology / Q000473:pathology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009132:Muscles / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D009136:Muscular Dystrophies / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D032446:Myoblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D055435:Myostatin / Q000378:metabolism; D010713:Phosphatidylcholines / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D018110:Receptors, Lipoprotein / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects; D013379:Substrate Specificity / Q000187:drug effects
chemical_list: D055435:Myostatin; D010713:Phosphatidylcholines; D018809:Proliferating Cell Nuclear Antigen; D018110:Receptors, Lipoprotein; C519530:insulin-like growth factor-1, mouse; D003566:Cytidine Diphosphate Choline; D007334:Insulin-Like Growth Factor I; D002797:Choline Kinase; D003402:Creatine Kinase