Understanding the muscular dystrophy caused by deletion of choline kinase beta in mice.
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.
Wu
Gengshu
G
Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
Sher
Roger B
RB
Cox
Gregory A
GA
Vance
Dennis E
DE
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
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