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Understanding the muscular dystrophy caused by deletion of choline kinase beta in mice
Gengshu Wu1, Roger B Sher, Gregory A Cox
1Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
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.
Insights
Choline kinase beta deficiency in mice causes hindlimb muscular dystrophy by impairing phosphatidylcholine biosynthesis and enhancing its breakdown. This leads to mitochondrial dysfunction and impaired muscle regeneration.
Area of Science:
- Biochemistry
- Genetics
- Cell Biology
Background:
- Choline kinase beta (Chkb) deficiency in mice results in neonatal bone deformity and hindlimb muscular dystrophy.
- Understanding the molecular mechanisms underlying Chkb-deficient muscular dystrophy is crucial for potential therapeutic interventions.
Purpose of the Study:
- To elucidate the mechanism by which the absence of choline kinase beta leads to hindlimb muscular dystrophy.
- To investigate the biochemical and cellular consequences of Chkb deficiency in mouse hindlimb muscle.
Main Methods:
- Analysis of phosphatidylcholine (PC) biosynthesis and catabolism pathways in Chkb -/- mice.
- Assessment of enzyme activities, including CTP: phosphocholine cytidylyltransferase, PC phospholipase C, and phospholipase A2.
- Mitochondrial function analysis (inner membrane potential).
- Evaluation of muscle regeneration capacity following cardiotoxin injury.
Main Results:
- Impaired PC biosynthesis and accumulation of choline in Chkb -/- hindlimb muscle.
- Decreased CTP: phosphocholine cytidylyltransferase activity and increased PC phospholipase C and A2 activities.
- Abnormal mitochondrial morphology and reduced inner membrane potential in Chkb -/- mice.
- Impaired muscle regeneration despite increased IGF-1 and PCNA expression.
- CDP-choline administration partially restored PC levels and reduced plasma creatine kinase.
Conclusions:
- Hindlimb muscular dystrophy in Chkb -/- mice is caused by attenuated PC biosynthesis and enhanced PC catabolism.
- Mitochondrial dysfunction and impaired muscle regeneration are key pathological features.
- Targeting PC metabolism may offer a therapeutic strategy for Chkb-related muscular dystrophy.
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