Why does a defect in choline kinase beta cause muscular dystrophy in mice?

Abstract

Muscular dystrophies (MD) are a group of more than 30 genetic diseases characterized by progressive weakness and degeneration of the skeletal muscles. There is no specific treatment to stop or reverse any form of MD due to limited knowledge. We recently uncovered a natural mutation (rmd) in the Chkb gene that resulted in a complete loss of choline kinase (CK) activity in skeletal muscle, and the mice developed severe and progressive hindlimb MD. It is the first demonstration of a defect in a phospholipid biosynthetic enzyme causing MD. Why does muscular dystrophy occur? We observed decreased phosphatidylcholine (PC)/phosphatidylethanolamine (PE) ratio both in hindlimb muscle and in mitochondria associated with sarcolemmal integrity and megamitochondria formation. Decreased PC level is due to three factors: down‐regulated CTP:phosphocholine cytidylyltransferase (CT) activity, the rate‐limiting enzyme for PC biosynthesis; increased PC turnover due to increased phospholipase activity, and a limited source of phosphocholine in Chkb−/– mice. In vivo experiments further demonstrated that the incorporation ability of 3H‐choline into PC was significantly decreased in affected muscle. Decreased regeneration ability of Chkb−/–mice may also contribute to muscular dystrophy. In affected muscle there was increased expression of myostatin and decreased proliferating cell nuclear antigen (PCNA).This research was supported by a grant from Alberta Heritage Foundation for Medical Research and Canadian Institutes of Health Research.