Ciprofibrate or bezafibrate combined with choline reduces myocyte damage in the mouse model of megaconic CMD

Choline kinase beta (CHKB) catalyses the first step in the formation of phosphatidylcholine, a major component of eukaryotic cell membranes. Its deficiency leads to the occurrence of megaconium congenital muscular dystrophy.

The study of a KO mouse for the Chkb gene shows :

  • no significant alteration in phosphatidylcholine levels whatever the stage of the disease;
  • a change in the metabolism of lipids in the affected muscles, i.e. their diversion from energy supply by beta-oxidation to their storage as triglycerides as the disease progresses;
  • a decrease in the peroxisome proliferator-activated receptor (PPAR), a transcription factor that directs fatty acid metabolism towards storage, energy provision or phospholipid synthesis.

Treatment of Chkb-deficient myocytes with PPAR agonists (ciprofibrate, fenofibrate) allows fatty acids to be utilised by beta-oxidation, prevents triglyceride accumulation and leads to an increase in the expression of the alpha isoform of choline kinase.

The administration of choline combined with ciprofibrate or bezafibrate very significantly reduces muscle cell damage.

 

Mechanism of action and therapeutic route for a muscular dystrophy caused by a genetic defect in lipid metabolism. Tavasoli M, Lahire S, Sokolenko S, Novorolsky R, Reid SA, Lefsay A, Otley MOC, Uaesoontrachoon K, Rowsell J, Srinivassane S, Praest M, MacKinnon A, Mammoliti MS, Maloney AA, Moraca M, Pedro Fernandez-Murray J, McKenna M, Sinal CJ, Nagaraju K, Robertson GS, Hoffman EP, McMaster CR. Nat Commun. 2022 Mar 23;13(1):1559.