Mechanism of action and therapeutic route for a muscular dystrophy caused by a genetic defect in lipid metabolism.

Autor: Tavasoli M; Department of Pharmacology, Dalhousie University, Halifax, NS, Canada., Lahire S; University of Reims Champagne-Ardenne, Reims, France., Sokolenko S; Department of Process Engineering & Applied Science, Dalhousie University, Halifax, NS, Canada., Novorolsky R; Department of Pharmacology, Dalhousie University, Halifax, NS, Canada., Reid SA; Department of Pharmacology, Dalhousie University, Halifax, NS, Canada., Lefsay A; Mass Spectrometry Core Facility, Dalhousie University, Halifax, NS, Canada., Otley MOC; Department of Pharmacology, Dalhousie University, Halifax, NS, Canada., Uaesoontrachoon K; Agada Biosciences Inc., Halifax, NS, Canada., Rowsell J; Agada Biosciences Inc., Halifax, NS, Canada., Srinivassane S; Agada Biosciences Inc., Halifax, NS, Canada., Praest M; Agada Biosciences Inc., Halifax, NS, Canada., MacKinnon A; Agada Biosciences Inc., Halifax, NS, Canada., Mammoliti MS; Agada Biosciences Inc., Halifax, NS, Canada., Maloney AA; Agada Biosciences Inc., Halifax, NS, Canada., Moraca M; Agada Biosciences Inc., Halifax, NS, Canada., Pedro Fernandez-Murray J; Department of Pharmacology, Dalhousie University, Halifax, NS, Canada., McKenna M; Agada Biosciences Inc., Halifax, NS, Canada., Sinal CJ; Department of Pharmacology, Dalhousie University, Halifax, NS, Canada., Nagaraju K; Agada Biosciences Inc., Halifax, NS, Canada.; School of Pharmacy and Pharmaceutical Sciences, Binghamton University, State University of New York (SUNY), Binghamton, NY, USA., Robertson GS; Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.; Department of Psychiatry, Dalhousie University, Halifax, NS, Canada., Hoffman EP; Agada Biosciences Inc., Halifax, NS, Canada.; School of Pharmacy and Pharmaceutical Sciences, Binghamton University, State University of New York (SUNY), Binghamton, NY, USA., McMaster CR; Department of Pharmacology, Dalhousie University, Halifax, NS, Canada. christopher.mcmaster@dal.ca.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Mar 23; Vol. 13 (1), pp. 1559. Date of Electronic Publication: 2022 Mar 23.
DOI: 10.1038/s41467-022-29270-z
Abstrakt: CHKB encodes one of two mammalian choline kinase enzymes that catalyze the first step in the synthesis of the membrane phospholipid phosphatidylcholine. In humans and mice, inactivation of the CHKB gene (Chkb in mice) causes a recessive rostral-to-caudal muscular dystrophy. Using Chkb knockout mice, we reveal that at no stage of the disease is phosphatidylcholine level significantly altered. We observe that in affected muscle a temporal change in lipid metabolism occurs with an initial inability to utilize fatty acids for energy via mitochondrial β-oxidation resulting in shunting of fatty acids into triacyglycerol as the disease progresses. There is a decrease in peroxisome proliferator-activated receptors and target gene expression specific to Chkb -/- affected muscle. Treatment of Chkb -/- myocytes with peroxisome proliferator-activated receptor agonists enables fatty acids to be used for β-oxidation and prevents triacyglyerol accumulation, while simultaneously increasing expression of the compensatory choline kinase alpha (Chka) isoform, preventing muscle cell injury.
(© 2022. The Author(s).)
Databáze: MEDLINE
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