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

Mahtab Tavasoli, Sarah Lahire, Stanislav Sokolenko, Robyn Novorolsky, Sarah Anne Reid, Abir Lefsay, Meredith O. C. Otley, Kitipong Uaesoontrachoon, Joyce Rowsell, Sadish Srinivassane, Molly Praest, Alexandra MacKinnon, Melissa Stella Mammoliti, Ashley Alyssa Maloney, Marina Moraca, J. Pedro Fernandez-Murray, Meagan McKenna, Christopher J. Sinal, Kanneboyina Nagaraju, George S. Robertson, Eric P. Hoffman and Christopher R. McMaster ()
Additional contact information
Mahtab Tavasoli: Dalhousie University
Sarah Lahire: University of Reims Champagne-Ardenne
Stanislav Sokolenko: Dalhousie University
Robyn Novorolsky: Dalhousie University
Sarah Anne Reid: Dalhousie University
Abir Lefsay: Mass Spectrometry Core Facility, Dalhousie University
Meredith O. C. Otley: Dalhousie University
Kitipong Uaesoontrachoon: Agada Biosciences Inc.
Joyce Rowsell: Agada Biosciences Inc.
Sadish Srinivassane: Agada Biosciences Inc.
Molly Praest: Agada Biosciences Inc.
Alexandra MacKinnon: Agada Biosciences Inc.
Melissa Stella Mammoliti: Agada Biosciences Inc.
Ashley Alyssa Maloney: Agada Biosciences Inc.
Marina Moraca: Agada Biosciences Inc.
J. Pedro Fernandez-Murray: Dalhousie University
Meagan McKenna: Agada Biosciences Inc.
Christopher J. Sinal: Dalhousie University
Kanneboyina Nagaraju: Agada Biosciences Inc.
George S. Robertson: Dalhousie University
Eric P. Hoffman: Agada Biosciences Inc.
Christopher R. McMaster: Dalhousie University

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-29270-z

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