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

• Published in: Nature communications Vol. 13; no. 1; p. 1559
• Main Authors: Tavasoli, Mahtab, Lahire, Sarah, Sokolenko, Stanislav, Novorolsky, Robyn, Reid, Sarah Anne, Lefsay, Abir, Otley, Meredith O. C., Uaesoontrachoon, Kitipong, Rowsell, Joyce, Srinivassane, Sadish, Praest, Molly, MacKinnon, Alexandra, Mammoliti, Melissa Stella, Maloney, Ashley Alyssa, Moraca, Marina, Pedro Fernandez-Murray, J., McKenna, Meagan, Sinal, Christopher J., Nagaraju, Kanneboyina, Robertson, George S., Hoffman, Eric P., McMaster, Christopher R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23-03-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 14; 14/19; 631/45/608; 64; 64/60; 692/308/2056; 692/698/1671; Agonists; Animal models; Animals; Cell injury; Choline; Choline kinase; Choline Kinase - genetics; Choline Kinase - metabolism; Dystrophy; Fatty Acids; Gene expression; Humanities and Social Sciences; Inactivation; Injury prevention; Kinases; Lecithin; Lipid metabolism; Lipid Metabolism - genetics; Lipids; Mammals - metabolism; Metabolism; Mice; Mitochondria; multidisciplinary; Muscles; Muscular Diseases; Muscular Dystrophies - genetics; Muscular Dystrophies - therapy; Muscular dystrophy; Mutation; Myocytes; Oxidation; Peroxisome proliferator-activated receptors; Phosphatidylcholine; Phosphatidylcholines - metabolism; Phospholipids; Receptors; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-29270-z

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.
Mutations in the
CHKB
gene cause muscular dystrophy. Here, the authors show that in mouse models of the disease changes in lipid metabolism are associated with decreased PPAR signaling, and show PPAR agonists can rescue expression of injury markers in myocytes in vitro.