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

作者：Mahtab Tavasoli, Sarah Lahire, Stanislav Sokolenko, Robyn J. Novorolsky, Sarah Anne Reid, Abir Lefsay, Meredith O. C. Otley, Kitipong Uaesoontrachoon, Joyce Rowsell, Sadish Srinivassane, Molly Praest, Alexandra MacKinnon, Melissa Mammoliti, Ashley Maloney, Marina Moraca, J. Pedro Fernández-Murray, Meagan McKenna, Christopher J. Sinal, Kanneboyina Nagaraju, George S. Robertson, Eric P. Hoffman, Christopher R. McMaster · 发表于：Nature Communications · 年份：2022 · DOI：10.1038/s41467-022-29270-z · 被引用次数：29 · 研究领域：Adipose Tissue and Metabolism、Mitochondrial Function and Pathology、Metabolism and Genetic Disorders

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.