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1.
Nat Commun ; 13(1): 1559, 2022 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-35322809

RESUMO

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 ß-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 ß-oxidation and prevents triacyglyerol accumulation, while simultaneously increasing expression of the compensatory choline kinase alpha (Chka) isoform, preventing muscle cell injury.


Assuntos
Doenças Musculares , Distrofias Musculares , Animais , Colina Quinase/genética , Colina Quinase/metabolismo , Ácidos Graxos , Metabolismo dos Lipídeos/genética , Mamíferos/metabolismo , Camundongos , Distrofias Musculares/genética , Distrofias Musculares/terapia , Fosfatidilcolinas/metabolismo
2.
J Biol Chem ; 298(3): 101716, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35151687

RESUMO

The CHKB gene encodes choline kinase ß, which catalyzes the first step in the biosynthetic pathway for the major phospholipid phosphatidylcholine. Homozygous loss-of-function variants in human CHKB are associated with a congenital muscular dystrophy. Dilated cardiomyopathy is present in some CHKB patients and can cause heart failure and death. Mechanisms underlying a cardiac phenotype due to decreased CHKB levels are not well characterized. We determined that there is cardiac hypertrophy in Chkb-/- mice along with a decrease in left ventricle size, internal diameter, and stroke volume compared with wildtype and Chkb+/- mice. Unlike wildtype mice, 60% of the Chkb+/- and all Chkb-/- mice tested displayed arrhythmic events when challenged with isoproterenol. Lipidomic analysis revealed that the major change in lipid level in Chkb+/- and Chkb-/- hearts was an increase in the arrhythmogenic lipid acylcarnitine. An increase in acylcarnitine level is also associated with a defect in the ability of mitochondria to use fatty acids for energy and we observed that mitochondria from Chkb-/- hearts had abnormal cristae and inefficient electron transport chain activity. Atrial natriuretic peptide (ANP) is a hormone produced by the heart that protects against the development of heart failure including ventricular conduction defects. We determined that there was a decrease in expression of ANP, its receptor NPRA, as well as ventricular conduction system markers in Chkb+/- and Chkb-/- mice.


Assuntos
Arritmias Cardíacas , Colina Quinase , Insuficiência Cardíaca , Animais , Arritmias Cardíacas/enzimologia , Arritmias Cardíacas/genética , Fator Natriurético Atrial/genética , Colina Quinase/deficiência , Colina Quinase/genética , Colina Quinase/metabolismo , Modelos Animais de Doenças , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/genética , Humanos , Camundongos , Fosfatidilcolinas/metabolismo
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