A mouse model of inherited choline kinase β-deficiency presents with specific cardiac abnormalities and a predisposition to arrhythmia

Mahtab Tavasoli,Tiam Feridooni,Hirad Feridooni,Stanislav Sokolenko,Abhishek Mishra,Abir Lefsay,Sadish Srinivassane,Sarah Anne Reid,Joyce Rowsell,Molly Praest,Alexandra Mackinnon,Melissa Mammoliti,Ashley Alyssa Maloney,Marina Moraca,Kitipong Uaesoontrachoon,Kanneboyina Nagaraju,Eric P Hoffman,Kishore B.S Pasumarthi,Christopher R Mcmaster

doi:10.1016/j.jbc.2022.101716

Abstract

The CHKB gene encodes choline kinase β, 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.

Highlights

Human cell membranes separate and protect cells from their external environment, transmit cellular signals, establish an electrochemical gradient via the transport of ions, and generate action potential in neurons and muscle cells [1]
We investigated the protein expression pattern of these two choline kinase isoforms in cardiac muscle from Chkb+/+, Chkb+/- and Chkb-/- mice
We have previously shown that Atrial natriuretic peptide (ANP) increases the expression of ventricular conduction system (VCS) markers in embryonic ventricular cells and NPRA deficiency leads to defects in Purkinje fiber arborization [27], we determined if the expression of the VCS markers hyperpolarization-activated cyclic nucleotide-gated channel-4 (HCN4) and connexin 40 (Cx40) are affected in hearts from Chkb deficient mice

Summary

Introduction

Human cell membranes separate and protect cells from their external environment, transmit cellular signals, establish an electrochemical gradient via the transport of ions, and generate action potential in neurons and muscle cells [1]. In humans and mice autosomal recessive loss of function mutations in CHKB (Chkb in mouse) cause congenital muscular dystrophy with megaconial myopathy (OMIM: 602541) [4,5]. Variable cardiac phenotypes including dilated cardiomyopathy, decreased left ventricular systolic function, and congenital heart defects are reported in at least one third of all known cases and remain a major reason of early death in affected individuals [5,6,7,8,9]. Chkb+/- and Chkb-/- mice displayed reduced expression of atrial natriuretic peptide (ANP) and its receptor (NPRA), along with specific defects in cellular signaling pathways known to enable heart function. Journal Pre-proof mice provide mechanistic and observational insights into how a defect in PC synthesis can result in cardiac defects and may help explain similar phenotypes observed in CHKB deficient patients

Results

Discussion

Experimental Procedures