Altered Myocardial Lipid Regulation in Junctophilin-2-Associated Familial Cardiomyopathies

Authors

Satadru K Lahiri
Feng Jin
Yue Zhou
Ann P Quick
Carlos F Kramm
Meng C Wang
Xander Ht Wehrens

Publication Date

5-1-2024

Journal

Life Science Alliance

DOI

10.26508/lsa.202302330

PMID

38438248

PMCID

PMC10912815

PubMedCentral® Posted Date

3-4-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Humans, Mice, Cardiomyopathies, Cardiomyopathy, Dilated, Ceramides, Heart Diseases, Membrane Proteins, Myocardium

Abstract

Myocardial lipid metabolism is critical to normal heart function, whereas altered lipid regulation has been linked to cardiac diseases including cardiomyopathies. Genetic variants in the JPH2 gene can cause hypertrophic cardiomyopathy (HCM) and, in some cases, dilated cardiomyopathy (DCM). In this study, we tested the hypothesis that JPH2 variants identified in patients with HCM and DCM, respectively, cause distinct alterations in myocardial lipid profiles. Echocardiography revealed clinically significant cardiac dysfunction in both knock-in mouse models of cardiomyopathy. Unbiased myocardial lipidomic analysis demonstrated significantly reduced levels of total unsaturated fatty acids, ceramides, and various phospholipids in both mice with HCM and DCM, suggesting a common metabolic alteration in both models. On the contrary, significantly increased di- and triglycerides, and decreased co-enzyme were only found in mice with HCM. Moreover, mice with DCM uniquely exhibited elevated levels of cholesterol ester. Further in-depth analysis revealed significantly altered metabolites from all the lipid classes with either similar or opposing trends in JPH2 mutant mice with HCM or DCM. Together, these studies revealed, for the first time, unique alterations in the cardiac lipid composition—including distinct increases in neutral lipids and decreases in polar membrane lipids—in mice with HCM and DCM were caused by distinct JPH2 variants. These studies may aid the development of novel biomarkers or therapeutics for these inherited disorders.

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