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.

中文翻译：

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junctophilin-2 相关家族性心肌病中心肌脂质调节的改变。

心肌脂质代谢对于正常心脏功能至关重要，而脂质调节的改变与包括心肌病在内的心脏病有关。JPH2基因的遗传变异可导致肥厚型心肌病 (HCM)，在某些情况下还会导致扩张型心肌病 (DCM)。在这项研究中，我们测试了以下假设：分别在 HCM 和 DCM 患者中发现的 JPH2 变异会导致心肌血脂谱发生明显改变。超声心动图显示两种心肌病敲入小鼠模型均存在临床显着的心功能障碍。无偏见的心肌脂质组学分析表明，HCM 和 DCM 小鼠的总不饱和脂肪酸、神经酰胺和各种磷脂水平显着降低，表明这两种模型中存在共同的代谢改变。相反，仅在 HCM 小鼠中发现甘油二酯和甘油三酯显着升高，辅酶降低。此外，患有 DCM 的小鼠独特地表现出胆固醇酯水平升高。进一步的深入分析显示，在患有 HCM 或 DCM 的JPH2突变小鼠中，所有脂质类别的代谢物均发生显着改变，具有相似或相反的趋势。总之，这些研究首次揭示了患有 HCM 和 DCM 的小鼠心脏脂质成分的独特变化，包括中性脂质的明显增加和极性膜脂质的减少，是由不同的JPH2变异引起的。这些研究可能有助于开发针对这些遗传性疾病的新型生物标志物或疗法。