Nollet Edgar E, Algül Sila, Goebel Max, Schlossarek Saskia, van der Wel Nicole N, Jans Judith J M, van de Wiel Mark A, Knol Jaco C, Pham Thang V, Piersma Sander R, de Goeij-de Haas Richard, Hermans Jill, van Klinken Jan Bert, van Weeghel Michel, Houtkooper Riekelt H, Carrier Lucie, Jimenez Connie R, Kuster Diederik W D, van der Velden Jolanda
Department of Physiology, Amsterdam UMC, Amsterdam, the Netherlands.
Amsterdam Cardiovascular Sciences, Heart failure & Arrhythmias, Amsterdam, the Netherlands.
J Mol Cell Cardiol Plus. 2023 Sep 19;6:100050. doi: 10.1016/j.jmccpl.2023.100050. eCollection 2023 Dec.
Phenotypic expression of hypertrophic cardiomyopathy (HCM) and disease course are associated with unfavorable metabolic health. We investigated if Western diet (WD) feeding is sufficient to trigger cardiac hypertrophy and dysfunction in heterozygous (HET) knock-in mice.
Wild-type (WT) and HET mice (3-months-old) were fed a WD or normal chow (NC) for 8 weeks. Metabolomic analyses on serum revealed systemic metabolic derailment in WD-fed WT and HET mice. Strikingly, only WD-fed HET mice developed cardiac hypertrophy and dysfunction, which was not driven by aggravated cardiac myosin binding protein-C haploinsufficiency. WD reduced oxidative phosphorylation and increased toxic lipids in the heart irrespective of genotype. Cardiac proteomic analyses revealed higher abundance of proteins involved in fatty acid oxidation in WD-fed mice, however this increase was blunted in HET compared to WT mice. Accordingly, cardiac metabolomic and lipidomic analyses showed accumulation of acylcarnitines in WD-fed HET vs WT mice.
WD feeding triggered cardiac dysfunction and hypertrophy in otherwise phenotype-negative HET mice. We propose that the presence of a HCM mutation predisposes the heart to metabolic inflexibility when subjected to systemic metabolic stress. Our study represents a novel approach to study the interplay between unfavorable metabolic health and mutation-induced defects in HCM disease development.
肥厚型心肌病（HCM）的表型表达和病程与不良的代谢健康状况相关。我们研究了西式饮食（WD）喂养是否足以引发杂合（HET）基因敲入小鼠的心脏肥大和功能障碍。
野生型（WT）和HET小鼠（3个月大）分别喂食WD或正常饲料（NC）8周。血清代谢组学分析显示，喂食WD的WT和HET小鼠存在全身代谢紊乱。令人惊讶的是，只有喂食WD的HET小鼠出现了心脏肥大和功能障碍，这并非由心肌肌球蛋白结合蛋白C单倍体不足加重所致。无论基因型如何，WD都会降低心脏的氧化磷酸化并增加有毒脂质。心脏蛋白质组学分析显示，喂食WD的小鼠中参与脂肪酸氧化的蛋白质丰度更高，然而与WT小鼠相比，HET小鼠中的这种增加并不明显。因此，心脏代谢组学和脂质组学分析显示，喂食WD的HET小鼠与WT小鼠相比，酰基肉碱有所积累。
WD喂养在原本表型阴性的HET小鼠中引发了心脏功能障碍和肥大。我们提出，当受到全身代谢应激时，HCM突变的存在使心脏易发生代谢不灵活性。我们的研究代表了一种研究不良代谢健康与HCM疾病发展中突变诱导缺陷之间相互作用的新方法。
