Ali Samia A, Perera Gayani, Laird Jason, Batorsky Rebecca, Maron Martin S, Rivas Victor N, Stern Joshua A, Harris Samantha, Chin Michael T
Tufts Graduate School of Biomedical Sciences Boston MA USA.
Molecular Cardiology Research Institute, Tufts Medical Center Boston MA USA.
J Am Heart Assoc. 2025 Jan 7;14(1):e035780. doi: 10.1161/JAHA.124.035780. Epub 2024 Dec 24.
Hypertrophic cardiomyopathy (HCM) is a common heritable heart disease where the most frequently associated mutations occur in the myosin-binding protein C () sarcomere-associated gene. HCM is also a common veterinary clinical problem in certain cat breeds such as Maine Coons and Ragdolls, also most associated with mutations in . Mouse models of HCM in which mutations are introduced recapitulate some, but not all, features of human HCM.
To elucidate the common and distinctive pathological pathways across species and foster a greater understanding of the concordance of mouse HCM models to clinical -associated HCM, we generated single nuclei RNA-sequencing data sets from feline, human, and murine heart tissue carrying variants. Numerous genes were differentially expressed between mutation positive and mutation negative cell types within each species, identified using the model-based analysis of single-cell transcriptomics algorithm. Gene Ontology enrichment analysis of differentially expressed genes in cardiomyocytes across species revealed alterations in genes involved in muscle development, muscle contraction, muscle hypertrophy, regulation of sarcoplasmic calcium release, ATP metabolic process, and oxidative phosphorylation.
These common biological processes across species are consistent with known phenotypic aspects of HCM such as hypertrophy, hypercontractility, diastolic dysfunction, and altered energy metabolism. Surprisingly, among conserved biological processes within cardiomyocytes across species, the individual genes driving the biological processes were distinct. This work to identify common and species-specific disease-promoting pathway differences will allow development of targeted therapies for both human and veterinary application and will facilitate an understanding of the idiosyncrasies of mouse models.
肥厚型心肌病（HCM）是一种常见的遗传性心脏病，最常相关的突变发生在肌球蛋白结合蛋白C（）肌节相关基因中。HCM在某些猫品种（如缅因猫和布偶猫）中也是常见的兽医临床问题，也大多与中的突变相关。引入突变的HCM小鼠模型再现了人类HCM的一些但不是所有特征。
为了阐明跨物种的共同和独特病理途径，并促进对小鼠HCM模型与临床相关HCM一致性的更好理解，我们从携带变体的猫、人和小鼠心脏组织中生成了单核RNA测序数据集。使用基于模型的单细胞转录组学算法，在每个物种中突变阳性和突变阴性细胞类型之间鉴定出许多差异表达的基因。跨物种心肌细胞中差异表达基因的基因本体富集分析揭示了参与肌肉发育、肌肉收缩、肌肉肥大、肌浆网钙释放调节、ATP代谢过程和氧化磷酸化的基因的改变。
这些跨物种的共同生物学过程与HCM的已知表型方面一致，如肥大、高收缩性、舒张功能障碍和能量代谢改变。令人惊讶的是，在跨物种心肌细胞内保守的生物学过程中，驱动生物学过程的单个基因是不同的。这项识别共同和物种特异性疾病促进途径差异的工作将允许开发用于人类和兽医应用的靶向治疗，并将有助于理解小鼠模型的特性。
