Integrated multi-omics analysis of myosin heavy chain mutations in iPSC-derived cardiomyocytes revealed altered mechanisms in mitochondrial homeostasis and excitation-coupling maladaptation.
Integrated multi-omics profiling of human iPSC-derived cardiomyocytes and patient myectomies reveals early mitochondrial and excitation-contraction coupling maladaptations in hypertrophic cardiomyopathy.
Hypertrophic cardiomyopathy is one of the most common inherited cardiomyopathies and a leading cause of sudden cardiac death in young adults. Despite profound insights into the genetics, there is imperfect correlation between mutation and clinical prognosis, suggesting complex molecular cascades driving pathogenesis. To investigate this, we performed an integrated quantitative multi-omics (proteomic, phosphoproteomic, and metabolomic) analysis to illuminate the early and direct consequences of mutations in myosin heavy chain in engineered human induced pluripotent stem-cell-derived cardiomyocytes relative to late-stage disease using patient myectomies. We captured hundreds of differential features, which map to distinct molecular mechanisms modulating mitochondrial homeostasis at the earliest stages of pathobiology, as well as stage-specific metabolic and excitation-coupling maladaptation. Collectively, this study fills in gaps from previous studies by expanding knowledge of the initial responses to mutations that protect cells against the early stress prior to contractile dysfunction and overt disease.
Moore et al. (Wed,) conducted a other in Hypertrophic cardiomyopathy. Myosin heavy chain mutations (in vitro model) vs. Late-stage disease (patient myectomies) was evaluated on Differential features mapping to molecular mechanisms modulating mitochondrial homeostasis and excitation-coupling maladaptation. Integrated multi-omics analysis of myosin heavy chain mutations in iPSC-derived cardiomyocytes revealed altered mechanisms in mitochondrial homeostasis and excitation-coupling maladaptation.