The MYH7 G256E mutation drives hypercontractility across multiple scales and increases mitochondrial respiration, suggesting altered bioenergetics as an early feature of hypertrophic cardiomyopathy.
Does the MYH7 G256E mutation alter myosin function and cellular bioenergetics in multi-scale models of hypertrophic cardiomyopathy?
The MYH7 G256E mutation drives hypercontractility and elevated mitochondrial respiration across multiple scales, suggesting altered bioenergetics is an early feature of HCM.
Rationale: Over 200 mutations in the sarcomeric protein β-myosin heavy chain (MYH7) have been linked to hypertrophic cardiomyopathy (HCM). However, different mutations in MYH7 lead to variable penetrance and clinical severity, and alter myosin function to varying degrees, making it difficult to determine genotype-phenotype relationships, especially when caused by rare gene variants such as the G256E mutation. Objective: This study aims to determine the effects of low penetrant MYH7 G256E mutation on myosin function. We hypothesize that the G256E mutation would alter myosin function, precipitating compensatory responses in cellular functions. Methods: We developed a collaborative pipeline to characterize myosin function at multiple scales (protein to myofibril to cell to tissue). We also used our previously published data on other mutations to compare the degree to which myosin function was altered. Results: ) generated greater tension, had faster tension development and slower early phase relaxation, suggesting altered myosin-actin crossbridge cycling kinetics. This hypercontractile phenotype persisted in single-cell hiPSC-CMs and engineered heart tissues. Single-cell transcriptomic and metabolic profiling demonstrated upregulation of mitochondrial genes and increased mitochondrial respiration, suggesting altered bioenergetics as an early feature of HCM. Conclusions: MYH7 G256E mutation causes structural instability in the transducer region, leading to hypercontractility across scales, perhaps from increased myosin recruitment and altered crossbridge cycling. Hypercontractile function of the mutant myosin was accompanied by increased mitochondrial respiration, while cellular hypertrophy was modest in the physiological stiffness environment. We believe that this multi-scale platform will be useful to elucidate genotype-phenotype relationships underlying other genetic cardiovascular diseases.
Lee et al. (Fri,) conducted a other in Hypertrophic cardiomyopathy. MYH7 G256E mutation was evaluated on Myosin function and cellular responses. The MYH7 G256E mutation drives hypercontractility across multiple scales and increases mitochondrial respiration, suggesting altered bioenergetics as an early feature of hypertrophic cardiomyopathy.