MYBPC3 D389V Variant Induces Hypercontractility in Cardiac Organoids

Area of Science:

• Cardiovascular Biology
• Genetics
• Stem Cell Biology

Background:

• Hypertrophic cardiomyopathy (HCM) is primarily caused by mutations in the MYBPC3 gene.
• The molecular mechanisms underlying MYBPC3-associated HCM require further elucidation.
• A specific MYBPC3 variant (D389V) is prevalent in South Asian populations and linked to increased cardiac function.

Purpose of the Study:

• To investigate the molecular and cellular mechanisms of HCM caused by the MYBPC3 D389V variant.
• To utilize isogenic human-induced pluripotent stem cell-derived cardiac organoids (hCOs) for studying disease pathogenesis.
• To define the functional and energetic consequences of the MYBPC3 D389V variant.

Main Methods:

• Generation of isogenic human cardiac organoids (hCOs) from MYBPC3 D389V variant carriers and non-carriers.
• Confocal and electron microscopy for sarcomere organization analysis.
• Functional assays measuring contractility, calcium cycling, and cellular energetics.
• In vitro binding assays using recombinant proteins.
• Treatment with myosin inhibitor mavacamten.

Main Results:

• MYBPC3 D389V hCOs exhibited hypercontractility, faster calcium cycling, and accelerated contractile kinetics.
• Increased MYBPC3 phosphorylation, oxidative stress, and reduced mitochondrial membrane potential were observed in MYBPC3 D389V hCOs.
• In vitro binding assays showed reduced affinity between MYBPC3 D389V and myosin S2.
• Mavacamten treatment rescued the hypercontractile phenotype in MYBPC3 D389V hCOs.

Conclusions:

• The MYBPC3 D389V variant induces a hypercontractile phenotype in cardiac organoids.
• Altered protein binding affinity and mitochondrial dysfunction contribute to HCM pathogenesis.
• Human cardiac organoids are a viable model for studying HCM mechanisms.
• Myosin inhibition represents a potential therapeutic strategy for MYBPC3-associated HCM.