Muscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic...

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Biomedical Engineering

Background:

• Familial hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease.
• HCM is typically caused by mutations in sarcomeric proteins, leading to left ventricular hypertrophy, heart failure, arrhythmias, and sudden cardiac death.
• The sensing mechanisms of dysregulated sarcomeric force production and subsequent pathological remodeling in HCM are not well understood, hindering therapeutic development.

Purpose of the Study:

• To investigate the biomechanical mechanisms underlying pathological remodeling in familial hypertrophic cardiomyopathy (HCM).
• To identify novel mechanotransduction pathways involved in the phenotypic expression of HCM.
• To establish a foundation for developing mechanism-based treatments for HCM.

Main Methods:

• Derived patient-specific induced pluripotent stem cell-derived cardiomyocytes.
• Developed engineered heart tissues with native cardiac fiber alignment using laser-cut scaffolds.
• Utilized computational modeling, gene editing, and pharmacological interventions to study muscle contraction and rescue disease phenotypes.

Main Results:

• Identified enhanced actomyosin crossbridge formation due to sarcomeric mutations (e.g., in MYH7) leading to increased cardiac force.
• Demonstrated that increased force destabilizes the muscle LIM protein (MLP) stretch-sensing complex at the Z-disc.
• Showed that reduced MLP levels disinhibit calcineurin-NFAT signaling, promoting cardiac hypertrophy, and identified MLP-W4R as a modifier variant.

Conclusions:

• Uncovered a novel biomechanical mechanism linking dysregulated sarcomeric force production to pathological signaling and hypertrophy in HCM.
• Established the Z-disc MLP-mechanosensory complex as a critical component in sensing aberrant cardiac force.
• Provided a foundation for developing mechanism-based therapies targeting the Z-disc MLP complex to stabilize it and prevent HCM-related hypertrophy.