Probing relaxed myosin states in hypertrophic cardiomyopathy by second harmonic-generation microscopy.

Second harmonic-generation microscopy reveals that hypertrophic cardiomyopathy-associated R403Q MYH7 mutation increases the myosin ON state fraction in cardiac tissue by approximately 20%.

• Why it matters: Understanding myosin conformational states is crucial for deciphering the molecular basis of hypertrophic cardiomyopathy, yet current methods lack the ability to quantify these states in intact tissue.
• What they did: The study employed polarized second-harmonic generation (pSHG) to measure myosin conformations in skeletal and cardiac tissues, manipulating the ON/OFF equilibrium with physical and chemical agents, and validated findings with X-ray diffraction and ATPase assays.
• The result: Findings show the R403Q mutation shifts myosin toward the ON state, increasing energy consumption, and this shift can be reversed with myosin modulators, providing insights into disease mechanisms and potential therapeutic targets.