The Impact of Myosin-Binding Protein C on Myosin Mobility and Proteostasis. - Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in the MYBPC3 gene, which lead to reduced levels of myosin-binding protein C (MyBP-C). MyBP-C is a key protein in myosin-based thick filaments within cardiac muscle sarcomeres. Reduced levels of MyBP-C are proposed to disrupt normal heart structure by effecting the function of myosin, leading to hypercontractility. While the FDA-approved drug mavacamten (Camzyos) targets the function of myosin, it does not compensate for MyBP-C's other known role in muscle contraction, including its interactions with actin-based thin filaments, or emerging roles in the maintenance of thick filament structure. This gap raises concerns about the efficacy of mavacamten, particularly for patients with MYBPC3-related HCM. Innovative techniques now allow for deeper investigation into the mechanisms by which reduced levels of MyBP-C result in HCM. Early findings suggest that the absence of MyBP-C in MyBP-C knockout (KO) mouse hearts is energetically costly due to enhance myosin replacement through synthesis and degradation. In addition, the absence of MyBP-C reduces the dynamic exchange of myosin molecules between thick filaments and a pool of soluble monomers within the sarcomere and limits the contractile function of the myocardium. These insights allow for a novel hypothesis that MYBPC3-related HCM results from dysregulation in myosin proteostasis, involving reduces myosin dynamics and contractile function. Such a hypothesis has not been previously explored in any HCM models. In addition, research into MyBP-C has primarily focused on its N- terminal regions, but new data show the C-terminal domains may play a critical role in modulating each of these processes. Understanding these mechanisms could reveal new aspects as to how MyBP-C' contributions to heart health. Clinically, although mavacamten shows promise for the treatment of HCM due to mutations in myosin itself, preliminary data from MyBP-C KO mice indicate that mavacamten has limited efficacy in restoring myosin proteostasis, mobility, or contractile due to the loss of MyBP-C. This suggests that mavacamten may not be optimal for these patients. This supports the need for a more personalized treatment, like gene therapy to restore full-length MyBP-C expression. This study utilizes advanced technologies to closely replicate whole-heart physiology, including stable isotope labeling, adeno-associated viral (AAV)-induced protein labeling, quantitative mass spectrometry, multiphoton imaging, and cardiac tissue slice mechanics. These methods are applied to transgenic mouse models that mimic human hypertrophic cardiomyopathy (HCM). The results will enhance our understanding of the complex interplay between myosin proteostasis, dynamics and contractility in HCM and will provide data that helps guide future, more tailored treatments for MYBPC3-related HCM.
