Investigating the Role of MYH14 in Tension-Dependent Cardiomyocyte Hypertrophy

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PROJECT SUMMARY / ABSTRACT Heart failure is a leading cause of hospitalization and a primary driver behind rising healthcare costs. Using a systems genetics approach in mice, we have previously identified a non-muscle myosin encoded by the gene Myh14 as a genetic modifier of heart failure. Using a genetically modified Myh14 knockout mouse model, we have further validated its importance in the maintenance of cardiac homeostasis through ongoing NIH K08 supported research. As a part of the K08 award, we have determined the subcellular localization of MYH14 in murine heart tissue and neonatal rat ventricular cell culture. However, its specific roles in maintenance of cardiac homeostasis remains elusive. MYH14, also known as non-muscle myosin II-C (NMIIC), is the newest member of the non-muscle myosin II family of ATP-dependent molecular motors. MYH14 is an established causal gene for hereditary hearing loss and is believed to be the master integrators of force within epithelial apical junctions, mediating epithelial tissue morphogenesis and tensional homeostasis. Recently, the R941L mutation in MYH14 was demonstrated to act in a dominant-negative fashion to inhibit mitochondrial fission, especially in the cell periphery, and to alter the organization of the mitochondrial genome in patient fibroblast lines. In addition to localization in the intercalated disc, as shown in prior literature, we found that MYH14 is expressed at or near the costameres. We hypothesize that MYH14 may be key player in modulating the heart’s adaptive response to mechanical stress. This R03 proposal describes a 2-year plan to detail MYH14’s subsarcolemmal and cytoplasmic localization, relationships with the other known non-muscle myosin in cardiomyocyte, MYH10, response to hormonal signals and physical interactors. Fundamental understanding of MYH14’s function in the cardiomyocytes will provide insights into how the cardiomyocyte responds to mechanical stress as well as hormonal signals that may modulate this response. Moreover, these insights will allow us to predict outcomes when such homeostatic mechanisms break down in different forms of cardiac pathologies. Finally, insights from this study may shed light how such homeostatic system may be nudge to promote health versus disease.