Physiological Stress and Cardiomyocyte Cycling Drive Hypertrophic Cardiomyopathy with MYBPC3 truncation mutation

Hypertrophic cardiomyopathy (HCM) affects up to 1:500 young people worldwide. Known genetic mutations account for approximately 60% of HCM cases, with identified mutations in cardiac myosin binding protein C (MYBPC3) accounting for up to 40-50% of those genetic cases. Monoallelic MYBPC3 truncating mutations are the most common variants in symptomatic HCM. We used CRISPR-based genome editing to create a mouse harboring a truncated MYBPC3 (MYBPC3 W1082* ) based on the genetic testing of an HCM patient at UVA. We observed histologic and morphometry phenotypes consistent with human HCM. Mice carrying the homozygous mutation (MYBPC3 W1082* ) display the characteristic phenotypes of HCM patients, including a significant increase in heart mass, CM cross-sectional area, and wall thickness at eight weeks of age in both males and females. These mice demonstrate a significant decrease in ejection fraction as early as eight weeks of age, which continues to decline with up until death with a median age of survival of 32 weeks. Finally, homozygous mutation results in a significant increase in fibrosis as measured by Masson’s trichrome staining. Interestingly, adult murine MYCBP3 W1082* cardiomyocytes express cell cycling markers, including a substantial increase in phospho-histone 3 staining, suggesting continued cycling and endoreplication. This finding correlates with human data, which indicates a significant increase in pathways of “regulation of cell population proliferation” and “regulation of cyclin-dependent kinase activity” when comparing previously published snRNA-Seq from cardiomyocytes of HCM to non-failing controls. While the homozygous mutation results in severe disease as early as 8 weeks of age, mice carrying the heterozygous mutation display no overt cardiac or developmental defects at baseline. Unexpectedly, we determined that pregnancy as a physiological stressor can elicit a persistent increase in LV volume, coupled with a significant decrease in ejection fraction compared to baseline measurements by echocardiography. These findings indicate a novel role for monoallelic MYBPC3 mutation in driving disease under stress and reveal a novel regulatory pathway in HCM, which could serve as a therapeutic target. The investigations elucidate the importance of understanding the cellular mechanisms that drive HCM in the context of a MYBPC3 mutation. NIH T32 HL007284 NIH R01 HL162925-03 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.