Abstract 188: Sarcomere Protein Cardiac Myosin Binding Protein C Regulates Cardiomyocyte Proliferation
Introduction: Wildtype neonatal murine cardiomyocytes become bi-nucleated, hypertrophy and terminally differentiate, and concurrently develop well-organized striation patterns of sarcomeres of myofibrils. Neonatal mice lacking cardiac myosin binding protein C (Mybpct/t) have subtle abnormalities in myofibrillar structure and ventricular dilation, but remain healthy life-long.
Hypothesis: Deficits in MybpC impacts formation of bi-nucleated and cell proliferation of cardiomyocytes.
Methods: We studied the cardiac development in Mybpct/t mice and hearts depleted of cMyBP-C by adeno-associated virus (AAV)-mediated RNAi.
Results: Mybpct/t hearts presented significant increase in mono-nucleated cardiomyocytes (18.28 ± 1.68%) and decrease in bi-nucleated cardiomyocytes (74.87 ± 87%), compared to wildtype hearts (mono-nucleated: 5.85% ± 1.14%, p<0.001; bi-nucleated: 89.83 ± 2.04%, p<0.001, n=4 in each genotype). Similar distribution of mono-nucleated (25.25 ± 3.15%) and bi-nucleated cardiomyocytes (73.55 ± 3.8%) was also observed in cardiomyocytes depleted of cMyBP-C by AAV-mediated RNAi (n=4). Significant increase in EdU incorporation was observed in Mybpct/t cardiomyocytes (47.02 ± 2.5%) compared to wildtype cardiomyocytes (29.35 ± 3.06%, p<0.005). Phosphorylated histone H3, a marker of mitosis, was approximately two-fold more positive in Mybpct/t than wildtype cardiomyocytes at postnatal day 3, day 7 and day10 (p<0.01). In addition, we observed a 15-fold increase of Aurora B expression within the cytoplasmic bridge between cardiomyocytes undergoing cytokinesis in Mybpct/t hearts compared to wildtype hearts at postnatal day 7 (p<0.001). The predicted consequence of protracted cardiomyocyte proliferation in neonatal Mybpct/t mice, a significantly increased number of cardiomyocytes, was demonstrated. In comparison to wildtype, the number of cardiomyocytes in Mybpct/t hearts was significantly increased by 40% (n=3 in each group, p<0.01).
Conclusions: Loss of cMyBP-C causes neonatal cardiomyocytes to undergo extra round of cytokinesis and continued progression of the cell cycles. Changes in cell number, rather than cell size, may be responsible for morphologic abnormalities of some cardiomyopathies.
- © 2013 by American Heart Association, Inc.