Abstract
Abstract only BubR1 is a serine/threonine protein kinase with a well-established role in regulating the spindle assembly checkpoint during mitosis. Previous studies have shown that BubR1 insufficiency leads to premature aging phenotypes such as kyphosis, cataracts, loss of subcutaneous fat, and a shortened lifespan. Furthermore, BubR1 naturally declines with age a wide range of tissues due to enhanced proteosome-mediated degradation. BubR1 hypomorphic mice expressing approximately 10% of the protein die suddenly in a manner reminiscent of sudden cardiac death. Subsequent studies have further shown that these mice suffer from conduction abnormalities such as a prolonged QTc interval. In humans, the incidence of QTc interval prolongation increases with age, and is associated with sudden cardiac death. Given BubR1 protein levels decline with age, we reasoned that BubR1 is critical for the maintenance of adult cardiac structure and function and its loss with age may drive age-related pathophysiology in the heart. We generated a conditional BubR1 knockout mouse which we crossed to the cardiac-specific cre driver line, Nkx2.5-cre , to assess the consequence of loss of BubR1 specifically in the heart. Electrocardiography analysis of BubR1 heterozygous knockouts also have a prolonged QTc interval in vivo . Structural analysis of the hearts of these mice revealed that they suffer from cardiac hypertrophy as shown by an increase in both heart weight as well as ventricular cardiomyocyte size. Masson’s trichrome staining revealed that BubR1 heterozygous knockout hearts have increased fibrosis both in the ventricular space and the perivascular region. At the molecular level, these mice also show increased levels of p21 and phospho-γH2AX staining, which represent key hallmarks of cellular senescence. Transcriptomic analysis further revealed dysregulation of multiple pathways involved in hypertrophy and senescence. Therefore, reduced expression of BubR1 drives cardiac aging as observed by increases in cardiac hypertrophy, fibrosis, senescence, and DNA damage response. Our results indicate that BubR1 plays a vital role in regulating adult cardiac structure and function, and its loss with age may drive deleterious phenotypes during heart aging.