Ataxia Telangiectasia-Mutated Kinase Deficiency Induces Cardiac Dysfunction with Increased Myocyte Apoptosis and Hypertrophy with Age

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Background: Heart failure is the leading cause of death globally. The risk for heart disease increases exponentially with age. The incidence of heart disease is approximately 40% in humans that are 40-59 years old. Ataxia telangiectasia-mutated kinase (ATM), a cell cycle protein, controls growth and repair in response to double-stranded DNA damage. Mutations in the ATM gene lead to a multisystemic disease known as Ataxia Telangiectasia (A-T). These individuals exhibit signs of premature aging. A-T heterozygotes make up about 2% of the population and are more susceptible to ischemic heart disease and die 11 years earlier compared to non-carriers. Previous work has shown that ATM deficiency increases myocyte hypertrophy in 4-month-old (young) ATM heterozygous knockout (hKO) mice vs. age-matched wild-type (WT) mice. However, there was no difference in myocyte apoptosis or heart function between the two groups. Hypothesis: It is hypothesized that with age, ATM deficiency induces myocytes apoptosis and hypertrophy, and cardiac dysfunction. Methods: Heart function was measured in young and 14-month-old WT and hKO mice using echocardiography. Cross sections (5 μm) of heart were used to measure myocyte apoptosis and hypertrophy using terminal deoxynucleotidyl transferase nick end labeling (TUNEL) and rhodamine wheat germ agglutinin (WGA) staining, respectively. Results: Heart function, measured by fractional shortening (%FS) and ejection fraction (%EF), remained unchanged in young and 14-month-old WT mice. However, %FS and %EF were significantly lower in 14-month-old hKO mice vs. young hKO and age-matched WT mice. Myocyte apoptosis and cross-sectional area (hypertrophy) were significantly higher in 14-month-old hKO vs. age-matched WT mice. Conclusion: The data indicates that ATM deficiency induces cardiac dysfunction with increased myocyte apoptosis and hypertrophy with age. This research was supported by Department of Biological Sciences, Undergraduate Research Honors Program, Offce of Research and Sponsored Programs, Department of Biomedical Sciences, and Department of Health Sciences. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.