Deficiency of Ataxia Telangiectasia‐mutated Kinase (ATM) Preserves Heart Function by Affecting Cardiac Remodeling in Response to Western‐type Diet in Female Mice

BACKGROUND Western‐type Diet (WD) and deficiency of ATM protein independently associate with heart disease. Previous work demonstrated that WD in male ATM deficient mice induces accelerated body weight gain and heart dysfunction (Am J Physiol Heart Circ Physiol. 2021;320:H2324‐H2338). Conversely, WD in female ATM deficient mice attenuates weight gain and preserves heart function (unpublished data). Here, we investigated the mechanism by which ATM deficiency preserves heart function in female mice. It is hypothesized that ATM deficiency attenuates adverse myocardial remodeling in female mice, thereby preserving heart function. METHODS Female wild‐type (WT) and ATM heterozygous knockout (hKO) mice, aged 6 weeks, were fed with normal chow (NC) or WD for 14 weeks. Heart sections were stained with Masson’s trichrome to quantify fibrosis, TUNEL‐stained to quantify apoptosis, and WGA (wheat germ agglutinin)‐stained to quantify myocyte hypertrophy. Data were analyzed using ANOVA followed by Student‐Newman‐Keuls test. RESULTS ATM deficiency associated with increased fibrosis, apoptosis (myocytes and non‐myocytes) and hypertrophy in hKO‐NC vs WT‐NC (p<0.05; n=4). WD significantly increased fibrosis in WT‐WD mice, while no increase in fibrosis was observed in hKO‐WD. WD significantly increased apoptosis in both genotypes. However, the increase in apoptosis was significantly lower in hKO‐WD vs WT‐WD (p<0.05; n=4). WD increased hypertrophy in WT group. However, the hypertrophy remained significantly higher in hKO‐WD vs WT‐WD (p<0.05; n=4). CONCLUSION Decrease in myocardial fibrosis and apoptosis, and increase in myocyte hypertrophy may play a role in preservation of heart function in ATM deficient female mice in response to WD.