Gender-specific Role of ATM in the Heart

ATM（共济失调毛细血管扩张突变激酶）基因突变会导致共济失调毛细血管扩张症 （AT）。AT患者喜欢吃高脂肪和高糖的饮食。体重方面的生长迟缓， 身高在女性AT患者中更为突出。大约2%的普通人群携带杂合子 ATM突变ATM杂合子死于缺血性心脏病（IHD）比非携带者早11年。 过氧化物酶体和线粒体是脂肪酸氧化（FAO）的关键细胞器。使用ATM不足 （杂合敲除; hKO）小鼠，我们提供了证据表明ATM在β-AR刺激的 和心肌梗死（MI）诱导的心脏重塑，影响心室功能、自噬、纤维化 和凋亡。ATM缺陷也与MI后小鼠死亡率增加相关。我们的初步数据 在用西式饮食（WD）喂养14周的小鼠中显示出有趣的性别特异性差异。女性 在hKO小鼠（雄性小鼠除外）中，WD诱导的体重和脂肪重量增加较低，而心脏功能显著降低。 与野生型（WT）雌性组相比更好。然而，ATM缺乏对女性心脏的保护作用 MI后1天处死小鼠。AMPK（细胞能量稳态和代谢的关键调节因子）的活化 自噬/自噬）和过氧化氢酶（过氧化物酶体中的主要抗氧化酶）的表达较低， 而PGC 1 α（能量代谢和过氧化物酶体生物合成的关键调节因子）、PMP 70（ 过氧化物酶体生物发生）、ACOX 1（酰基-CoA氧化酶1;过氧化物酶体FAO中的限速酶）和CPT 1B （肉毒碱棕榈酰转移酶1B;线粒体脂肪酸输入的关键酶）在 MI后1天hKO-WD雌性动物左心室的非梗死区。这项建议的一个主要目标是 了解ATM缺陷在WD诱导的心肌重塑之前和之后的性别特异性作用， MI.推测心脏中过氧化物酶体生物合成的增强在女性中起心脏保护作用。 在MI之前ATM缺陷期间的小鼠。然而，AMPK活性降低和 PGC 1 α、PMP 70和ACOX 1损害葡萄糖利用、pexophagy/自噬和线粒体功能 导致心肌梗死后心脏功能障碍加重。目的1调查，在体内，性别特异性作用的ATM 心脏中过氧化物酶体和线粒体的稳态对WD的反应。目的2检查，在体内， 进食WD的雌性大鼠心肌ATM缺乏时葡萄糖利用增强的有益作用 MI后小鼠。目的3探讨ATM缺陷对线粒体和过氧化物酶体的影响机制 使用从成年WT和hKO雌性的心肌分离的肌细胞对脂肪酸的反应的生物发生 小鼠ATM缺乏时影响过氧化物酶体和线粒体稳态的信号的鉴定 以性别特异性的方式，可以提供预防/最大限度地减少WD和IHD相关的潜在目标。 心脏的有害变化，特别是在ATM缺乏症的女性中。此外，这些研究可能会发现， 治疗IHD的治疗策略和/或ATM缺乏症个体的营养咨询。

Mutations in ATM (ataxia telangiectasia mutated kinase) gene cause a disease known as ataxia telangiectasia (AT). AT patients prefer to consume a diet high in fat and sugar. Growth retardation with respect to weight and height is more prominent in female AT patients. Approximately 2% of the general population carries heterozygous ATM mutation. ATM heterozygotes die 11 years earlier due to ischemic heart disease (IHD) than non-carriers. Peroxisomes and mitochondria are the key organelles for fatty acid oxidation (FAO). Using ATM deficient (heterozygous knockout; hKO) mice, we provided evidence that ATM plays an important role in β-AR-stimulated and myocardial infarction (MI)-induced cardiac remodeling with effects on ventricular function, autophagy, fibrosis and apoptosis. ATM deficiency also associated with enhanced mortality in mice post-MI. Our preliminary data show interesting gender-specific differences in mice fed with Western-type diet (WD) for 14 weeks. In female hKO mice (not in males), WD-induced body and fat weight gains were lower, while heart function was significantly better versus the wild-type (WT) female group. However, the cardioprotective effects of ATM deficiency in female mice were abolished 1 day post-MI. Activation of AMPK (key regulator of cellular energy homeostasis and autophagy/pexophagy) and expression of catalase (predominant antioxidant enzyme in peroxisomes) were lower, while expression of PGC1α (key regulator of energy metabolism and peroxisome biogenesis), PMP70 (marker of peroxisome biogenesis), ACOX1 (acyl-CoA oxidase 1; rate-limiting enzyme in peroxisomal FAO) and CPT1B (carnitine palmitoyltransferase 1B; pivotal enzyme for mitochondrial fatty acid import) was dysregulated in the non-infarcted zone of left ventricle of hKO-WD females 1 day post-MI. A major objective of this proposal is to understand the gender-specific role of ATM deficiency in WD-induced myocardial remodeling prior to and post- MI. It is hypothesized that enhanced peroxisome biogenesis in the heart plays a cardioprotective role in female mice during ATM deficiency prior to MI. However, decreased AMPK activity and dysregulated expression of PGC1α, PMP70 and ACOX1 impairs glucose utilization, pexophagy/autophagy and mitochondrial function leading to exacerbated cardiac dysfunction post-MI. Aim 1 investigates, in vivo, the gender-specific role of ATM in peroxisomal and mitochondrial homeostasis in the heart in response to WD. Aim 2 examines, in vivo, the beneficial effects of enhanced glucose utilization during ATM deficiency in the myocardium of WD-fed female mice post-MI. Aim 3 investigates the mechanism by which ATM deficiency alters peroxisomal and mitochondrial biogenesis in response to fatty acids using myocytes isolated from the myocardium of adult WT and hKO female mice. Identification of signals affecting the peroxisomal and mitochondrial homeostasis during ATM deficiency in a gender-specific manner may provide potential targets for preventing/minimizing WD- and IHD-related deleterious changes in the heart, particularly in females with ATM deficiency. In addition, the studies may uncover therapeutic strategies for the treatment of IHD and/or nutritional counseling for individuals with ATM deficiency.