Gender-specific Role of ATM in the Heart - 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.
