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 ß-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 PGC1a (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
PGC1a, 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.