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Published in final edited form as: Life Sci. 2024 Feb 28;342:122541. doi: 10.1016/j.lfs.2024.122541

ATM deficiency differentially affects expression of proteins related to fatty acid oxidation and oxidative stress in a sex-specific manner in response to Western-type diet prior to and following myocardial infarction

Hui Wang-Heaton 1, Mary C Wingard 1, Suman Dalal 2,3, Paige L Shook 1, Barbara A Connelly 1, Patrick Johnson 1, Phillip L Nichols 1, Mahipal Singh 1, Krishna Singh 1,3,4,5
PMCID: PMC10949412  NIHMSID: NIHMS1971552  PMID: 38428572

Abstract

Aims:

Published work has shown that ataxia-telangiectasia mutated kinase (ATM) deficiency is associated with cardioprotective effects in Western-type diet (WD)-fed female mice. This study assessed the expression of proteins related to fatty acid oxidation (FAO) and oxidative stress in WD-fed male and female mouse hearts, and investigated if sex-specific cardioprotective effects in WD-fed female ATM-deficient mice are maintained following myocardial infarction (MI).

Main Methods:

Wild-type (WT) and ATM-deficient (hKO) mice (both sexes) were placed on WD for 14 weeks. Myocardial tissue from a subset of mice was used for western blot analyses, while another subset of WD-fed mice underwent MI. Heart function was analyzed by echocardiography prior to and 1 day post-MI.

Key Findings:

CPT1B (mitochondrial FAO enzyme) expression was lower in male hKO-WD, while it was higher in female hKO-WD versus WT-WD. WD-mediated decrease in ACOX1 (peroxisomal FAO enzyme) expression was only observed in male WT-WD. PMP70 (transports fatty acyl-CoA across peroxisomal membrane) expression was lower in male hKO-WD vs WT-WD. Catalase (antioxidant enzyme) expression was higher, while Nox4 (pro-oxidant enzyme) expression was lower in female hKO-WD vs WT-WD. Heart function was better in female hKO-WD vs W-TWD. However, post-MI heart function was not significantly different among all MI groups. Post-MI, CPT1B and catalase expression was higher in male hKO-WD-MI vs WT-WD-MI, while Nox4 expression was higher in female hKO-WD-MI vs WT-WD-MI.

Significance:

Increased mitochondrial FAO and decreased oxidative stress contribute towards ATM deficiency-mediated cardioprotective effects in WD-fed female mice which are abolished post-MI with increased Nox4 expression.

Keywords: ATM, Heart, Western-type diet, myocardial infarction

Introduction

Chronic consumption of Western-type diet (WD), diet rich in fat and sugar, contributes to the prevalence of obesity which has nearly tripled worldwide since 1975 [1]. Concomitant with this, a significant number of people suffer from chronic illnesses such as type 2 diabetes and cardiovascular diseases [2]. Obesity cardiomyopathy, which occurs following consumption of WD for extended periods of time, describes increased hemodynamic load, right and left ventricular hypertrophy, chamber dilation, increased fibrosis, and systolic and diastolic dysfunction [3,4]. Fatty acid oxidation (FAO) generally occurs in mitochondria and peroxisomes, small organelles found in every cell. FAO provides 60–90% of ATP to meet the high-energy demand of the heart [5]. Because of the Randle cycle, FAO is increased in the heart in response to a WD which is accompanied with oxidative stress due to the oxidant/antioxidant imbalance [6–8]. Oxidative stress is considered as a major contributing factor toward cardiac remodeling and heart failure [8–10].

Ataxia-telangiectasia mutated kinase (ATM), a serine/threonine kinase, plays an important role in genome integrity and stability [11,12]. ATM mainly gets activated in response to DNA double-strand breaks and oxidative stress [13–16]. Mutations in the ATM gene cause an autosomal recessive disorder known as Ataxia-telangiectasia (A-T). A-T patients exhibit multisystemic disorder characterized by immunodeficiency, progressive cerebellar ataxia, neurodegeneration, radiation sensitivity, predisposition to cancers and increased metabolic diseases [12,17,18]. Approximately 1.4–2.0% of the general population is heterozygous A-T carriers with mutation in one ATM allele [19]. These patients do not exhibit the majority of the symptoms of A-T. However, they are at a higher risk of developing metabolic dysfunction, cancers and ischemia heart disease [19,20].

Previously, using ATM-deficient (heterozygous knockout; ATM+/−) mice, we provided evidence that ATM deficiency in WD-fed male mice is associated with accelerated weight gain, systolic dysfunction with increased preload, and exacerbated cardiac remodeling [21]. Conversely, ATM deficiency in female mice is associated with attenuated weight gain and preserved heart function in response to WD [22]. The objectives of this study were to gain an insight into the mechanism by which ATM deficiency impacts sex-specific cardioprotective effects in response to WD, and to investigate if cardioprotective effects of ATM deficiency in WD-fed female mice are sustained 1 day post-MI. We analyzed expression of CPT1B, ACOX1, PMP70, catalase, SOD2 and Nox4. CPT1 (carnitine palmitoyltransferase 1) localizes on the mitochondrial outer membrane, and is considered as a key rate-limiting enzyme in the mitochondrial FAO by regulating the transport of long-chain fatty acids (C14–20) [23]. CPT1B is the major isoform in the heart [5]. ACOX1 (acyl-CoA oxidase 1) is the first and rate-limiting enzyme in peroxisomal FAO [24–27]. PMP70, an integral membrane protein of peroxisomes, belongs to a superfamily of proteins named as ATP binding cassette transporters [28–30]. PMP70 is suggested to be involved in metabolic transport of very long-chain fatty acids, branched-chain fatty acids like phytanic acid, the bile acid precursors di- and trihydroxycholestanoic acid, and long-chain dicarboxylic fatty acids into peroxisomes [31]. Catalase is a peroxisomal enzyme involved in the conversion of hydrogen peroxide produced from FAO into water and oxygen. SOD2 (superoxide dismutase 2) is a mitochondrial matrix protein involved in the conversion of superoxide into hydrogen peroxide [32]. Nox4 (NADPH oxidase 4), a constitutively active enzyme, is considered as a major source of oxidative stress in the heart [33–35]. The major finding of the study is that ATM deficiency in WD-fed female mice is associated with increased CPT1B and catalase, and decreased Nox4 expression. The cardioprotective effects of ATM deficiency in WD-fed female mice are abolished 1 day post-MI, which is associated with increased Nox4 expression.

Materials and Methods

Vertebrate animals, diets and experimental group:

This study followed the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85–23, revised 1996). All the animal protocols were approved by the East Tennessee State University Committee on Animal Care and Use prior to the start of the experiments. ATM-deficient mice (129S6/SvEvTac) were purchased from Jackson Laboratory (Strain#: 002753). Due to the limited lifespan (~ 2 months) of the ATM-knockout mice, heterozygous knockout (hKO) mice were used for breeding. Mice were genotyped by PCR using the primers suggested by Jackson Laboratory. Age-matched (~6 weeks old) WT and hKO male and female mice were fed with normal chow (NC; Envigo, 8604) or WD (Envigo, TD.88137) for 14 weeks as described previously [21]. The energy composition for NC is 32.0% kcal protein, 14.0% kcal fat, 54.0% kcal carbohydrate and 4.0% sucrose (by weight). The energy composition for WD is 15.2% kcal protein, 42.0% kcal fat, 42.7% kcal carbohydrate and 34.0% sucrose (by weight). After 14 weeks, myocardial tissue from a subset of animals was used for western blot analysis (n=3–4 per group), while another subset of WD-fed mice underwent MI. Heart function was measured in the same cohort of animals (n=10) prior to and post-MI. All mice had food and water available ad libitum, and were kept on a 12-hour light/12-hour dark cycle.

Myocardial infarction (MI):

MI was performed as previously described [36]. Briefly, mice were anesthetized using a mixture of isoflurane (2%) and oxygen (0.5 L/min) inhalation. During surgery, anesthesia was maintained using a mixture of isoflurane (1%) and oxygen (0.5 L/min). The mice were ventilated using a rodent ventilator (Harvard Apparatus) and body temperature was maintained at ~37°C using a heating pad during the surgery. After exposing the heart via left thoracotomy, the left anterior descending coronary artery (LCA) was ligated using a 7–0 polypropylene suture. Heart function was measured using echocardiography prior to and 1 day post-MI. The isolated heart was perfused with Krebs-Henseleit buffer to ensure blood clearance and arrested in diastole using 30 mM KCl. Heart tissue was used for biochemical assays.

Echocardiography:

The structural and functional parameters of the heart were measured with a Vevo 1100 imaging system (VisualSonics, Fujifilm) equipped with a 22- to 55-MHz MS550D transducer [21,22]. The M-mode recordings were obtained using the transthoracic short-axis view at the mid-papillary level view. These recordings were used to calculate percent ejection fraction (%EF) and fractional shortening (%FS) as previously described [21].

Western blot analysis:

Myocardial tissue lysates were prepared in RIPA buffer supplemented with Halt Protease Inhibitor Cocktail as described [21]. Equal amounts of proteins (30 or 50ug) were resolved by SDS-PAGE and transferred to PVDF membranes. The membranes were blocked with 5% non-fat dry milk for 1 hour at room temperature and incubated overnight at 4°C with primary antibodies against CPT1B (1:5000; Cat# PA5–79065, Invitrogen), ACOX1 (1:1000; Cat# GTX32989, GeneTex), Catalase (1:2000; Cat# ab209211, Abcam), SOD2 (1:500; Cat# sc-18504, Santa Cruz Biotechnology), Nox4 (1:1000; Cat# NB110–58849, Novus Biologicals), and PMP70 (1:1000; Cat# PA1–650, Invitrogen). The immune complexes were detected using corresponding secondary antibodies and chemiluminescent reagents. Western blot data were normalized to total protein using Pierce™ reversible protein stain kit (Cat# 24585, Thermo Fisher Scientific).

Statistical analysis:

All the data are expressed as means ± SE. Data were analyzed by one-way analysis of variance (ANOVA) followed by the Newman-Keuls test (GraphPad Prism 9). Probability (p) values of <0.05 considered to be significant. The number (n) represents biological replicates.

Results

Expression of proteins involved in fatty acid oxidation:

Western blot analyses showed that CPT1B protein levels were significantly higher in male hKO-NC versus WT-NC group. WD increased CPT1B protein levels in WT group. However, CPT1B expression was significantly lower in hKO-WD vs hKO-NC and WT-WD (Fig 1A). In female hearts, WD significantly increased CPT1B protein levels in WT and hKO groups vs their NC controls. However, CPT1B protein levels were significantly higher in hKO-WD vs WT-WD (Fig 1B).

Figure 1.

Figure 1.

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Expression of CPT1B. Heart lysates from male (A) and female (B) mice were analyzed by western blots using anti-CPT1B antibody. Upper panels exhibit immunostaining for CPT1B and total protein staining. Lower panels exhibit quantitative analyses normalized to total protein staining in each lane. *p<0.05 versus WT-NC, $p<0.05 versus hKO-NC, #p<0.05 versus WT-WD, n = 3–4.

Western blot analyses of heart lysates from male mice showed that ACOX1 protein levels are significantly lower in hKO-NC versus WT-NC group. WD decreased ACOX1 protein levels (~50% less) in WT group. However, no significant decrease of the ACOX1 protein levels was observed in hKO-WD versus hKO-NC (Fig 2A). In female hearts, no significant change of ACOX1 expression was observed among all four groups (Fig 2B).

Figure 2.

Figure 2.

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Expression of ACOX1. Heart lysates from male (A) and female (B) mice were analyzed by western blots using anti-ACOX1 antibody. Upper panels exhibit immunostaining for ACOX1 and total protein staining. Lower panels exhibit quantitative analyses normalized to total protein staining in each lane. *p<0.05 versus WT-NC, n = 3–4.

WD increased PMP70 protein levels in both genotypes and sexes versus their NC counterparts. However, the increase in PMP70 protein levels was significantly lower in male hKO-WD versus male WT-WD (Fig 3A&B).

Figure 3.

Figure 3.

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Expression of PMP70. Heart lysates from male (A) and female (B) were analyzed by western blots using anti-PMP70 antibody. Upper panels exhibit immunostaining for PMP70 and total protein staining. Lower panels exhibit quantitative analyses normalized to total protein staining in each lane. *p<0.05 versus WT-NC, $p<0.05 versus hKO-NC, #p<0.05 versus WT-WD, n = 3–4.

Expression of proteins associated with oxidative stress:

In male mice, WD increased catalase protein levels in both genotypes versus their NC counterparts with no significant difference between the two WD groups (Fig 4A). In female mice, WD increased catalase protein levels only in hKO group, and catalase protein levels were significantly higher in hKO-WD versus WT-WD (Fig 4B).

Figure 4.

Figure 4.

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Expression of catalase. Heart lysates from male (A) and female (B) mice were analyzed by western blots using anti-catalase antibody. Upper panels exhibit immunostaining for catalase and total protein staining. Lower panels exhibit quantitative analyses normalized to total protein staining in each lane. *p<0.05 versus WT-NC, $p<0.05 versus hKO-NC, #p<0.05 versus WT-WD, n = 3–4.

Western blot analyses showed no change in SOD2 protein levels in the myocardium of both genotypes and sexes on NC or WD (data not shown).

In male mice, Nox4 protein levels were significantly higher in hKO-NC versus WT-NC. WD decreased Nox4 protein levels in hKO group, and Nox4 protein levels were significantly lower in hKO-WD versus WT-WD (Fig 5A). In female mice, WD increased Nox4 protein levels in WT, not in hKO, and Nox4 protein levels were significantly lower in hKO-WD versus WT-WD (Fig 5B).

Figure 5.

Figure 5.

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Expression of Nox4. Heart lysates from male (A) and female (B) mice were analyzed by western blots using anti-Nox4 antibody. Upper panels exhibit immunostaining for Nox4 and total protein staining. Lower panels exhibit quantitative analyses normalized to total protein staining in each lane. *p<0.05 versus WT-NC, $p<0.05 versus hKO-NC, #p<0.05 versus WT-WD, n = 3–4.

Heart function post-MI:

As previously observed [21], there was no significant difference in %EF and %FS between male WT and hKO mice 14 weeks post-WD (Fig 6A&C). MI significantly decreased %EF and %FS to a similar extent in male WT and hKO groups. Consistent with the previous findings [22], %EF and %FS were significantly higher in female hKO-WD vs WT-WD group (Fig 6B&D). However, this increase in %EF and %FS was abolished in WD-fed ATM-deficient female mice and no significant difference in %EF and %FS was observed between hKO and WT female mice 1 day post-MI (Fig 6B&D).

Figure 6.

Figure 6.

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WD-induced changes in %EF and %FS of mice hearts. % Ejection fraction (%EF) and % fractional shortening (%FS) in male (A&C) and female (B&D) were calculated using M-mode echocardiography prior to and 1 day post-MI. αp<0.05 versus WT-WD-B, βp<0.05 versus hKO-WD-B, n=10; WT-WD-B, wild-type on Western-type diet prior to MI; hKO-WD-B, heterozygous knockout on Western-type diet prior to MI; WT-WD-MI, wild-type on Western-type diet 1 day post-MI; hKO-WD-MI, heterozygous knockout on Western-type diet 1 day post-MI.

Post-MI expression of proteins associated with FAO and oxidative stress:

Examination of the expression levels of proteins associated with FAO and oxidative stress using western blot analyses showed that MI significantly increases CPT1B protein levels in male hKO-WD-MI vs WT-WD-MI group (Fig 7A). In female mice, CPT1B protein levels were higher in WT and hKO groups versus their male counterparts. However, there was no significant change in CPT1B protein levels between female WT and hKO MI groups.

Figure 7.

Figure 7.

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Expression of CPT1B and catalase 1 day post-MI. Heart lysates from WD-fed (WT and hKO) male and female mice 1 day post-MI were analyzed by western blots using anti-CPT1B (A) and anti-catalase (B) antibodies. Upper panels exhibit immunostaining for CPT1B, catalase and total protein staining. Lower panels exhibit quantitative analyses normalized to total protein staining in each lane. δp<0.05 versus M-WT-WD-MI, θp<0.05 versus M-hKO-WD-MI, n = 3; M-WT-WD-MI, male wild-type on Western-type diet 1 day post-MI; M-hKO-WD-MI, male heterozygous knockout on Western-type diet 1 day post-MI; F-WT-WD-MI, female wild-type on Western-type diet 1 day post-MI; F-hKO-WD-MI, female heterozygous knockout on Western-type diet 1 day post-MI.

MI increased catalase protein levels in male hKO-WD-MI vs WT-WD-MI group (Fig 7B). Catalase protein levels were significantly lower in female hKO group (F-hKO-WD-MI) vs its male counterpart (M-hKO-WD-MI). However, there was no change in catalase protein levels between female WT and hKO groups post-MI. Conversely, Nox4 protein levels were found to be significantly higher in female hKO-WD vs female WT-WD and male hKO-WD post-MI (Fig 8).

Figure 8.

Figure 8.

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Expression of Nox4 1 day post-MI. Heart lysates from WD-fed (WT and hKO) male and female mice 1 day post-MI were analyzed by western blot using anti-Nox4 antibody. Upper panel exhibits immunostaining for Nox4 and total protein staining. Lower panel exhibits quantitative analyses normalized to total protein staining in each lane. θp<0.05 versus M-hKO-WD-MI, λp<0.05 versus F-WT-WD-MI, n = 3; M-WT-WD-MI, male wild-type on Western-type diet 1 day post-MI; M-hKO-WD-MI, male heterozygous knockout on Western-type diet 1 day post-MI; F-WT-WD-MI, female wild-type on Western-type diet 1 day post-MI; F-hKO-WD-MI, female heterozygous knockout on Western-type diet 1 day post-MI.

Discussion

The major findings of this study are that ATM deficiency in WD-fed female mice is associated with increased CPT1B and catalase expression, and decreased Nox4 expression in the heart prior to MI. However, MI abolishes the cardioprotective effects of ATM deficiency in WD-fed female mice. This abolishment of cardioprotective effect in WD-fed female ATM-deficient mice is associated with increased Nox4 expression. Collectively, these data provide evidence that increased mitochondrial FAO (as observed by increased CPT1B) and decreased oxidative stress (as observed by increased catalase and decreased Nox4) may contribute towards the previously observed cardioprotective effects in ATM-deficient female mice in response to WD [22], while increased oxidative stress (as observed by increased Nox4 expression) may contribute to the abolishment of cardioprotective effects of ATM deficiency in WD-fed female mice 1 day post-MI.

Balance between lipid uptake and FAO is important for heart function. Because of the Randle cycle, FAO is increased in response to WD [37]. FAO provides 60–90% of the total energy for the beating heart [5]. Mitochondria and peroxisomes are two major organelles for FAO in animal cells. Unlike passive diffusion of short- and medium-chain fatty acids (C≤12) into mitochondria, CPT system is required for long-chain fatty acids transport. CPT1 catalyzes the first rate-limiting step of lipid metabolism in which the long-chain acyl-CoA and carnitine are converted into long-chain acylcarnitine and CoA. The transesterified acylcarnitines are then transferred from cytosol into mitochondrial intermembrane space for further processing. The formation of transesterified acylcarnitine by CPT1 is essential as the inner mitochondrial membrane is impermeable to long-chain CoA fatty acids [38]. In a pressure overload mouse model, deficiency of CPT1B (a major isoform in the heart) is shown to be associated with exacerbation of heart function [39]. Here we observed that WD increases CPT1B protein levels in both male and female WT mice hearts versus their NC counterparts, suggesting increased long-chain fatty acid mitochondrial FAO in both sexes. However, deficiency of ATM differentially affected the expression of CPT1B protein levels in a sex-specific manner at basal levels and in response to WD. At basal levels, CPT1B protein levels were higher in male ATM-deficient group versus WT. In response to WD, CPT1B expression was lower in the myocardium of male ATM-deficient mice, while it was higher in the myocardium of female ATM-deficient mice versus their WT counterparts. These data suggest that the lipid uptake and mitochondrial FAO are compensated better in the myocardium of female ATM-deficient mice vs male ATM-deficient mice in response to WD.

Peroxisomes, membrane-bound organelle found in eukaryotic cells, catalyze a range of unique and essential metabolic reactions such as FAO, ether phospholipid biosynthesis and glyoxylate detoxification in which FAO is the most notable one [40,41]. Diverse metabolic processes are dependent on the concerted action of both mitochondria and peroxisomes [42]. The FAO of medium- (C6–12), long- (C14–20), very-long-chain (C≥22) and branched fatty acids can be initiated in peroxisomes followed by the complete catabolism and ATP production in mitochondria [25,43–45]. Metabolic transport of long-chain fatty acids across peroxisomal membranes is suggested to be carried out by PMP70. In Chinese hamster ovary (CHO) cells, increased expression of PMP70 enhanced palmitic acid (16:0) oxidation, while expression of mutated PMP70 decreased palmitic acid oxidation [28]. ACOX1 catalyzes the first step of very long-chain fatty acid β-oxidation in peroxisomes [26]. Here, WD increased PMP70 protein levels in both genotypes of both sexes. However, WD-mediated increase in PMP70 protein levels was significantly lower in male ATM-deficient hearts vs male WT hearts. In addition, we observed decreased protein levels of ACOX1 in the myocardium of male ATM-deficient mice at basal levels vs WT controls. WD led to a significant decrease in ACOX1 protein levels in male WT, not in hKO, hearts. Conversely, ACOX1 protein levels remained unchanged among all four female groups. Thus, peroxisomal FAO is also affected in a sex-specific manner at basal levels and in response to WD. A decrease in ACOX1 may suggest decreased peroxisomal FAO during ATM deficiency at basal levels and in response to WD in the male mice. Lower expression of PMP70 and ACOX1 in the myocardium of male ATM-deficient mice may negatively impact heart function as observed previously [21].

Increased mitochondrial and peroxisomal FAO in response to WD is generally associated with oxidative stress [46–48]. Catalase, a peroxisomal enzyme, is also shown to be present in the mitochondrial matrix of cardiac cells. High fat diet is shown to increase cardiac mitochondrial catalase content and activity in mice [49]. Nox4, primarily expressed in mitochondria of human and mouse cardiac myocytes, is suggested as a major source of oxidative stress in the heart through the production of Nox4-derived hydrogen peroxide [33–35]. In our study, WD increased catalase protein levels to a similar extent in the myocardium of male mice of both genotypes.

Conversely, WD-mediated increase in catalase protein levels was only observed in the myocardium of female ATM-deficient mice. On the other hand, WD-mediated increase in Nox4 protein levels was only observed in female WT hearts, and Nox4 protein levels were significantly lower in the myocardium of female ATM-deficient mice versus WT in response to WD. These data suggest that decreased oxidative stress due to increased catalase expression and decreased Nox4 expression may contribute to ATM deficiency-mediated cardioprotective effects in WD-fed female mice.

As shown previously [22], WD consumption during ATM deficiency is associated with cardioprotective effects in female mice. The data presented here show that heart function, as measured by %EF and %FS, was not significantly different 1 day post-MI among the two genotypes and sexes, suggesting that MI abolishes the cardioprotective effects of ATM deficiency in WD-fed female mice. MI increased expression of CPT1B and catalase in ATM-deficient WD-fed male hearts, while the expression of CPT1B and catalase did not differ significantly in the myocardium of WT and ATM-deficient WD-fed female mice post-MI. However, levels of Nox4 were significantly higher in the myocardium of WD-fed female ATM-deficient mice, suggesting that increased oxidative stress may contribute to the abolishment of the cardioprotective effects observed in WD-fed female ATM-deficient mice.

In summary, the data presented here in combination with our previous findings [21,22] suggest that increased mitochondrial FAO and decreased oxidative stress may contribute towards ATM deficiency-mediated cardioprotective effects in WD-fed female mice. The sex-specific cardioprotective effects of ATM deficiency in WD-fed female mice were negated 1 day post-MI. This negation of cardioprotective effects is associated with increased Nox4 expression, suggesting a role for increased oxidative stress. As highly dynamic and ubiquitous organelles in cells, the metabolic capabilities of peroxisomes are suggested to be dependent on the functional interaction with other organelles such as mitochondria and endoplasmic reticulum. The interaction with mitochondria is specifically important for the metabolism of end-products of peroxisomal β-oxidation [41,42,50,51]. Future investigations are needed to understand the functional dynamics between peroxisomes and mitochondria during ATM deficiency in WD-fed female mice prior to and post-MI.

Funding

This work was supported by Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development Merit Review award I01BX004045, National Institutes of Health (NHLBI) grant R15HL156214, and funds from the Institutional Research and Improvement account.

Footnotes

Disclosures

No conflicts of interest, financial or otherwise, are declared by the authors.

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