Ataxia telangiectasia mutated kinase is an autophagic balancer at the onset of heart failure

Ataxia telangiectasia syndrome represents a genetic disorder due to the absence or reduced levels of ataxia telangiectasia mutated kinase (ATM) activity. Patients exhibit a wide array of abnormalities, including ataxia, telangiectasia, neurodegeneration, increased sensitivity to ionizing radiation, predisposition to cancer, and variable immunodeficiencies. Ataxia telangiectasia occurs in 1 of 88,000–100,000 live births in the United States with the onset of symptoms in infancy (9). Telangiectasia appears between 2 and 8 yr of age. The median age at death is around 20 yr in homozygous mutation carriers, mostly caused by respiratory failure or cancer.

One the other hand, single heterozygosity is not rare and occurs in 0.5–2% of the general population (7). These patients have much milder clinical symptoms than the homozygote phenotype because of remaining ATM activity. It is likely that there are many individuals who are not even diagnosed as ATM mutation carriers until a later stage of life. Importantly, an epidemiological study (8) has now suggested that these individuals have a higher risk of ischemic heart disease compared with the general population. Thus, understanding the role of ATM in the development of ischemic heart disease is highly important.

ATM was initially thought to be associated with the DNA damage response and cell cycle checkpoint signaling, as the classical symptoms seen in patients with ataxia telangiectasia are consistent with defects in these pathways. Once ATM is recruited to the site of DNA damage, it facilitates with various chromatin remodeling enzymes, supporting the process of DNA repair, replication, and transcription. An important notion is that DNA replication does not normally occur in terminally differentiated cells such as cardiomyocytes. Cardiomyocytes are set apart from other cell types with their high energy requirement and limited regeneration potential. Because of these factors, a specific role of ATM may be different in cardiomyocytes compared with in other proliferating cells. More recent reports, however, have suggested that extranuclear effects of ATM might explain the prominent functions of ATM besides the well-established DNA damage response pathway. The additional functions potentially regulated by ATM include redox balance, mitochondrial biogenesis, and autophagy.

Despite all evidence, little is known about how the expression and function of this gene are modulated during the development of ischemic heart disease. The mRNA level of ATM is increased in patients with type 2 diabetes and coronary artery disease (1). Such an upregulation may be a part of responses to elevated DNA damage in the ischemic heart. Heterozygous mutations in ATM have been shown to be associated with higher mortality and earlier death from coronary artery disease (8). However, the question remains as to how ATM mutations lead to the formation of an aberrant cardiac response to myocardial infarction (MI).

In a recent article published in the American Journal of Physiology-Heart and Circulatory Physiology, Thrasher et al. (10) provide novel evidence demonstrating a blunted autophagic response at the onset of heart failure in heterozygous ATM-deficient animals. To take a closer look at the role of ATM in the cardiac response, the authors used a MI model, which is widely used in mice to induce ischemia and subsequent cell damage (6). With their present and previous studies (3–5, 10), the authors’ group has demonstrated that MI upregulates ATM protein expression levels in both noninfarct and infarct regions (3). ATM-deficient mice display altered left ventricular size parameters, disrupted cardiomyocyte morphology, and different effects on mechanical function in acute, subacute, and chronic phases post-MI (Table 1). ATM deficiency eventually ends up worsening cardiac function with increased fibrosis at the chronic phase (28 days) after MI (4). Although the decision of how to maintain function and cell survival seems dependent on the specific pathological process at each time point post-MI, several factors have been described to underlie the increased susceptibility to left ventricular remodeling in ATM-deficient animals. These include abnormal injury repair, reduced angiogenesis, and a delayed inflammatory response (3).

Table 1.

Cardiac phenotypes during or after myocardial infarction in ataxia telangiectasia mutated heterozygous knockout mice compared with wild-type control mice

		Time After Coronary Ligation
	Sham	4 h	1 day	3 days	7 days	28 days
Heart size
Heart weight/body weight	→	NA	→	→	→	→
Left ventricular end-diastolic volume or end-diastolic diameter	→	↓	↓	↓	↓	→
Left ventricular end-systolic volume or end-systolic diameter	→	↓	↓	↓	↓	↑
Mechanical function
Percent fractional shortening	→	→	↑	→	↑	↓
Cardiac cell conditions
Cross-sectional area	↑	NA	→	→	NA	↑
Apoptosis	→	NA	↑	↑	↑	↓
Autophagy	↑	↓	NA	NA	NA	NA
Myocardial fibrosis	↑	NA	NA	↑	↑	↑
Reference(s)	3, 4, 5, 10	10	3	3	5	4

↑, increase; ↓, decrease; →, unchanged; NA, no data available.

Thrasher et al. (10) have further added the effects of ATM deletion on autophagy in cardiomyocytes. By characterizing cardiac expression from ATM-deficient mice, the authors showed a decreased level of microtubule-associated protein 1A/1B-light chain (LC)3-II and an increased number of aggresomes (aggregates of misfolded proteins) during MI, accompanied by inactivation of AMP-activated protein kinase (AMPK) and activation of the mammalian target of rapamycin (mTOR) compared with wild-type mice. These results suggest that loss of ATM leads to an impaired autophagic response to ongoing MI, by blocking a signaling cascade from ATM to mTOR via AMPK. Autophagy is the catabolic process responsible for the selective removal of cytoplasmic components to maintain intracellular homeostasis. A recent study (2) has suggested that ATM sustains an autophagic pathway by inhibiting the negative regulator mTOR complex 1 (mTORC1). Reactive oxygen species initiate signaling from ATM to AMPK to suppress activity of mTORC1 to maintain homeostasis of organelles by activating autophagy (2). In this scenario, it is reasonable to hypothesize that ATM sustains autophagy under ischemic insults as a protective mechanism for the functions of cardiomyocytes by clearing dysfunctional organelles. ATM helps the redox balance through autophagy-associated peroxisome degradation. Thus, diminishing the autophagic response in ATM-deficient cardiomyocytes may augment oxidative stress. As a result, the higher levels of reactive oxygen species may cause nuclear and mitochondrial DNA damages, leading to higher levels of apoptotic cells in ATM-deficient hearts (Table 1).

The phenotype raises two questions. First, why does the different timing after MI affect cardiac function and cardiomyocyte survival in different ways (3–5, 10)? For instance, the percentage of fractional shortening increases at 1 and 7 days post-MI but decreases at 28 days post-MI in ATM-deficient mice compared with wild-type control mice. Part of the answer to this lies in the fact that the extracellular environment of different time points of MI can vary. In particular, the functionality of the inflammatory response may be crucial for the maintenance of cardiomyocyte homeostasis and protection. Systemic immunodeficiency is one of common pathological findings in ATM deficiency. A change in the infiltration of neutrophils may contribute to the different extracellular environment in ATM-deficient hearts throughout the post-MI time course (3). The second question is whether ATM has tasks in cardioprotection either related to or apart from DNA repair. ATM plays a central role in the DNA damage response and, as such, should be important in the pathogenesis of heart failure. This question was not addressed in this report. But, as a secondary effect of DNA damage response induction, ATM may turn on mitochondrial biogenesis by activating AMPK and thus protect cardiomyocytes with mitochondrial dysfunction from cell death. Other possible underlying mechanisms in ATM-deficient hearts may include stem cell exhaustion, cellular senescence, and epigenetic alterations, all of which have already been determined as caused by ATM deficiency in other pathological contexts. Despite these mixed findings and perspectives, ATM clearly modulates the left ventricular remodeling processes after MI in acute and chronic phases.

Finally, we need to be careful that, while many aberrations of human ataxia telangiectasia can be observed in mouse ATM knockout models, the cardiovascular findings in these animals may not always reflect the phenotype of human disease. However, because of its rarity of mutation carriers, performing robust clinical studies on ataxia telangiectasia is very challenging. The recent advancement of patient-specific induced pluripotent stem cells may offer a great opportunity to gain insights into the genetic basis of ataxia telangiectasia. We anticipate that the availability of cardiomyocytes from human induced pluripotent stem cells from patients with ataxia telangiectasia will provide further understanding of the complex network of ATM signaling pathways under various types of myocardial stress.

In conclusion, a series of studies by Singh and colleagues (3–5, 10) has demonstrated a cardiac phenotype in the ATM-deficient mouse model that might reflect the clinical course of cardiac damage in ataxia telangiectasia. These studies highlight the interplay between ATM and cardiomyocyte survival and how tightly they are balanced to orchestrate the response to ischemic stress. Identification of ATM as a critical molecule of the autophagic response sheds light on a new molecular pathway that involves the cascade of cardiac adaptation after MI. Nevertheless, further studies are required to ascertain the molecular mechanisms by which ATM modulates myocardial homeostasis in the development of heart failure.

GRANTS

This work was supported by awards from the Philip V. & Anna S. Brown Foundation, the LaRue S. Fisher and Walter F. Fisher Memorial Trust, and Bank of America, N.A., Trustee, and by National Heart, Lung, and Blood Institute Grant 1-R01-HL-130861 (to J. Yoshioka).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author(s).

AUTHOR CONTRIBUTIONS

J.Y. conceived and designed research; J.Y. analyzed data; J.Y. interpreted results of experiments; J.Y. drafted manuscript; J.Y. edited and revised manuscript; J.Y. approved final version of manuscript.