Ataxia-telangiectasia mutated kinase (ATM), a serine/threonine kinase primarily located in the nucleus, is typically activated in response to DNA damage. Individuals with mutations in ATM gene develop a disease called Ataxia telangiectasia (AT). These individuals are more susceptible to ischemic heart disease and metabolic disorder. Our lab has previously shown that ATM plays a critical role in β-adrenergic receptor (β-AR) - and myocardial infarction (MI)-stimulated myocyte apoptosis and cardiac remodeling. This study tested the hypothesis that ATM plays a critical role in cardiac autophagy and glucose metabolism following MI and ischemia, respectively. Early during MI (4 hours after its onset) and 4 hours post-treatment with ATM inhibitor KU-55933, ATM deficiency resulted in autophagic impairment in the heart and in cardiac fibroblasts, respectively. Such autophagic changes in the heart and in cardiac fibroblasts associated with the activation of GSK-3β and mTOR, and inactivation of Akt and AMPK. ATM deficiency also augmented autophagy in the infarct region of the heart 28 days post-MI as well as in cardiac fibroblasts treated with ATM inhibitor KU-55933 for 24 hours. Autophagic changes in the infarct region during ATM deficiency associated with enhanced Akt, Erk1/2, and mTOR activation. Additionally, the lack of ATM accelerated glycolysis and gluconeogenesis and augmented TCA cycle metabolism under non-ischemic conditions. Following a 20 minute global ischemic period, the glycolytic pathway, not the gluconeogenic pathway, was down-regulated during ATM deficiency which was found to be associated with alterations in TCA cycle metabolism. Such metabolic rearrangements associated with changes in the phosphorylation of Akt, GSK-3β, and AMPK alongside alterations in Glut4 protein expression. Thus, ATM deficiency impairs autophagy early after the onset of MI and in cardiac fibroblasts treated with ATM inhibitor KU-55933 for 4 hours. In contrast, ATM deficiency appears to augment autophagy late post-MI in the infarct region of the heart and in cardiac fibroblasts treated with ATM inhibitor KU-55933 for 24 hours. Lack of ATM alters glucose and TCA cycle metabolism with and without ischemia. Such findings implicate ATM as a key player in autophagic changes in the heart in response to MI as well as in glucose metabolism under non-ischemic and ischemic conditions.
| Identifer | oai:union.ndltd.org:ETSU/oai:dc.etsu.edu:etd-4892 |
| Date | 01 August 2018 |
| Creators | Thrasher, Patsy |
| Publisher | Digital Commons @ East Tennessee State University |
| Source Sets | East Tennessee State University |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Electronic Theses and Dissertations |
| Rights | Copyright by the authors. |
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