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Metabolic Shifts during Aging and Pathology

Yina Ma, Ji Li

10.1002/cphy.c140041

Source: Volume 5, Issue 2, April 2015

Published online: March 2015

Full Article on Wiley Online Library



ABSTRACT

The heart is a very special organ in the body and has a high requirement for metabolism due to its constant workload. As a consequence, to provide a consistent and sufficient energy a high steady‐state demand of metabolism is required by the heart. When delicately balanced mechanisms are changed by physiological or pathophysiological conditions, the whole system's homeostasis will be altered to a new balance, which contributes to the pathologic process. So it is no wonder that almost every heart disease is related to metabolic shift. Furthermore, aging is also found to be related to the reduction in mitochondrial function, insulin resistance, and dysregulated intracellular lipid metabolism. Adenosine monophosphate‐activated protein kinase (AMPK) functions as an energy sensor to detect intracellular ATP/AMP ratio and plays a pivotal role in intracellular adaptation to energy stress. During different pathology (like myocardial ischemia and hypertension), the activation of cardiac AMPK appears to be essential for repairing cardiomyocyte's function by accelerating ATP generation, attenuating ATP depletion, and protecting the myocardium against cardiac dysfunction and apoptosis. In this overview, we will talk about the normal heart's metabolism, how metabolic shifts during aging and different pathologies, and how AMPK regulates metabolic changes during these conditions. © 2015 American Physiological Society. Compr Physiol 5:667‐686, 2015.

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Figure 1. Figure 1. Schematic diagram illustrates the metabolism of glucose and fatty acid in cardiomyocyte. G‐6‐P, glucose 6‐phosphorylase; CPT‐1, carnitine palmitoyl transferae I; TAC, tricarboxylic acid cycle.
Figure 2. Figure 2. APC reduces myocardial infarct size after ischemia/reperfusion. Hearts were subjected to 20 min ischemia followed by 3 h reperfusion. APC derivatives or saline (control) were administered via the tail vein 5 min before reperfusion. (A) Representative sections of myocardial infarction. (B) The ratio of area at risk (AAR) to myocardial area (left panel) and the ratio of infarct area to AAR (right panel) in mouse hearts of different treatment groups. Values are means ± standard error for four independent experiments. *P < 0.01 versus saline, respectively. Adapted with permission from Wang et al., 2011, ref 162.
Figure 3. Figure 3. APC stimulates AMPK activation. (A) In vivo regional ischemia stimulates phosphorylation of AMPK as shown by immunoblots. Values are means ± S.E., n = 3. *p < 0.05 vs. Sham. (B) Both APC and 2Cys but not E170A trigger AMPK and ACC phosphorylation during reperfusion. (C) and (D) Activation of AMPKα1 and AMPKα2 in the same heart samples as assessed by a kinase assay. Values are means ± standard error, n = 4‐6. *p < 0.05 vs. Sham saline; †p < 0.05 vs. I/R saline. Adapted with permission, from Wang et al., 2011, ref 162.
Figure 4. Figure 4. APC increases glucose uptake during ischemia/reperfusion (I/R). (A) APC modulates glucose transporter type 4 (GLUT4) translocation to the membrane. Immunoblotting analysis of cell membrane‐bound and total GLUT4 in the heart tissues. (B) C57BL/6 mouse hearts were isolated and perfused with d‐[2‐3H] glucose‐labeled perfusion buffer in the ex vivo working heart perfused system. Isolated hearts were subjected to 10 min of global ischemia followed by 20 min of reperfusion. Values are means ± standard error, n = 6 per group, *P < 0.05 versus control, †P < 0.05 versus I/R vehicle. RLU, relative light units. Adapted with permission from Costa et al., 2011, ref 23.
Figure 5. Figure 5. APC augments glucose oxidation in the heart during ischemia/reperfusion (I/R). Glucose oxidation was analyzed by measuring [14C]glucose incorporation into 14CO2 in ex vivo C57BL/6 mouse hearts subjected to 10 min of ischemia and 20 min of reperfusion. Oleate oxidation was analyzed by measuring the incorporation of [9,10‐3H]oleate into 3H2O. Values are means ± standard error, n = 5‐6 per group, *P < 0.05 versus control, †P < 0.05 versus I/R vehicle, #P < 0.01 versus I/R APC. PC‐2Cys, protein C‐2Cys. Adapted with permission, from Costa et al., 2011, ref 23.
Figure 6. Figure 6. APC‐2Cys improves intracellular redox status in the heart during ischemia/reperfusion (I/R). GSH/GSSG ratios were measured with a glutathione detection kit. Values are means ± standard error, n = 11 per group, *P < 0.01 vs. control, †P < 0.01 vs. I/R vehicle. RLU, relative light units. Adapted with permission, from Costa et al., 2011.
Figure 7. Figure 7. Schematic diagram illustrates how AMPK activator administrated during I/R could limit the ROS damage brought by fatty acid oxidation. TAC, tricarboxylic acid cycle; ROS, reactive oxygen species.


Figure 1. Schematic diagram illustrates the metabolism of glucose and fatty acid in cardiomyocyte. G‐6‐P, glucose 6‐phosphorylase; CPT‐1, carnitine palmitoyl transferae I; TAC, tricarboxylic acid cycle.


Figure 2. APC reduces myocardial infarct size after ischemia/reperfusion. Hearts were subjected to 20 min ischemia followed by 3 h reperfusion. APC derivatives or saline (control) were administered via the tail vein 5 min before reperfusion. (A) Representative sections of myocardial infarction. (B) The ratio of area at risk (AAR) to myocardial area (left panel) and the ratio of infarct area to AAR (right panel) in mouse hearts of different treatment groups. Values are means ± standard error for four independent experiments. *P < 0.01 versus saline, respectively. Adapted with permission from Wang et al., 2011, ref 162.


Figure 3. APC stimulates AMPK activation. (A) In vivo regional ischemia stimulates phosphorylation of AMPK as shown by immunoblots. Values are means ± S.E., n = 3. *p < 0.05 vs. Sham. (B) Both APC and 2Cys but not E170A trigger AMPK and ACC phosphorylation during reperfusion. (C) and (D) Activation of AMPKα1 and AMPKα2 in the same heart samples as assessed by a kinase assay. Values are means ± standard error, n = 4‐6. *p < 0.05 vs. Sham saline; †p < 0.05 vs. I/R saline. Adapted with permission, from Wang et al., 2011, ref 162.


Figure 4. APC increases glucose uptake during ischemia/reperfusion (I/R). (A) APC modulates glucose transporter type 4 (GLUT4) translocation to the membrane. Immunoblotting analysis of cell membrane‐bound and total GLUT4 in the heart tissues. (B) C57BL/6 mouse hearts were isolated and perfused with d‐[2‐3H] glucose‐labeled perfusion buffer in the ex vivo working heart perfused system. Isolated hearts were subjected to 10 min of global ischemia followed by 20 min of reperfusion. Values are means ± standard error, n = 6 per group, *P < 0.05 versus control, †P < 0.05 versus I/R vehicle. RLU, relative light units. Adapted with permission from Costa et al., 2011, ref 23.


Figure 5. APC augments glucose oxidation in the heart during ischemia/reperfusion (I/R). Glucose oxidation was analyzed by measuring [14C]glucose incorporation into 14CO2 in ex vivo C57BL/6 mouse hearts subjected to 10 min of ischemia and 20 min of reperfusion. Oleate oxidation was analyzed by measuring the incorporation of [9,10‐3H]oleate into 3H2O. Values are means ± standard error, n = 5‐6 per group, *P < 0.05 versus control, †P < 0.05 versus I/R vehicle, #P < 0.01 versus I/R APC. PC‐2Cys, protein C‐2Cys. Adapted with permission, from Costa et al., 2011, ref 23.


Figure 6. APC‐2Cys improves intracellular redox status in the heart during ischemia/reperfusion (I/R). GSH/GSSG ratios were measured with a glutathione detection kit. Values are means ± standard error, n = 11 per group, *P < 0.01 vs. control, †P < 0.01 vs. I/R vehicle. RLU, relative light units. Adapted with permission, from Costa et al., 2011.


Figure 7. Schematic diagram illustrates how AMPK activator administrated during I/R could limit the ROS damage brought by fatty acid oxidation. TAC, tricarboxylic acid cycle; ROS, reactive oxygen species.
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Further Reading

Katz, Arnold M. Physiology of the Heart. Lippincott Williams & Wilkins, 2010.

Opie, Lionel H., Editor. Heart Physiology: From Cell to Circulation. Lippincott Williams & Wilkins, 2004.


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Article Title: Metabolic Shifts during Aging and Pathology
 

How to Cite

Yina Ma, Ji Li. Metabolic Shifts during Aging and Pathology. Compr Physiol 2015, 5: 667-686. doi: 10.1002/cphy.c140041