Increased glycogen stores due to γ-AMPK overexpression protects against ischemia and reperfusion damage

Ofir, Michal; Arad, Michael; Porat, Eyal E.; Freimark, Dov; Chepurko, Yelena; Vidne, Bernardo A.; Seidman, Christine E.; Seidman, Jonathan G.; Kemp, Bruce E.; Hochhauser, Edith

doi:10.1016/j.bcp.2007.12.011

Cited by 28 publications

(21 citation statements)

References 38 publications

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“…A mutation in human gene PRKAG2, encoding the ␥ 2 -subunit results in massive glycogen building and cardiac hypertrophy (1,15). Interestingly, overexpressing the PRKAG2 gene in mice protects against ischemia reperfusion damage, probably as an effect of increased consumption of glycogen and increased glycolysis during ischemia (44). The crucian carp has seasonal variation in the glycogen content in both heart and brain (65,66), and it is likely that these stores contribute to anoxic survival in addition to the large liver glycogen store (41).…”

Section: Discussionmentioning

confidence: 99%

Differential regulation of AMP-activated kinase and AKT kinase in response to oxygen availability in crucian carp (Carassius carassius)

Stensløkken

Ellefsen²,

Stecyk³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Stensløkken KO, Ellefsen S, Stecyk JAW, Dahl MB, Nilsson GE, Vaage J. Differential regulation of AMP-activated kinase and AKT kinase in response to oxygen availability in crucian carp (Carassius carassius). Am J Physiol Regul Integr Comp Physiol 295: R1803-R1814, 2008. First published October 15, 2008 doi:10.1152/ajpregu.90590.2008.-We investigated whether two kinases critical for survival during periods of energy deficiency in anoxia-intolerant mammalian species, AMP-activated kinase (AMPK), and protein kinase B (AKT), are equally important for hypoxic/anoxic survival in the extremely anoxia-tolerant crucian carp (Carassius carassius). We report that phosphorylation of AMPK and AKT in heart and brain showed small changes after 10 days of severe hypoxia (0.3 mg O 2/l at 9°C). In contrast, anoxia exposure (0.01 mg O2/l at 8°C) substantially increased AMPK phosphorylation but decreased AKT phosphorylation in carp heart and brain, indicating activation of AMPK and deactivation of AKT. In agreement, blocking the activity of AMPK in anoxic fish in vivo with 20 mg/kg Compound C resulted in an elevated metabolic rate (as indicated by increased ethanol production) and tended to reduce energy charge. This is the first in vivo experiment with Compound C in a nonmammalian vertebrate, and it appears that AMPK plays a role in mediating anoxic metabolic depression in crucian carp. Real-time RT-PCR analysis of the investigated AMPK subunit revealed that the most likely composition of subunits in the carp heart is ␣ 2, ␤1B, ␥2a, whereas a more even expression of subunits was found in the brain. In the heart, expression of the regulatory ␥ 2-subunit increased in the heart during anoxia. In the brain, expression of the ␣ 1-, ␣2-, and ␥1-subunits decreased with anoxia exposure, but expression of the ␥ 2-subunit remained constant. Combined, our findings suggest that AMPK and AKT may play important, but opposing roles for hypoxic/anoxic survival in the anoxia-tolerant crucian carp. metabolism; hypoxia; ATP; ADP; ethanol ANOXIA TOLERANCE IN VERTEBRATES is limited to a few species, the most extreme being the crucian carp (Carassius carassius) and the freshwater turtles (genera Trachemys, Chrysemys, and Chelydra). These ectothermic animals can survive for months without oxygen at temperatures near 0°C (43,50). A key to survival in prolonged anoxia is the successful matching of ATP demand to the limited ATP production from anaerobic glycolysis. The anoxia-tolerant species appear to have evolved different strategies to meet this challenge (32). The turtle is strongly metabolically depressed during anoxia, with a drastically suppressed rate of ATP-turnover. Anoxic Carassius also decreases metabolic rate, but to a more moderate extent (62).The anoxic carp also upregulates glycolysis to match ATP supply and demand (33), but has evolved a unique strategy of producing ethanol as the major end product of anaerobic glycolysis (56). Ethanol is released to the surrounding water to avoid severe acidosis (42), and liver glycogen content is likely...

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Section: Discussionmentioning

confidence: 99%

Differential regulation of AMP-activated kinase and AKT kinase in response to oxygen availability in crucian carp (Carassius carassius)

Stensløkken

Ellefsen²,

Stecyk³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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“…The cardioprotective effect of insulin is induced metabolically by optimizing cardiac metabolism [8, 9], and also nonmetabolically by promoting cardiomyocyte survival pathway [10, 11]. Insulin promotes cardiomyocyte survival by activation of Akt, phosphatidylinositol 3-kinase (PI3K), and p70s6 kinase [10, 12]. The PKB/Akt [13, 14] signaling pathway is implicated in inducing cardioprotection via an antiapoptotic effect [10, 15].…”

Section: Introductionmentioning

confidence: 99%

Insulin Preconditioning Elevates p-Akt and Cardiac Contractility after Reperfusion in the Isolated Ischemic Rat Heart

Sato

Oguchi

et al. 2014

BioMed Research International

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Insulin induces cardioprotection partly via an antiapoptotic effect. However, the optimal timing of insulin administration for the best quality cardioprotection remains unclear. We tested the hypothesis that insulin administered prior to ischemia provides better cardioprotection than insulin administration after ischemia. Isolated rat hearts were prepared using Langendorff method and divided into three groups. The Pre-Ins group (Pre-Ins) received 0.5 U/L insulin prior to 15 min no-flow ischemia for 20 min followed by 20 min of reperfusion. The Post-Ins group (Post-Ins) received 0.5 U/L insulin during the reperfusion period only. The control group (Control) was perfused with KH buffer throughout. The maximum of left ventricular derivative of pressure development (dP/dt(max)) was recorded continuously. Measurements of TNF-α and p-Akt in each time point were assayed by ELISA. After reperfusion, dP/dt(max) in Pre-Ins was elevated, compared with Post-Ins at 10 minutes after reperfusion and Control at all-time points. TNF-α levels at 5 minutes after reperfusion in the Pre-Ins were lower than the others. After 5 minutes of reperfusion, p-Akt was elevated in Pre-Ins compared with the other groups. Insulin administration prior to ischemia provides better cardioprotection than insulin administration only at reperfusion. TNF-α suppression is possibly mediated via p-Akt leading to a reduction in contractile myocardial dysfunction.

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“…Glycogen is markedly depleted during the process of euthanasia and heart extraction, and, to reestablish normal baseline rates of glycogen turnover and glucose metabolism, it must be replenished during baseline perfusion (34). Inasmuch as glycogenolysis is an important source of substrate for glycolysis and ATP generation during ischemia and can affect energy availability (33), as well as glucose uptake (34), hearts in all subsequent groups were perfused with Krebs-Henseleit solution containing 11 mmol/l glucose along with 1.2 mmol/l palmitate as energy substrates.…”

Section: Discussionmentioning

confidence: 99%

Role of glucose metabolism in the recovery of postischemic LV mechanical function: effects of insulin and other metabolic modulators

Gandhi

Finegan²,

Clanachan³

2008

American Journal of Physiology-Heart and Circulatory Physiology

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Increased glycogen stores due to γ-AMPK overexpression protects against ischemia and reperfusion damage

Cited by 28 publications

References 38 publications

Differential regulation of AMP-activated kinase and AKT kinase in response to oxygen availability in crucian carp (Carassius carassius)

Differential regulation of AMP-activated kinase and AKT kinase in response to oxygen availability in crucian carp (Carassius carassius)

Insulin Preconditioning Elevates p-Akt and Cardiac Contractility after Reperfusion in the Isolated Ischemic Rat Heart

Role of glucose metabolism in the recovery of postischemic LV mechanical function: effects of insulin and other metabolic modulators

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