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

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

Research output: Contribution to journalArticlepeer-review

Abstract

During ischemia, endogenous glycogen becomes the principal substrate for energy through glycolysis. Cardiac-specific manipulation of AMP-activated protein kinase (AMPK) by over-expression of its regulatory γ-subunit induces glycogen storage. The aim of this study was to examine whether heart glycogen in transgenic mice overexpressing PRKAG2 may protect from ischemia and reperfusion injury. Isolated hearts were mounted on Langendorff apparatus and subjected to 30 min 'no-flow' or 'low-flow' ischemia and 60 min reperfusion. Hemodynamic measurements, tetrazolium staining, glycogen and lactate were used to monitor ischemia reperfusion damage. After low-flow ischemia, left ventricular pressure, coronary flow (CF) and the area of viable myocardium were 20-30% higher in PRKAG2 mice compared to controls. The basal levels of glycogen in PRKAG2 were 9.2 μg/g, markedly higher than in controls, but after low-flow ischemia they declined concomitantly with increased lactate washout in the coronary effluent. During no-flow ischemia there was neither protection nor consumption of glycogen in PRKAG2 hearts. Cardioprotection was also eliminated when PRKAG2 hearts were depleted of glycogen prior to low-flow ischemia. AMPK α Thr172 phosphorylation did not differ between PRKAG2 hearts and controls either during low-flow ischemia or reperfusion. We conclude that PRKAG2 hearts resist low-flow ischemia injury better than controls. Improved recovery was associated with increased consumption of glycogen, and was unrelated to AMPK activation. These findings demonstrate the potential of heart protection from ischemia and reperfusion injury through metabolic manipulation increasing the level and utilization of myocardial glycogen.

Original languageEnglish
Pages (from-to)1482-1491
Number of pages10
JournalBiochemical Pharmacology
Volume75
Issue number7
DOIs
StatePublished - 1 Apr 2008
Externally publishedYes

Keywords

  • AMP-activated protein kinase
  • Glycogen
  • Ischemia reperfusion
  • Lactate
  • Low-flow ischemia
  • Myocardium

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