Ischemia-induced activation of AMPK does not increase glucose uptake in glycogen-replete isolated working rat hearts.
Alterations in myocardial glucose metabolism are a key determinant of ischemia-induced depression of left ventricular mechanical function. Since myocardial glycogen is an important source of endogenous glucose, we compared the effects of ischemia on glucose uptake and utilization in isolated working rat hearts in which glycogen content was either replete (G replete, 114 micromol/g dry wt) or partially depleted (G depleted, 71 mumol/g dry wt). The effects of low-flow ischemia (LFI, 0.5 ml/min) on glucose uptake, glycogen turnover (glycogenolysis and glycogen synthesis), glycolysis, adenosine 5'-monophosphate-activated protein kinase (AMPK) activity, and GLUT4 translocation were measured. Relative to preischemic values, LFI caused a time-dependent reduction in glycogen content in both G-replete and G-depleted groups due to an acceleration of glycogenolysis (by 12-fold and 6-fold, respectively). In G-replete hearts, LFI (15 min) decreased glucose uptake (by 59%) and did not affect GLUT4 translocation. In G-depleted hearts, LFI also decreased initially glucose uptake (by 90%) and glycogen synthesis, but after 15 min, when glycogenolysis slowed due to exhaustion of glycogen content, glucose uptake increased (by 31%) in association with an increase in GLUT4 translocation. After 60 min of LFI, glucose uptake, glycogenolysis, and glycolysis recovered to near-preischemic values in both groups. LFI increased AMPK activity in a time-dependent manner in both groups (by 6-fold and 4-fold, respectively). Thus, when glycogen stores are replete before ischemia, ischemia-induced AMPK activation is not sufficient to increase glucose uptake. Under these conditions, an acceleration of glycogen degradation provides sufficient endogenous substrate for glycolysis during ischemia.
Omar
Mohamed A
MA
Department of Pharmacology, Faculty of Medicine and Dentistry, Univ. of Alberta, Edmonton, Alberta, T6G 2H7, Canada.
Fraser
Heather
H
Clanachan
Alexander S
AS
D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000332:Aerobiosis; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003401:Creatine / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D004734:Energy Metabolism / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology; D008297:Male; D017202:Myocardial Ischemia / Q000201:enzymology*; D009206:Myocardium / Q000378:metabolism*; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism; D016277:Ventricular Function, Left / Q000502:physiology
D005227:Fatty Acids; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; D010725:Phosphocreatine; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D006003:Glycogen; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose; D003401:Creatine