Journal
CIRCULATION-HEART FAILURE
Volume 6, Issue 5, Pages 1058-1066Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCHEARTFAILURE.112.000342
Keywords
acute metabolic changes; fatty acid metabolism; glucose metabolism; ischemia reperfusion
Categories
Funding
- Diabetes UK [11/0004175]
- British Heart Foundation [RG/07/004/22659]
- British Council
- Platform Beta Techniek
- BBSRC [BB/H013539/2] Funding Source: UKRI
- MRC [MC_UP_A090_1006] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/H013539/2] Funding Source: researchfish
- British Heart Foundation [PS/02/002/14893, RG/07/004/22659] Funding Source: researchfish
- Diabetes UK [11/0004175] Funding Source: researchfish
- Medical Research Council [MC_UP_A090_1006] Funding Source: researchfish
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Background Fatty acid and glucose transporters translocate between the sarcolemma and intracellular compartments to regulate substrate metabolism acutely. We hypothesised that during ischemia fatty acid translocase (FAT/CD36) would translocate away from the sarcolemma to limit fatty acid uptake when fatty acid oxidation is inhibited. Methods and Results Wistar rat hearts were perfused during preischemia, low-flow ischemia, and reperfusion, using H-3-substrates for measurement of metabolic rates, followed by metabolomic analysis and subcellular fractionation. During ischemia, there was a 32% decrease in sarcolemmal FAT/CD36 accompanied by a 95% decrease in fatty acid oxidation rates, with no change in intramyocardial lipids. Concomitantly, the sarcolemmal content of the glucose transporter, GLUT4, increased by 90% during ischemia, associated with an 86% increase in glycolytic rates, 45% decrease in glycogen content, and a 3-fold increase in phosphorylated AMP-activated protein kinase. Following reperfusion, decreased sarcolemmal FAT/CD36 persisted, but fatty acid oxidation rates returned to preischemic levels, resulting in a 35% decrease in myocardial triglyceride content. Elevated sarcolemmal GLUT4 persisted during reperfusion; in contrast, glycolytic rates decreased to 30% of preischemic rates, accompanied by a 5-fold increase in intracellular citrate levels and restoration of glycogen content. Conclusions During ischemia, FAT/CD36 moved away from the sarcolemma as GLUT4 moved toward the sarcolemma, associated with a shift from fatty acid oxidation to glycolysis, while intramyocardial lipid accumulation was prevented. This relocation was maintained during reperfusion, which was associated with replenishing glycogen stores as a priority, occurring at the expense of glycolysis and mediated by an increase in citrate levels.
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