Cardiac glycolytic rates is altered under many pathological conditions, although the mechanism(s) responsible for these changes in glycolysis is not completely clear. Since cardiac hyperacetylation also occurs under many pathological conditions, we determined if glycolytic enzyme lysine acetylation can regulate cardiac glycolysis rates. The effects of modifying cardiac acetylation on glycolysis was examined in isolated working rat hearts and H9c2 cardiomyocytes using SIRT2 inhibition (AGK2 or siRNA knockdown), SIRT1 inhibition (EX-527), pan-sirtuin inhibition (NAM), or acetyltransferase inhibition (C646). Glycolysis rates were directly measured in hearts or cardiomyocytes perfused with 5 mM glucose and 0.8 mM palmitate, using radiolabeled 5- 3 H glucose. SIRT2 inhibition significantly decreased glycolysis rates in isolated working rat hearts compared to controls (1844±153 vs 2753±236 nmol.g dry wt -1 .min -1 , p<0.05) with no significant effect on glucose oxidation rates. In H9c2 cardiomyocytes, both SIRT2 inhibition and knockdown reduced glycolysis rates compared to controls (524±108 vs 2631±372 and 745±31 vs 1659±168 nmol.mg protien -1 .hr -1 , p<0.05, respectively). This decrease in glycolysis was accompanied by increased acetylation of glycolytic enzymes, including glyceraldehyde phosphate dehydrogenase (GAPDH) and phosphoglycerate mutase (PGAM), without changes in global acetylation patterns. SIRT2 inhibition or knockdown did not affect the phosphorylation status of insulin signaling proteins. However, SIRT2 inhibition did attenuate the phenylephrine-mediated hypertrophic response in H9c2 cells. We conclude that SIRT2 inhibition increases the acetylation of cardiac glycolytic enzymes and decreases glycolysis rates, suggesting that post-translational acetylation is an important pathway regulating cardiac glycolysis.
Ketema et al. (Mon,) studied this question.