Control of glycolysis in pathologic cardiac hypertrophy

Abstract

5′-AMP activated protein kinase (AMPK), whose activation by a low energy status due to impaired long-chain fatty acid oxidation, may be responsible for acceleration of glycolysis in pathologic cardiac hypertrophy. Therefore, we determined if enhanced fatty acid oxidation would improve energy status and normalize AMPK activity and glycolysis in hypertrophied hearts. Glycolysis, fatty acid oxidation, AMPK activity, and high energy phosphates were measured in isolated working hypertrophied (HYP) and control (CON) hearts from aortic-constricted and sham-operated male rats. Hearts were perfused with Krebs-Henseleit solution containing 5.5mM [5-3H]-glucose, 0.5mM lactate, 100mU/L insulin and either 1.2mM [1-14C]-palmitate (P) or a combination of [1-14C]-octanoate (1.2mM) and [9,10-3H]-palmitate (0.6mM) (O-P). Compared to CON, fatty acid oxidation was not different in HYP perfused with O-P but was ∼37 % lower in HYP perfused with P (p<0.05). Glycolysis was normalized in HYP by O-P perfusion and was accelerated ∼59 % in HYP perfused with P (p<0.05). AMPK activity, which was 70 % higher than CON in HYP perfused with P (P<0.05), no longer differed between CON and HYP perfused with O-P. Energy status did not differ between CON and HYP, although it was improved in hearts perfused with O-P. These findings are consistent with the view that activation of AMPK is responsible, at least in part, for the acceleration of glycolysis in pathologic cardiac hypertrophy. However, AMPK activation occurs in hypertrophied hearts occurs in the absence of measurable changes in energy status suggesting other mechanisms are responsible.