Glycolysis in heart failure: a31P-NMR and surface fluorometry study

Abstract

Glycolysis is slow in the heart, especially in the cardiomyopathic heart. Glycolysis is partially rate-limited by phosphofructokinase (PFK), an enzyme which is inhibited by calcium (Ca2+)i and hydrogen ions (H+)i and activated by cAMP. (H+)i and (Ca2+)i are augmented in cardiomyopathy. With glucose as the only substrate (NADH)/(NAD) the phosphorylation potential and developed pressure were significantly lower, and concentrations of phosphomonoester sugars and hydrogen ions (H+)i were significantly higher in isolated cardiomyopathic hearts as compared to healthy hamster hearts. Pyruvate lowered diastolic (Ca2+)i in cardiomyopathic hamster hearts. With pyruvate as the substrate (NADH)/(NAD), the phosphorylation potential and developed pressure increased significantly and concentrations of phosphomonoester sugars (PME), (H+)i and diastolic (Ca2+)i decreased significantly in myopathic hamster hearts. The results suggest that late heart failure in the myopathic hamster is associated with calcium and/or hydrogen ion-induced inhibition of glycolysis.

Excitation-contraction coupling and mitochondrial energetics

“…Diastolic force development, however, is occurring at the same energy expenditure as systolic force generation in human failing myocardium [132]. If indeed, higher energy consumption and, thus, ATP hydrolysis occurs in failing myocardium, but with an insufficient compensatory increase of NADH production by the TCA cycle, this may explain the pronounced oxidation of the NADH-pool in failing hearts [4], which may eventually result in a mismatch between ATP supply and demand. It has been suggested that such a mismatch precedes the reduction in the total cellular levels of PCr in patients with heart failure [11,99,188].…”

“…Thus, both the reduced amplitude of cytosolic Ca 2+ transients [59] and elevated [Na + ] i [117] may hamper Ca 2+ -activation of TCA cycle enzymes in heart failure. Furthermore, glycolysis and, thus, the availability of pyruvate as a substrate for the TCA cycle was reduced in myopathic compared to control hamsters, resulting in more oxidized NADH and decreased phosphorylation potential and developed LV pressure [4]. Application of pyruvate in this model improved both energetic and hemodynamic parameters [4].…”

“…Furthermore, glycolysis and, thus, the availability of pyruvate as a substrate for the TCA cycle was reduced in myopathic compared to control hamsters, resulting in more oxidized NADH and decreased phosphorylation potential and developed LV pressure [4]. Application of pyruvate in this model improved both energetic and hemodynamic parameters [4]. Accordingly, application of pyruvate to human heart failure patients in vivo increased LV systolic and diastolic function [87,88], which was related to an increase of SR Ca 2+ load and thus, cytosolic Ca 2+ transient amplitude in vitro [82,89].…”

“…1), driven by the large electrochemical gradient for Ca 2+ across the inner mitochondrial membrane (Δψ m ∼ −180 mV). From experiments on suspensions of isolated mitochondria, a half-maximal activation constant (K 0.5 ) of ∼10-20 µM Ca 2+ was calculated for mCU-mediated Ca 2+ transport, yielding a maximum Ca 2+ flux (V max ) of approximately 2·10 4 Ca 2+ s −1 for a single mCU molecule [76,77]. The mCU is inhibited by ruthenium red [124,138,157] or Ru360 [109,117,124], with the latter being more mCUselective than ruthenium red [124], which also inhibits SR Ca 2+ release via RyR2 [35].…”

Failing energetics in failing hearts

“…In fact, the availability of different substrates has a profound influence on the function of the diseased myocardium [13]. Supplying energy substrates, such as pyruvate, to the failing myocardium markedly improves contractile performance [24]. Also, enhanced glycolysis within cardiomyocytes increases the supply of substrates to mitochondria and promotes ATP production [25].…”