Abstract
BackgroundA computational model of myocardial energy metabolism was used to assess the metabolic responses to normal and reduced myocardial blood flow. The goal was to examine to what extent glycolysis and lactate formation are controlled by the supply of glycolytic substrate and/or the cellular redox (NADH/NAD+) and phosphorylation (ATP/ADP) states.MethodsFlow was reduced over a wide range and for a sufficient duration in order to investigate the sequence of events that occur during the transition to a new metabolic steady state.ResultsSimulation results indicated multiple time-dependent controls over both glycolysis and lactate formation.ConclusionsChanges in phosphorylation state and glucose uptake only significantly affect the initial phase of the glycolytic response to ischemia, while glycogen breakdown exerts control over glycolysis during the entire duration of ischemia. Similarly, changes in the redox state affect the rates of lactate formation and release primarily during the initial transient phase of the response to the reductions in blood flow, while the rate of glycolysis controls the rate of lactate formation throughout the entire period of adaptation.
Highlights
A computational model of myocardial energy metabolism was used to assess the metabolic responses to normal and reduced myocardial blood flow
The primary effect of reduced myocardial blood flow is a decrease in the rate of aerobic ATP resynthesis, an increase in the cellular redox state (NADH/NAD+), acceleration of glycogenolysis and glycolysis, accumulation of lactate, and a switch from net lactate uptake to net lactate release by the myocardium
O2 delivery to the myocardium determines the rate of oxidative phosphorylation, which sets the cellular NADH/NAD+ and ATP/ADP ratios, both of which control the rate of glycolysis and lactate formation [10]
Summary
A computational model of myocardial energy metabolism was used to assess the metabolic responses to normal and reduced myocardial blood flow. The goal was to examine to what extent glycolysis and lactate formation are controlled by the supply of glycolytic substrate and/or the cellular redox (NADH/NAD+) and phosphorylation (ATP/ADP) states. The primary effect of reduced myocardial blood flow is a decrease in the rate of aerobic ATP resynthesis, an increase in the cellular redox state (NADH/NAD+), acceleration of glycogenolysis and glycolysis, accumulation of lactate, and a switch from net lactate uptake to net lactate release by the myocardium. Glucose uptake increases during moderate ischemia, but decreases in severely ischemic myocardium due to limited glucose delivery [7,8], causing a greater reliance on glycogen for glycolytic substrate. O2 delivery to the myocardium determines the rate of oxidative phosphorylation, which sets the cellular NADH/NAD+ and ATP/ADP ratios, both of which control the rate of glycolysis and lactate formation [10]. Ischemia results in impaired oxidative (page number not for citation purposes)
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