Anaplerosis of the citric acid cycle: role in energy metabolism of heart and skeletal muscle

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Abstract
Efficient energy transfer in heart and skeletal muscle requires a series of moiety‐conserved cycles. The intermediaries of the metabolic cycles are finely regulated to maintain a dynamic state of equilibrium. In heart muscle, depletion of the citric acid cycle (TCA cycle) through a block of 2‐oxoglutarate dehydrogenase results in a rapid decline of contractile function, which is reversed by the addition of substrates promoting flux through the carboxylating enzymes, malic enzyme, pyruvate carboxylase and propionyl‐CoA carboxylase. Anaplerosis describes a pathway, which replenishes a metabolic cycle. We show that enzymes for anaplerosis of the TCA cycle are expressed in heart and skeletal muscles. The role of anaplerosis of the TCA cycle in skeletal muscle is not entirely clear, but there is substantial evidence for its operational control during exercise. While the anaplerotic flux of carbon into the TCA cycle exceeds the removal of cycle intermediates, this process is only transient and reverses with prolonged exercise. It remains to be determined, however, whether the initial increase in TCA cycle intermediates is obligatory in order to attain high rates of TCA cycle flux, or primarily reflects a mass action phenomenon owing to increased substrate availability for anaplerotic pathways.