Contractile Function Is Regulated by Regulation of Pyruvate Supply

Objectives: While it was initially suggested that intramitochondrial calcium is a key player for regulation of metabolic activity, this concept has recently been questioned and regulation of pyruvate supply via regulation of the malate aspartate shuttle has been suggested as mechanism. We thus aimed to assess the effect of an inhibition of the malate-aspartate shuttle on cardiac power and metabolism in the isolated working rat heart.

Methods: Isolated rat hearts were perfused in the working mode with glucose or pyruvate as substrate. The malate aspartate shuttle was inhibited with aminooxyacetate (AOA) and pyruvate uptake into mitochondria with cinnamate. Cardiac power was determined in regular intervals and glucose uptake or glucose oxidation determined.

Result: In the isolated working heart with glucose as substrate, inhibition of the malate-aspartate shuttle led to a strong impairment in cardiac power with reduced glucose oxidation and increased glucose uptake. Glucose addition was not able to relieve this effect indicating substrate was not limiting. Instead, pyruvate addition re-established cardiac power. Glucose oxidation remained low as added pyruvate was used as substrate in this situation. Addition of cinnamate as inhibitor for mitochondrial pyruvate uptake reverted the effect of pyruvate addition, again leading to reduced cardiac power. Perfusion of the isolated heart with pyruvate as the only substrate, application of AOA had no effect on cardiac power, while cinnamate impaired contractility.

Conclusion: Our findings suggest that influencing pyruvate supply to the mitochondria (regulation of malate aspartate shuttle) is one of the key regulators of mitochondrial substrate consumption and ATP production.

Publication History

Article published online:
19 February 2021