Rethinking cardiac metabolism: metabolic cycles to refuel and rebuild the failing heart

Abstract

The heart is a self-renewing biological pump that converts chemical energy into mechanical energy. The entire process of energy conversion is subject to complex regulation at the transcriptional, translational and post-translational levels. Within this system, energy transfer occurs with high efficiency, facilitated by a series of compound-conserved cycles. At the same time, the constituent myocardial proteins themselves are continuously made and degraded in order to adjust to changes in energy demand and changes in the extracellular environment. We recently have identified signals arising from intermediary metabolism that regulate the cycle of myocardial protein turnover. Using a new conceptual framework, we discuss the principle of metabolic cycles and their importance for refueling and for rebuilding the failing heart.

Figure 1.. Energy substrate metabolism and contraction are tightly linked

Intermediary metabolism of energy-providing substrates provides the energy needed for rephosphorylation of ADP to ATP. ATP hydrolysis provides the energy for contraction. In the schematic presented here, it is apparent that metabolic dysregulation begets contractile dysfunction and, vice versa, contractile dysfunction begets metabolic dysregulation. The system also reveals that metabolic dysregulation can either be the cause or the consequence of contractile dysfunction. See text for further discussion. Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate; Pi, inorganic phosphate.

Figure 2.. Cycles improve efficiency of energy transfer

The three panels show six compound-conserved cycles, beginning with the circulation (first cycle on the left) and ending with the cross-bridges in the sarcomeres (last cycle on the right). There are four interlinked cycles in the mitochondria: the Krebs cycle, the NAD⁺/NADH-H⁺ and FAD⁺/FADH-H⁺ cycle, the build-up and collapse of the proton (H⁺) gradient across the inner mitochondrial membrane, and the ADP/ATP cycle. Release and reuptake of Ca²⁺ by the sarcoendoplasmic reticulum regulates cross-bridge formation in the sarcomeres and also regulates dehydrogenase activities of the Krebs cycle in the mitochondria. Panel A depicts a model of normal energy transfer (arrow on top of each panel). Panel B depicts a model of increased energy transfer in the adaptive response to an increase in workload of the heart. Panel C depicts a model of decreased energy transfer in the maladaptive state of heart failure. Note the feedback loop from crossbridges to the circulation (arrow on the bottom of each panel). In the text we propose that boosting the circulation (↑) with mechanical support may restore the flow of energy through the series of interconnected moiety-conserved cycles (lower panel). Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate; FAD, flavine adenine dinucleotide; FADH, reduced flavine adenine dinucleotide; NAD, nicotinamide adenine dinucleotide; NADH, reduced nicotinamide dinucleotide.

Figure 3.. Structure and function of the cardiomyoctye is determined by the balance of protein synthesis and protein degradation

Activation of the enzyme AMPK by a decrease in the ATP/AMP ratio increases protein degradation, while the glycolytic intermediate, G6P, regulates the nutrient sensor mTOR and protein synthesis. Of note, amino acids themselves are also metabolized and some may serve as regulators of protein synthesis. Abbreviations: AAs, Amino Acids; AMP, adenosine monophosphate; AMPK, 5’AMP activated kinase; ATP, adenosine triphosphate; G6P, glucose 6-phosphate; mTOR, mammalian target of rapamycin; PD, protein degredation; PS, protein systhesis.