Treading slowly through hypoxic waters: dichloroacetate to the rescue!

Abstract

Metabolic flexibility is compromised during myocardial hypoxia and the development of heart failure. In this issue of The Journal of Physiology, Handzlik and colleagues provide novel findings that demonstrate how chronic hypoxia increases the susceptibility of the heart to acute hypoxia, although chronic hypoxia interestingly displays preserved pyruvate dehydrogenase (PDH) function (Handzlik et al. 2018). They also found that increasing PDH activity with the PDH kinase inhibitor dichloroacetate (DCA) improves the chronically hypoxic heart's tolerance to acute hypoxia, thereby reinforcing the importance of cardiac metabolic flexibility. In the setting of heart failure, a potential end stage of chronic hypoxia, cardiac energy metabolism becomes perturbed and inflexible, with energy production being both insufficient and inefficient. More specifically, the failing heart's energy metabolism is characterized by an increase in glycolysis and, concurrently, a significant reduction in glucose oxidation (for which PDH is the rate-limiting enzyme) (Figure 1). As such, there is therapeutic potential to stimulate glucose oxidation to improve the failing heart's energy production and efficiency. This study provides evidence for a beneficial effect of DCA treatment, administered concurrently with chronic hypoxia, for improving acetyl-carnitine stores to pre-emptively protect against acute hypoxic attacks. However, while the findings of Handzlik and colleagues demonstrate promising potential for DCA in the setting of chronic hypoxia, extrapolation to the pathophysiological setting of heart failure may be premature. During hypoxia and the development of heart failure, glycolysis increases and glucose oxidation decreases. DCA treatment increases glucose oxidation and can eventually improve the metabolic flexibility of the heart. Combining NAD+ precursors with DCA may have further benefits to increase mitochondrial quality and quantity as well. We previously demonstrated that acute treatment with DCA during reperfusion of ischaemic hearts has a beneficial effect on functional recovery, due to an increase in PDH activity and glucose oxidation (Lopaschuk et al. 1993). Handzlik et al. also observed that DCA treatment during chronic hypoxia can improve functional recovery during a subsequent acute hypoxic episode. However, although an acute hypoxic episode decreased functional recovery of chronically hypoxic hearts, this was curiously accompanied by an increase in PDH activity in the untreated hearts. Furthermore, while DCA treatment improved functional recovery following acute hypoxia, it did not further increase PDH activity. Additionally, glycolytic flux increased as expected with acute hypoxia, as did lactate efflux. On the contrary though, DCA treatment did not decrease lactate efflux, even though glycolytic flux was slightly decreased, suggesting that glucose oxidation was not increased with DCA treatment. Another interesting finding was that glycolytic flux normalized to function was inhibited by DCA treatment during acute hypoxia and reoxygenation but no changes in PDH activity following DCA treatment were observed. This suggests that the benefits of DCA on heart function may not originate from a DCA-induced increase in glucose oxidation. Unfortunately, direct measurements of glucose oxidation rates were not made in this study, which would help define the therapeutic mechanism and implication of DCA in the setting of chronic hypoxia and its potential applications in the failing heart. Cardiac mitochondrial function can be compromised in diabetes and obesity. Mitochondria are the main role-players in maintaining metabolic flexibility; however, manipulation of the mitochondrial acetyl-carnitines via DCA administration may only be a temporary solution for improving cardiac function. Furthermore, the effects of prolonging mitochondrial oxidative phosphorylation during acute hypoxia remain unclear. Regardless of the disease state, in a naive heart, pre-adaptation with adverse mitochondrial respiration may be an effective therapeutic approach to consider. However, making mitochondria solely dependent on PDH flux and the acetyl-carnitine pool may be a rate-limiting approach in the context of aging. An important factor to consider for future therapeutic approaches is the age-dependent decrease in mitochondrial number and function as well as different disease states. A major metabolic cofactor, NAD+, and its precursors (nicotinamide mononucleotide, NMN, and nicotinamide riboside, NR) have been shown to improve mitochondrial function and biogenesis in obesity, diabetes and in aging leading to considerable mitochondrial adaptation when metabolism is impaired (Uddin et al. 2017). Therefore, improving cardiac adaptations to acute hypoxic conditions or heart failure is a unique approach; however, future studies of combining DCA with NMN, NR or CD38 inhibitor (an NADase) could potentially make more mitochondria quantitatively and qualitatively to improve cardiac hypoxic tolerance. None declared. All authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.