Targeting myocardial substrate metabolism in heart failure: potential for new therapies

The incidence and prevalence of heart failure have increased significantly over the past few decades. Available data suggest that patients with heart failure independent of the aetiology have viable but dysfunctional myocardium that is potentially salvageable. Although a great deal of research effort has focused on characterizing the molecular basis of heart failure, cardiac metabolism in this disorder remains an understudied discipline. It is known that many aspects of cardiomyocyte energetics are altered in heart failure. These include a shift from fatty acid to glucose as a preferred substrate and a decline in the levels of ATP. Despite these demonstrated changes, there are currently no approved drugs that target metabolic enzymes or proteins in heart failure. This is partly due to our limited knowledge of the mechanisms and pathways that regulate cardiac metabolism. Better characterization of these pathways may potentially lead to new therapies for heart failure. Targeting myocardial energetics in the viable and potentially salvageable tissue may be particularly effective in the treatment of heart failure. Here, we will review metabolic changes that occur in fatty acid and glucose metabolism and AMP-activated kinase in heart failure. We propose that cardiac energetics should be considered as a potential target for therapy in heart failure and more research should be done in this area.     

Optical imaging of mitochondrial function uncovers actively propagating waves of mitochondrial membrane potential collapse across intact heart

Polarization of the mitochondrial membrane potential (ΔΨ_m) is critical for normal mitochondrial function and cellular energetics. Mitochondrial dysfunction, manifesting as disrupted ΔΨ_m polarization (i.e. depolarization or hyperpolarization), underlies several important and highly prevalent diseases, including a variety of cardiac and neurological disorders. As such, ΔΨ_m instability might form a unifying mechanism for a class of metabolic disorders affecting excitable tissues. Here, we measured the spatio-temporal kinetics of ΔΨ_m changes across the intact heart using high-resolution optical ΔΨ_m imaging and uncovered surprisingly complex spatial patterns and dynamically fluctuating changes in ΔΨ_m that developed into actively propagating waves of mitochondrial depolarization during global ischemia. Our data further indicated that the recovery of ΔΨ_m upon reperfusion is dictated by the duration of the preceding ischemic insult. Post-ischemic electrical and functional recovery was dependent on early ΔΨ_m recovery but independent of overall cellular injury measured using a standard assay of lactate dehydrogenase release. These findings reveal a novel mechanism by which instabilities in cellular energetic properties that are independent of irreversible cellular injury can scale to the level of the intact organ via an organized process of active conduction involving the multi-cellular network. This highlights the importance of investigating cellular metabolic properties in the context of the intact organ.     

Evolutionary origins of obesity

Although it appeared relatively suddenly, the current obesity epidemic – largely manifest in industrialized societies but now spreading to the rest of the world – is the result of interaction between human biology and human culture over the long period of human evolution. As mammals and primates, humans have the capacity to store body fat when opportunities to consume excess energy arise. But during the millions of years of human evolution such opportunities were rare and transient. More commonly ancestral hominins and modern humans were confronted with food scarcity and had to engage in high levels of physical activity. In tandem with encephalization, humans evolved elaborate and complex genetic and physiological systems to protect against starvation and defend stored body fat. They also devised technological aids for increasing energy consumption and reducing physical effort. In the last century, industrialization provided access to great quantities of mass‐produced, high‐calorie foods and many labour‐saving and transportation devices, virtually abolishing starvation and heavy manual work. In the modern obesogenic environment, individuals possessing the appropriate combination of ancestral energy‐conserving genes are at greater risk for overweight and obesity and associated chronic diseases.     

Energetics of walking in individuals with cerebral palsy and typical development,across severity and age: A systematic review and meta-analysis

BackgroundIndividuals with cerebral palsy (CP) report physical fatigue as a main cause of limitation, deterioration and eventually cessation of their walking ability. A consequence of higher level of fatigue in individuals with CP leads to a less efficient and long-distance walking ability.Research questionThis systematic review investigates the difference in 1) walking energy expenditure between individuals with CP and age-matched typically developing (TD) individuals; and 2) energetics of walking across Gross Motor Function Classification System (GMFCS) levels and age.MethodsFive electronic databases (PubMed, Web of Science, CINAHL, ScienceDirect and Scopus) were searched using search terms related to CP and energetics of walking.ResultsForty-one studies met inclusion criteria. Thirty-one studies compared energy expenditure between CP and age-matched controls. Twelve studies correlated energy expenditure and oxygen cost across GMFCS levels. Three studies investigated the walking efficiency across different ages or over a time period. A significant increase of energy expenditure and oxygen cost was found in individuals with CP compared to TD age-matched individuals, with a strong relationship across GMFCS levels.SignificanceDespite significant differences between individuals with CP compared to TD peers, variability in methods and testing protocols may play a confounding role. Analysis suggests oxygen cost being the preferred/unbiased physiological parameter to assess walking efficacy in CP. To date, there is a knowledge gap on age-related changes of walking efficiency across GMFCS levels and wider span of age ranges. Further systematic research looking at longitudinal age-related changes of energetics of walking in this population is warranted.