The human heart is a remarkable muscle, beating more than 2 billion times over the average life span. However, the heart’s efficiency can decrease over time. One major contributor to this decreased function is cardiac hypertrophy, a thickening of the heart muscle, resulting in a decrease in the size of the left and right ventricles. This makes the heart work harder and pump less blood per cycle than a healthy heart. Now, a study from researchers at Cornell University has identified a strong connection between a protein, SIRT5, and healthy heart function. The team state that SIRT5 has the ability to remove a harmful protein modification known as lysine succinylation, which robs the heart of its ability to burn fatty acids efficiently to generate the energy needed for pumping; their research suggests that perhaps one way to improve heart function is to find a way to improve SIRT5 activity.
Previous studies show that SIRT5 is one of a class of seven proteins called sirtuins that have been shown to influence a range of cellular processes. Most research on laboratory mice into sirtuin activity has focused on the liver, as opposed to the heart, due to the size of the liver and ease of obtaining tissue. Although many mammalian proteins have recently been found to be regulated by lysine succinylation and SIRT5, the physiological significance of succinylation and SIRT5 remains unknown. The current study shows that regulating heart metabolism and function is a major physiological function of lysine succinylation and SIRT5.
The current study utilised mouse tissue from five locations (heart, liver, kidney, brain, muscle) where SIRT5 was deleted, and found that protein lysine succinylation occurs to the greatest extent in the heart. Results show that the removal of SIRT5 resulted in reduced activity of ECHA, a protein involved in fatty acid oxidation, and decreased levels of adenosine triphosphate (ATP), which stores and transfers chemical energy within cells. Data findings show that the effect of SIRT5 removal on heart function was even more pronounced as the mice aged.
The lab also performed echocardiography on 8-week-old mice, with some reduced cardiac function observed. The mice were tested again at 39 weeks, when they showed hallmarks of cardiac hypertrophy, increased heart weight and left ventricular mass, along with reductions in both the shortening and ejection fractions of the heart.
The team surmise that their findings could spawn new methods for the preservation of heart health and extension of healthy life, which could have significant implications for human health. They go on to add that the identification of this new role of SIRT5 in cardiomyopathy assigns an important role of this ‘druggable’ enzyme in one of the major cardiac diseases. For the future, the researchers state that it can be expected that pharmacological interference with these pathways will lead to new therapies for cardiomyopathy that, as such, can extend healthy life span.
Source: Cornell University
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