A pathogenic component of diabetes in the heart has been discovered by researchers at the University of Texas Medical Branch at Galveston (UTMB). Heart disease and diabetes have been broadly studied, however it is not well understood how cardiomyopathy develops.
Diabetic cardiomyopathy is believed to be linked to protein kinase C (PKC), a group of enzymes that control the function of other proteins by using phosphates to turn them on and off. Led by Dr. Muge Kuyumcu-Martinez, assistant professor of biochemistry, UTMB researchers studied the effects of PKC signals in the hearts of diabetic mice.
According to Kuyumcu-Martinez, “We now know that the leading cause of diabetic cardiomyopathy can be attributed to PKC activation and its downstream effects on gene expression. Knowing how cardiomyopathy manifests, further research can use these results to concentrate on the prevention and treatment of heart failure in diabetics.” As a known symptom of diabetes, cardiomyopathy happens when heart muscle weakens. At that point, the heart is not strong enough to pump blood properly and poor circulation and heart failure results. It is reported that adults with diabetes are 2 to 4 times more likely to die of heart failure than the rest of the population.
UTMB researchers found that adult heart cells revert to splicing methods used during the embryonic state when PKC is over-activated. By altering splicing methods, a wide range of unique proteins can be created by varying the exon composition of the same mRNA (transcript). This is referred to as alternative splicing. This can occur in several ways by extending or skipping exons or retaining introns. Since the human genome contains around 20,000 protein-coding genes, making use of one gene to code for more than one protein is an efficient process when the system is working correctly. However, when mRNA is improperly spliced or reverts to a developmental state (embryonic state) of processing, an altered form of a protein is produced causing disease. It is reported that up to one-third of genetic diseases and a number of cancers are attributed to abnormal alternative splicing.
To identify alternative splicing in diabetic cardiomyopathy, researchers used RNA sequencing technology and discovered 22 specific alternative splicing events that cause a developmental shift in gene expression. This shift causes the heart to behave as if it were in an embryonic state. This prevents the heart from working properly in the adult.