Slow and steady wins the race: Genetic research sheds light on heart muscle disease

marathon runners close up
Manipulating genetic pathways could help diseased heart muscles gain more of the slow-twitch fibers abundant in marathon runners.

Heart muscles, like skeletal muscles, are made up of two major types of muscle fibers: fast twitch and slow twitch. Fast twitch fibers move quickly but tire easily, while slow twitch fibers move slower but last longer. Both serve important functions in different circumstances. For example, marathon runners tend to have a predominance of slow twitch fibers in their skeletal muscle; the opposite is true for sprinters.

At the Boston Children’s Hospital Cardiovascular Research Center, Da-Zhi Wang, PhD, and his colleagues recently discovered a genetic pathway responsible for fine-tuning twitch speed that, when disrupted, leads to cardiomyopathy, a disease of the heart muscle.

“We found that in a normally functioning heart, the ‘signature,’ or dominant speed, of heart muscle fibers is slow. In a diseased heart, the signature is fast,” says Wang.

In cardiomyopathy, a predominance of fast twitching ends up tiring the heart, weakening its ability to contract and potentially leading to heart failure. But Wang’s team found that this pattern can be changed through molecular manipulation.

“We were able to reverse the signature, and effectively reverse the phenotype for cardiomyopathy, by intervening early in the genetic coding process for the disease,” Wang says.

Cardiomyopathy-Trbp-Wang
The heart on the left is a normal heart, and the heart on the right is diseased

Working with lab mice, Wang and his team mutated the gene for a protein called Trbp, which binds to RNA and activates a series of other genes. Compared with a control group, lab mice with mutated Trbp experienced a severe decline in cardiac function, similar to the symptoms experienced by patients with heart failure.

Further investigation revealed that Trbp acts through a single microRNA called miR-208a, which regulates a gene called Sox6. Sox 6, in turn, regulates genes that encode for fast- and slow-twitch muscle proteins.

“By restoring the normal genetic pathway, we changed the signature back from fast to slow, offering a means to treat diseased hearts,” says Wang.

The implications for this research (recently published in Nature Genetics) are very promising, says Wang. MicroRNAs and their downstream targets could represent a new therapeutic strategy for enhancing cardiac function. “Next, we would like to see if this method is effective for different types of heart muscle diseases, such as hypertrophic cardiomyopathy.” Wang’s research is supported by the National Institutes of Health and the Muscular Dystrophy Association.