The DWORF micropeptide enhances contractility and prevents heart failure in a mouse model of dilated cardiomyopathy

摘要

The heart is a muscular organ that contracts regularly to pump blood around the body, ensuring that nutrients and oxygen are carried to the cells and organs. Heart failure is a disease where the heart muscle becomes weakened, does not beat as strongly, and cannot pump blood as well as it should. Eventually, the heart can no longer deliver enough blood to meet the body’s needs. Although heart failure is a widespread disease, we still do not fully understand its underlying causes and the molecular machinery driving its progression. However, one common feature in many cases of heart failure is a problem with the supply of calcium to the heart muscle. Calcium is the molecule responsible for the process of muscle contraction; the strength of contraction depends on the amount of calcium available. Movement of calcium within heart cells is in turn controlled by an enzyme pump called SERCA. In 2016, researchers identified a small protein, DWORF, which increased the activity of SERCA. Makarewich et al. – including many of the researchers involved in the 2016 study – therefore wanted to find out more about how DWORF and SERCA worked together. They also wanted to test if DWORF could be used to boost the heart’s ability to pump blood efficiently, and if so, whether it could treat heart failure. Genetically modified mice that produced larger than normal amounts of DWORF had more available calcium in the heart muscle, which made it contract more strongly. This was true even when the same mice were treated with an excessive amount of a specific protein (phospholamban) that can lower the activity of SERCA, suggesting that DWORF might have a protective effect on the heart. Experiments using mice engineered to show symptoms of heart disease confirmed that DWORF treatment did indeed help their hearts beat normally, and, crucially, prevented them from developing heart failure. This work has shown for the first time that DWORF can restore the heart’s ability to pump normally in an experimental model of heart disease. In the future, Makarewich et al. hope that DWORF could be a useful target for new, more effective drugs to treat heart failure.