Although exercise can lead to sudden death in people with genetic heart rhythm disorders, the cellular and molecular mechanisms behind the process haven’t been pinned down. Now, using mice with one of these heart rhythm disorders, Johns Hopkins Medicine researchers and their colleagues have teased out the intricate biological steps leading to heart cell death during exercise. These steps, they report, can create a buildup of scar tissue in the heart that interrupts the electrical waves propagating heart beats.

In their study published Feb. 17, 2021, in Science Translational Medicine, the researchers used a synthetic peptide — a laboratory-produced fragment of a protein — to prevent heart cells from dying in simulated exercise. The results of their findings suggest that researchers one day may develop therapies that enable people with genetic heart diseases to work out and participate in other physical activities.

“We’ve always thought that exercise promotes more arrhythmias, or irregular heartbeats, in people with these genetic heart rhythm disorders, but now we’ve demonstrated why exercise is bad for them on a cellular level,” says Stephen Chelko, Ph.D., an adjunct assistant professor of medicine at the Johns Hopkins University School of Medicine and assistant professor of biomedical sciences at Florida State University.

Using a mouse with the second most common mutation for arrhythmogenic cardiomyopathy — one of the genetic heart rhythm disorders — the researchers first showed that when these mice swam for exercise, it caused heart cells to accumulate calcium ions. This pushed the cells into a programmed death or suicide, known as apoptosis (a natural process to remove old or damaged cells). They found that exercise activates the protein calpain, which upon moving to the mitochondria in a cell — traditionally known as the cell’s power factory — triggers another protein: apoptosis-inducing factor (AIF). A normal component of the mitochondria, AIF ultimately causes heart muscle cell death. However, when it’s clipped by calpain, AIF migrates outside of the mitochondria and docks to the cell nucleus. There, it induces the DNA inside the nucleus to break apart and cause cell death.

“We believe that this mechanism is not something specific to this particular disease, but may be at the core of other cardiomyopathies and, very likely, many other heart diseases,” says Nazareno Paolocci, M.D., Ph.D., associate professor of medicine at the Johns Hopkins University School of Medicine. “We think that understanding how this works in great detail will enable us to develop therapeutics to treat these type of genetic heart diseases.”

To gain this insight, the researchers collaborated with Fabio Di Lisa, M.D., of the University of Padua and Nunzianna Doti, Ph.D., and Menotti Ruvo, Ph.D., at the National Research Council of Italy. The team developed a protein fragment made to look like a portion of AIF and put it inside mouse heart cells grown in the laboratory. After treating the cells with calcium ions and hormones from the adrenal glands to simulate conditions during exercise, the researchers observed that the mimic protein fragment blocked the activator and prevented the heart cell suicide from occurring.

Based on this finding, the researchers next plan to see if the mimic protein fragment can protect heart cells during exercise in live mice bred with the mutation for genetic heart disease.

Chelko and Paolocci are available for interviews.