Molecular-level insights into how physical activity influences the heart

Everyone knows that exercise comes with metabolic and cardiovascular benefits, but scientists understand surprisingly little about how physical activity influences the heart itself. Now, a new study in the December 23rd issue of Cell, a Cell Press publication, offers some of the first molecular-level insights.

The studies in mice suggest that exercise turns on a genetic program that leads the heart to grow as heart muscle cells divide. It appears that shift in activity is driven in part by a single transcription factor (a gene that controls other genes). That gene, known as C/EBPb, was known to play important roles in other parts of the body, but this is the first evidence for its influence in the heart.

"We've identified a pathway involved in beneficial cardiac hypertrophy - the good kind of heart growth," said Bruce Spiegelman of Harvard Medical School.

The findings may have clinical implications, particularly for those with heart failure or other conditions that make exercise difficult to impossible, the researchers say.

"This is yet another reason to keep on exercising," said Anthony Rosenzweig of Harvard Medical School. "In the longer term, by understanding the pathways that benefit the heart with exercise, we may be able to exploit those for patients who aren't able to exercise. If there were a way to modulate the same pathway in a beneficial way, it would open up new avenues for treatment."

There may also be ways to optimize training regimens such that they tap into this natural mechanism more efficiently, Spiegelman added.

Researchers had known that heart muscle adapts to increased pressure and volume by increasing in size. That's true in the case of exercise as it is in pathological conditions including high blood pressure. In disease states as opposed to exercise, those changes to the heart can ultimately lead to heart failure and arrhythmias.

In the new study, the researchers sought to better understand those differences using methods developed in the Spiegelman lab that allowed them to quantify changes in the expression of transcription factors in the heart at the genome-wide level in both exercised mice and those who had their aortas surgically constricted, a treatment that leads to a pathological increase in heart size.

The researchers found changes in 175 transcription factors in exercised mice and 96 in mice whose aortas were constricted. Importantly, the changes showed little overlap between the two animal models. For instance, the researchers said, 13 percent of the genes with differential expression following exercise have known or suggested roles in cell proliferation compared to less than one percent of those that changed with the surgery.

The researchers then zeroed in on one transcription factor, C/EBPb, which goes down about two-fold with exercise and a second that rises in turn. Studies in animals and cell culture showed that the decline in C/EPBb leads to changes that appear to be consistent with those that follow endurance exercise, including an increase in heart muscle size and proliferation. Those mice with lower C/EPBb levels also were resistant to heart failure.

That finding is key given that there is little prior evidence showing that the increase in heart size with exercise has direct benefits, the researchers say. The new evidence also gives important biological insights into the heart's potential for regeneration of muscle.

Rosenzweig said it will be important in future studies to explore all of the players in the pathway and to provide even more definitive evidence that exercise leads to an increased rate of cell proliferation in heart muscle.