Attenuating cardiac fibrosis and apoptosis by exercise is associated with modulation of the circSlc8a1/miR-133a axis in D-galactose-treated rats

As we grow older, our hearts naturally undergo changes that can make them less efficient and more prone to disease. This process, known as cardiac aging, involves the accumulation of damage within heart cells, the stiffening of heart tissue, and a gradual decline in the organ's ability to pump blood. For decades, scientists have searched for ways to slow this decline, looking beyond just medication to understand how the body's own biology responds to lifestyle. A key part of this biological puzzle involves tiny molecules that act as switches for our genes. Some of these molecules are circular strands of genetic material that do not code for proteins but instead regulate other genes by binding to them, much like a sponge soaking up water. Others are small RNA fragments that tell cells when to grow, when to repair themselves, and when to die. When these molecular switches malfunction, they can trigger excessive scarring of the heart tissue or cause healthy cells to die off prematurely, accelerating the aging process. Understanding how to reset these switches could offer a powerful, non-drug way to protect the heart as we age.

In a recent study, researchers at Kerman University of Medical Sciences explored whether physical exercise could reset these molecular switches in aging hearts. They focused on a specific interaction between a circular RNA molecule, called circSlc8a1, and a small RNA fragment known as miR-133a. Previous work had suggested that when the heart is under stress, levels of circSlc8a1 rise and act as a sponge, soaking up miR-133a. Since miR-133a normally helps prevent cell death and scarring, soaking it up leaves the heart vulnerable. The researchers wanted to see if two different types of exercise—steady, moderate running and short bursts of intense running—could reverse this process in rats whose hearts were aged using a chemical treatment.

To create a model of accelerated aging, the scientists injected male rats with a substance called D-galactose every day for eight weeks. This chemical is known to induce oxidative stress and mimic the biological changes seen in an aging heart. The rats were divided into several groups: some received only the aging chemical, some received the chemical while also performing moderate-intensity endurance training, and others received the chemical while performing high-intensity interval training. A control group received neither the chemical nor the exercise. The exercise protocols were carefully designed to last eight weeks, with the moderate group running at a steady pace and the high-intensity group alternating between fast sprints and slower recovery periods. After the eight weeks, the researchers examined the heart tissue to see how the molecular switches and the health of the heart cells had changed.

The results showed a clear link between exercise and the molecular health of the heart. In the rats that received the aging chemical but no exercise, the levels of the circular RNA, circSlc8a1, were significantly high. While miR-133a levels showed a slight, non-significant drop in this group compared to controls, the story changed dramatically with exercise. In the rats that exercised, regardless of whether they did moderate or high-intensity training, the levels of the harmful circular RNA were reduced, and the levels of the protective miR-133a were significantly increased. This shift in the molecular balance was not just a minor change; it represented a significant restoration of miR-133a expression, counteracting the aging chemical's effects.

The physical consequences of this molecular shift were equally important. The researchers measured specific proteins associated with fibrosis, which is the stiffening and scarring of heart tissue, and apoptosis, which is the programmed death of cells. In the aging rats that did not exercise, these harmful proteins were abundant. In contrast, the rats that exercised showed much lower levels of these damaging markers. The exercise appeared to stop the heart tissue from becoming overly stiff and prevented healthy heart cells from dying off in large numbers. The study suggests that the exercise did not just improve the heart's function directly but did so by correcting the underlying genetic regulation that had gone awry due to aging.

While the study provides strong evidence for how exercise influences these specific molecular pathways in rats, the researchers are careful to note that these findings are specific to their animal model. The aging process in rats is not identical to that in humans, and more research is needed to confirm if the same molecular mechanisms apply to people. Nevertheless, the findings offer a compelling glimpse into the biology of exercise. They suggest that the simple act of moving the body can trigger a cascade of molecular events that counteract the wear and tear of aging, turning off the signals for scarring and cell death while turning on the signals for protection and repair. This work supports the idea that exercise is a potent tool for maintaining heart health, acting deep within the cell to preserve the organ's structure and function.