Researchers at Johns Hopkins All Children’s Hospital identified a pathway that plays an integral role in the way the body repairs itself after sustaining muscle damage.

The findings help researchers better understand how the body regulates muscle repair, which can lead to advancements in the way certain diseases like Duchenne muscular dystrophy – a rare genetic disorder that causes progressive muscle degeneration in young children – are treated.

Andreas Patsalos, Ph.D., is the Johns Hopkins University research fellow who led the research team. He works in the lab of Laszlo Nagy, M.D., Ph.D., co-director of the Institute for Fundamental Biomedical Research. Their work was recently published in The Journal of Immunology.

The study focused on an important cell type called macrophages — large white blood cells that are part of the innate immune system — and how macrophages help repair injured tissue in the body.

Nagy calls macrophages the Swiss Army Knife of the immune system, Patsalos notes, because they serve a number of rather diverse functions, from defense against microbes that cause disease, to inhibiting or even enhancing tumor growth, to promoting muscle repair.

“We are interested in understanding how these macrophages help to repair the tissue,” Patsalos says. “We’ve done that by focusing on normal healing process called muscle regeneration.”

When muscle is damaged, macrophages infiltrate the affected area of the body to clear out the damaged tissue. An activation process occurs, and they begin secreting growth factors that promote regeneration and re-growth of the muscle.

“This happens in the muscle depending on the stimulus they receive,” Patsalos says.

The team identified a molecule called BACH1 that signals to the macrophage when it’s time to clear debris from an injured muscle, start repairing the muscle, and when the repair is complete. BACH1, they discovered, is in turn controlled by heme, which is a molecule present in blood and muscle cells.

“Whenever you have any tissue damage, heme molecules are released. They bind to BACH1 and remove it from the DNA, which leads to the removal of its repressor activity so that repair-genes can be activated” and regeneration can begin, Patsalos says. So, the repressor BACH1 in the absence of heme essentially functions like the brakes in a car, keeping the macrophage under control and on course. In the presence of heme, the braking function is suspended, and critical inflammatory and repair genes are turned on.

Identifying this “brake” gives researchers a clearer idea of the factors that control muscle regeneration and how these factors can be harnessed to improve quality of life and outcomes for patients with conditions like Duchenne muscular dystrophy.

“What happens in these kids is they have a mutation that does not allow them to properly contract their muscles,” Patsalos says. Every day activities lead to muscle break down.

“The body tries to repair it and by doing that so many times, the system becomes exhausted,” Patsalos says. This can lead to chronic fibrosis, which is the thickening and scarring of connective tissue. Children with Duchenne muscular dystrophy lose muscle function and typically require the use of a wheelchair.

“It’s a deadly disease; there is no cure as of now,” Patsalos says. “Even with gene therapy to repair the gene, because these patients have been in a chronic inflammatory state for so long, we need to make sure inflammation is tightly controlled. This is what we are doing by identifying these switches, or brakes, of the inflammatory response during normal regeneration.”