Researchers at the Sanford Burnham Prebys Medical Discovery Institute (SBP) reported new findings this week that may lead to novel therapeutic strategies for people suffering from Duchenne muscular dystrophy (DMD). DMD, a muscle-wasting disease that affects 1 in 7250 males aged 5 to 24 years in the United States, is caused by a genetic mutation leading to the lack of a protein called dystrophin. Without dystrophin, muscle cells become fragile and are easily damaged. Instead of self-repair, the muscles are replaced by scar tissue, a process called fibrosis that leads to muscle degeneration and wasting.

Dystrophin, a protein that maintains the structural integrity of muscle fibers, is missing in people with DMD. Image credit: Khan Academy

Boys with DMD first show signs of muscle weakness between ages 3-5 and often stop walking by the time they’re teenagers. Eventually the muscles critical for breathing and heart function stop working. Average life expectancy is 26 and there is no cure.

The SBP scientists are aiming to treat DMD by boosting muscle repair in affected individuals. But to do that, they sought to better understand how muscle regeneration works in the first place. In the current study, they focused their efforts on so-called fibro/adipogenic precursor (FAP) cells which, in response to acute injury, appear to play a role in stimulating muscle stem cells to divide and replace damaged muscle in healthy individuals. But FAPs are also implicated in the muscle wasting and scarring that’s seen in DMD.

By examining the gene activity of single FAP cells from mouse models of acute injury and DMD, the researchers identified a sub-population of FAP cells (sub-FAPs). Further study of these sub-FAPs showed that during early stages of muscle regeneration, these cells promote muscle stem cell activation but then at later stages, sub-FAPs – identified by a cell surface protein called Vcam1 – stimulate fibrosis. It turns out that during healthy acute muscle injury, the sub-FAPs with cell-surface Vcam1 protein are readily eaten up and removed by immune cells thereby avoiding muscle fibrosis. But in the DMD mouse model, removal of these sub-FAPs is impaired and instead collagen deposits and muscle fibrosis occur which are hallmarks of the progressive degeneration seen in DMD.

Barbora Malecova, Ph.D., a first author of the study, explained the implications of these results in a press release:

“This study elucidates the cellular and molecular pathogenesis of muscular dystrophy. These results indicate that removing or modulating the activity of Vcam1-positive sub-FAPs, which promote fibrosis, could be an effective treatment for DMD.”

The lab, led by Pier Lorenzo Puri, M.D., next will explore the possibility of finding drugs that target the Vcam1 sub-FAPs which in turn could help prevent fibrosis in DMD.

The study, funded in part by CIRM, appears in Nature Communications. CIRM is also funding a Phase 2 clinical trial testing a stem cell-based therapy that aims to improve the life-threatening heart muscle degeneration that occurs in DMD patients.