Duchenne muscular dystrophy (DMD) is caused by a mutation in the dystrophin gene, which produces a large protein essential for stabilizing muscle cell membranes that help protect muscle fibers. Without dystrophin, muscle damage occurs and builds, leading to persistent inflammation and fibrosis (scarring). The condition primarily affects boys-occurring in about 1 in 5,000 live male births-and leads to premature death due to respiratory and cardiac muscle weakness. There is currently no cure. A new study led by researchers at Hospital for Special Surgery suggests that currently available therapies may help control chronic muscle inflammation in DMD, a severe condition that leads to muscle weakness and premature death.
The study, published in PNAS, identifies new mechanisms that drive chronic muscle inflammation in a disease model of a DMD. Researchers believe that targeting these mechanisms with existing therapies could help reduce inflammation and support muscle function. The research team focused on monocytes (a type of white blood cell) that travel through the blood stream to infiltrate diseased muscles and become inflammatory macrophages, which promote muscle damage and scarring. They previously discovered that blocking monocyte recruitment from the blood circulation temporarily decreased macrophage accumulation, reduced scarring, and improved muscle function in a disease model of DMD.
To uncover additional factors driving macrophage accumulation, the investigators used state-of-the-art technologies, including single-cell RNA sequencing analysis and lineage tracing, to determine the key mechanism that is responsible for fueling chronic inflammation after macrophage infiltration is blocked. According to the newly published research, Dr. Zhou and her colleagues discovered that mesenchymal stromal cells (a type of stem cell) in muscle tissue called fibro/adipogenic progenitors (FAPs) produce cytokines or growth factors known as colony-stimulating factor (CSF-1). CSF-1 stimulates resident macrophages in skeletal muscles to proliferate and accumulate, which contributes to chronic inflammation and muscle dystrophy.
The findings uncover a new function of FAPs that fuels chronic inflammation and promotes DMD disease progression. The researchers concluded that it might be equally important to suppress resident macrophage expansion and activation in addition to inhibiting macrophage infiltration. According to scientists, this means that in order to control chronic muscle inflammation and improve muscle function in patients with DMD, both macrophages and FAPs may need to be targeted. Limited treatment options exist for patients with DMD. As a next step, Dr. Zhou and her team are planning to study the safety and efficacy of a combination therapy using two existing drugs developed for other conditions.
One is used to treat chronic inflammation by suppressing macrophage infiltration; it is called Cenicriviroc and is a chemokine CCR2 receptor antagonist. The other is a CSF-1 inhibitor (Pexidartinib) used to treat a type of joint tumor that consists of many macrophages due to excessive CSF-1 production. Therefore, the new therapy for this condition is essentially a drug-repurposing process of two drugs already known for other diseases. A hopeful speed-up to treat DMD despite the still complicated option of stem cells and gene therapy.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Wang Y, Wang X et al. PNAS USA. 2025; 122(11):e2410095122.
Riddell DO et al. Dis Model Mech. 2022; 15(12):dmm049394.
Babaeijandaghi F et al. Sci Transl Med. 2022; 14(651):eabg7504.
