We have identified Mrep, a macrophage population that plays an important role in muscle repair. However, in fibrodysplasia ossificans progressiva (FOP), Mrep acts as a pathogenic cell that causes heterotopic ossification. These research results are expected to contribute not only to muscle regeneration therapy but also to the development of new treatments for FOP.
Musculoskeletal diseases are a major cause of disability around the world, especially in aging societies like Japan. As we age, decreased muscle mass and physical activity weaken the body’s structural support, increasing the likelihood of falls, bruises, fractures, and subsequent functional decline. These injuries not only cause pain, but also impair mobility, reduce quality of life, and lead to further health complications. Addressing these widespread issues requires a deep understanding of how muscles regenerate and repair after injury.
Skeletal muscle is not only an organ that controls body movement, but also the largest energy consuming organ, accounting for approximately 40-50% of body weight. Muscle injuries rank among the most common everyday injuries. When a muscle is injured, inflammation first occurs, followed by a repair process that restores the tissue to its original state. This repair involves complex coordination between various immune cells and muscle satellite cells, which are stem cells essential for muscle regeneration. However, large gaps remain regarding which immune cells promote muscle repair and by what mechanisms.
Failure of muscle regeneration can lead to tissue fibrosis and heterotopic ossification. A serious example is fibrodysplasia ossificans progressiva (FOP). This is a rare genetic disorder where trauma causes bone formation in muscles and tendons. There is currently no fundamental treatment, and surgical intervention is contraindicated. Patients must take extreme care to avoid injury, and there is an urgent need to develop new treatments.
The researchers utilized a mouse model involving incisions in the hamstring muscle to analyze the muscle repair process. They focused on macrophages as the main immune cells that accumulate in damaged tissue and used RNA sequencing to investigate soluble factors produced by macrophages. This analysis revealed that muscle injury induced substantial expression of activin A. They also discovered that activin A promotes muscle satellite cell proliferation and promotes muscle regeneration.
Single-cell RNA sequencing of macrophages within injured muscle identified multiple subgroups. One particular population, expressing the cell membrane proteins CD9, PDPN, and IL-7R, produced particularly high levels of activin A and was specialized for muscle repair. In macrophage-deficient mice with muscle damage, repair was delayed compared to normal mice. However, while transplantation of this particular macrophage population improved muscle repair, transplantation of other populations did not show similar effects. Therefore, the researchers named this population “Mrep” (macrophages that direct muscle tissue repair). Mice engineered to prevent activin A production by Mrep exhibited a significant delay in muscle repair, confirming that Mrep-derived activin A is a major factor in normal muscle repair. Additionally, Mrep produces activin A when it receives danger signal molecules called DAMPs, which are released from injured muscles via TLR4 receptors.
The research team investigated the relationship between Mrep-mediated muscle repair and FOP pathology. Clinical observations suggested an immune system involvement in FOP, as ectopic ossification is preceded by intense inflammation and immunosuppressive drugs prevent new bone formation. Mutations in ACVR1 are involved in the gene responsible for FOP. Recent studies have shown that activin A binds to mutant ACVR1 and induces aberrant osteogenic signals, but how trauma-related inflammation relates to activin A production remained unclear. The researchers hypothesized that Mrep, which accumulates after muscle injury, functions as a cellular source of activin A that causes ectopic ossification in the FOP. Experiments using a FOP mouse model confirmed that muscle injury results in ectopic ossification at the injured site, and that Mrep produces activin A at these sites. Mrep-derived activin A acts on mutant ACVR1 in mesenchymal progenitor cells and induces their differentiation into bone-forming osteoblasts. Importantly, blocking activin A production by macrophages suppressed ectopic bone formation in a FOP mouse model. Additionally, administration of TLR4 inhibitor alone also inhibited ectopic ossification.
This study demonstrates that Mrep exerts a beneficial function by promoting muscle repair under normal injury conditions. However, in FOP, Mrep accumulates after trauma and paradoxically causes heterotopic ossification. These findings establish Mrep as a new macrophage population essential for muscle repair and elucidate the mechanism by which its normal function becomes pathological in FOP. This study suggests that Mrep-targeted therapeutic approaches may lead to innovative treatments that promote muscle regeneration and prevent heterotopic ossification in patients with FOP.
sauce:
Reference magazines:
In, W. Others. (2026). Activin A secretion by muscle repair macrophages induces ectopic ossification in mice. clinical research journal. DOI: 10.1172/jci193797. https://www.jci.org/articles/view/193797
