Chronic defects in muscle membrane repair drive harmful inflammation in muscular dystrophy by causing persistent tissue leaks that attract destructive immune cells, according to a study published in JCI Insight. Researchers at Northwestern Medicine discovered that ongoing cellular damage creates a unique environment where specific immune cells actively target injured muscle fibers rather than healing them.
The Mechanics of Membrane Failure
Muscle fibers routinely sustain small injuries during contraction that specialized repair machinery typically reseals to prevent cellular contents from leaking into surrounding tissue.
According to Elizabeth McNally, MD, PhD, Elizabeth J. Ward Professor of Genetic Medicine and director of the Center for Genetic Medicine, two proteins critical for this process are dysferlin and annexin A6. Patients with dysferlin gene mutations experience forms of muscular dystrophy marked by leaky muscles, which release muscle proteins into the bloodstream and cause progressive weakness that impairs walking.
Testing Annexin Deletion in Mouse Models
To understand the consequences of chronic membrane leakage, investigators in the study created a mouse model lacking both dysferlin and annexin A6. While removing annexin A6 alone had minimal impact on muscle health, its absence in dysferlin-deficient muscle sharply worsened membrane leaking and altered the surrounding tissue environment.
However, removing annexin A6 in a separate mouse model of Duchenne muscular dystrophy—which is caused by dystrophin loss—did not significantly worsen disease, indicating that defective membrane resealing triggers a distinct pathological mechanism.
Extracellular Matrix Alterations and Macrophages
Persistent membrane leaks attract large numbers of immune cells called macrophages, which alter the extracellular matrix, the network of proteins surrounding muscle fibers.
Co-senior author Alexis Demonbreun, PhD, associate professor of Pharmacology, noted that in the dysferlin model, researchers characterized how leaky membranes altered the protein content of the extracellular matrix, revealing that other annexins deposited into the matrix around the muscle. This excess extracellular annexin stimulates macrophage proliferation, creating an environment with heightened inflammation.
Immune Cells Targeting Viable Muscle
Rather than supporting tissue repair, these accumulated macrophages contribute directly to damage.
The research team, which included Edward Benjamin Thorp, PhD, Frederick Robert Zeit Professor of Pathology, found that macrophages carrying two specific markers—Mertk and Trem2—were drawn to the leaky muscles. These cells actively target injured muscle fibers for phagocytosis, a process normally used to clear dead or dying cells.
According to McNally, this tendency of excess macrophages to phagocytose leaky muscle fibers worsens the disease process significantly.