‘Leaky’ Muscle Fibers Drive Immune Response in Muscular Dystrophy

Elizabeth McNally, MD, PhD, the Elizabeth J. Ward Professor of Genetic Medicine and director of the Center for Genetic Medicine, was co-senior author of the study.

A Northwestern Medicine study has uncovered how chronic defects in muscle membrane repair can fuel harmful inflammation, according to the study published in JCI Insight.

The findings offer new details on an essential biological process and may be useful in understanding certain forms of muscular dystrophy, said Elizabeth McNally, MD, PhD, the Elizabeth J. Ward Professor of Genetic Medicine, director of the Center for Genetic Medicine, and co-senior author of the study.

Muscle fibers routinely sustain small injuries during contraction, which are then healed, allowing muscles to grow. Under normal conditions, the body’s specialized repair machinery reseals tears in the cell membrane, preventing cellular contents from leaking into surrounding tissue. Defects in this repair process are known to cause some forms of muscular dystrophy, but the consequences of chronic membrane leakage have remained poorly understood.

“Two proteins important for muscle repair are dysferlin and annexin A6, and these are the focus of our study,” said McNally, who is also a professor of Medicine in the Division of Cardiology and of Biochemistry and Molecular Genetics. “In humans, there is a form of muscular dystrophy that comes from having mutations in the dysferlin gene. In this form of disease, patients have very leaky muscles, which can be measured by detecting muscle proteins in the blood. For these patients, their muscles become dysfunctional, causing them to have weak muscles that cannot support walking.”

A macrophage eating the muscle fiber (arrow). The lower right is the composite image. Courtesy of the McNally laboratory.

In the study, investigators created a mouse model lacking both dysferlin and annexin A6. While the loss of annexin A6 alone had little effect on muscle health, its absence in dysferlin-deficient muscle dramatically worsened membrane leaking and altered the surrounding tissue environment. The team also found that removing annexin A6 in a separate model of Duchenne muscular dystrophy, which is caused by dystrophin loss, did not significantly worsen disease, suggesting that defective membrane resealing triggers a distinct pathological process.

The scientists also found that persistent membrane leaks attracted large numbers of immune cells called macrophages. Rather than supporting healing, these macrophages actually appeared to contribute to tissue damage by actively targeting injured muscle fibers.

“The main finding of this work is that prolonged membrane leak due to defective repair creates a unique muscle environment,” McNally said. “We identified that macrophages carrying two markers (Mertk and Trem2) were drawn to leaky muscles.”

The study also revealed how persistent leakage alters the extracellular matrix, the network of proteins surrounding muscle fibers.

Alexis Demonbreun, PhD, associate professor of Pharmacology, was co-senior author of the study.

“In the dysferlin model, we characterized how leaky membranes changed the protein content of the surrounding extracellular matrix, and we found that other annexins were deposited into the matrix around muscle,” McNally said. “This excess extracellular annexin stimulates macrophages, so that they proliferate, creating an overall muscle environment with excess inflammation.”

The team, which also included Edward Benjamin Thorp, PhD, the Frederick Robert Zeit Professor of Pathology, also found evidence that injured muscle fibers became targets for macrophage phagocytosis, a process typically used to remove dead or dying cells.

“A key finding is that leaky muscle fibers draw macrophages to come and ‘take a bite’ in a process called phagocytosis,” McNally said. “The excess macrophages and their tendency to phagocytose leaky muscle appears to contribute to making the disease process much worse.”

The findings also point to potential new therapeutic strategies. Rather than focusing on improving membrane repair, treatments could also target the inflammatory response triggered by chronic leaking, McNally said.

Beyond muscular dystrophy, the work highlights a growing recognition that the extracellular matrix can influence disease, rather than serving solely as structural support.

“One of the biggest takeaways of this work is that the matrix around cells should be considered an active participant in disease,” McNally said. “This concept of the microenvironment is gaining traction across many disease types, including degenerative disorders and cancer.”

Alexis Demonbreun, PhD, associate professor of Pharmacology, was co-senior author of the study.

The study was supported by National Institutes of Health grants NS047726, HD119693 and AR052646, as well as the Parent Project Muscular Dystrophy and the Muscular Dystrophy Association.

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