Northwestern Medicine Links Leaky Muscle Fibers to Muscular Dystrophy Inflammation

Elizabeth McNally and Dysferlin-Mediated Membrane Repair

Leaky Muscle Fibers and the Immune Response

In a study published in JCI Insight, researchers at Northwestern Medicine have uncovered a connection between chronic membrane repair defects and harmful inflammation in muscular dystrophy. 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, noted that the findings offer new details on an essential biological process. Under normal conditions, muscle fibers routinely sustain small injuries during contraction that are then healed, allowing muscles to grow. The body’s specialized repair machinery reseals tears in the cell membrane, preventing cellular contents from leaking into surrounding tissue. When this process fails, cellular contents leak into the surrounding tissue.

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. McNally explained that in humans, mutations in the dysferlin gene cause a form of muscular dystrophy characterized by very leaky muscles, which can be measured by detecting muscle proteins in the blood.

Candice Babarit and Pompe Disease Mouse Model Phenotype

Membrane Repair Proteins in Pompe Disease

Separate research into Pompe disease, a metabolic disorder that causes progressive skeletal muscle weakness, indicates that membrane repair-associated proteins are involved in muscle remodeling. In a study published in Acta Neuropathologica Communications, Candice Babarit, of Oniris, INRAE, PAnTher, in Nantes, France, and colleagues examined the muscle phenotype in a Pompe disease mouse model. Using longitudinal transcriptomic analysis, along with immunohistochemical and biochemical approaches, the team identified early and sustained overexpression of the membrane repair-associated proteins dysferlin, annexin A2 (ANXA2), and AHNAK2.

The study team observed abnormal localization of these three proteins during disease progression, which was associated with T-tubules, lysosomes, and autophagosomes, respectively. These findings indicate that Pompe disease is characterized by early accumulation and redistribution of these proteins, with compartment-specific remodeling. Furthermore, the researchers noted persistent post-transcriptional accumulation of mature myostatin (MSTN), a key negative regulator of muscle growth. They also observed a decrease in the phospho-SMAD3/SMAD3 ratio and reduced SMAD7 expression, indicating that the observed MSTN accumulation is associated with altered SMAD-dependent signaling.

Pompe disease is a lysosomal storage disorder in which acid alpha-glucosidase (GAA) is deficient or absent. This deficiency results in the progressive expansion of glycogen-filled lysosomes. While enzyme replacement therapy (ERT) has proven successful in reversing cardiac abnormalities, it has not successfully reversed skeletal muscle abnormalities. The pathological cascade involves dysfunctional autophagy, specifically impaired autophagosomal-lysosomal fusion, alongside the accelerated production of lipofuscin deposits—a marker of cellular oxidative damage and mitochondrial dysfunction.

Boston Children’s Hospital and Electrical Impedance Myography

Tracking Disease Severity with Electrical Impedance Myography

As researchers look for better ways to quantify muscle health, electrical impedance myography (EIM)—a painless, noninvasive test that sends a small electrical current through a muscle—has emerged as a potential tool. The study, Evaluation of Electrical Impedance Myography as a Noninvasive Musculoskeletal Biomarker in Infantile- and Late-Onset Pompe Disease, was published in Genetics in Medicine and funded by Sanofi. The study included 64 participants: 11 with infantile-onset Pompe disease (IOPD), 27 with late-onset Pompe disease (LOPD), and 26 healthy children (ages 4 to 17) for comparison. Recruitment was carried out through specialized clinics at Boston Children’s Hospital, Massachusetts General Brigham, New York Medical College, and patient advocacy groups.

Researchers wrote that EIM may represent a functionally relevant, noninvasive tool to evaluate disease severity. The study found that EIM measurements were lower in patients than in healthy controls. Because MRI scans and physical tests can be difficult for young children or patients with severe muscle weakness, EIM provides an alternative method, as its results closely match what is seen in MRI and physical tests.